=== Generating (published_papers) ===
=== Generating (teaching_experience) ===
=== Generating (education) ===
=== Generating (misc) ===
=== Generating (research_projects) ===
=== Generating (books_etc) ===
=== Generating (awards) ===
=== Generating (association_memberships) ===
=== Generating (presentations) ===
==== begin registerFile(/WWW/pub2/data/ERD/person/207340/researchmap/published_papers.jsonl) ====
line:1, {"insert":{"user_id":"B000340639","type":"published_papers","id":"45793382"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/119092","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/38466627","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405400","label":"url"}],"paper_title":{"en":"Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in embryonic thymus medulla epithelium.","ja":"Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in embryonic thymus medulla epithelium."},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"White Andrea"},{"name":"Yang Mei-Ting"},{"name":"Fujimori Sayumi"},{"name":"Tanaka Yu"},{"name":"Jacques Alison"},{"name":"Kiyonari Hiroshi"},{"name":"Matsushita Yosuke"},{"name":"Turan Sevilay"},{"name":"Kelly Michael"},{"name":"Anderson Graham"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"White Andrea"},{"name":"Yang Mei-Ting"},{"name":"藤森 さゆ美"},{"name":"Tanaka Yu"},{"name":"Jacques Alison"},{"name":"Kiyonari Hiroshi"},{"name":"Matsushita Yosuke"},{"name":"Turan Sevilay"},{"name":"Kelly Michael"},{"name":"Anderson Graham"},{"name":"Takahama Yousuke"}]},"description":{"en":"Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.","ja":"Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here, we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny in mice. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium."},"publication_date":"2024-03-11","publication_name":{"en":"eLife","ja":"eLife"},"volume":"Vol.12","starting_page":"RP92552","ending_page":"RP92552","languages":["eng"],"referee":true,"identifiers":{"doi":["10.7554/eLife.92552"],"issn":["2050-084X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:2, {"insert":{"user_id":"B000340639","type":"published_papers","id":"41260110"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405840","label":"url"}],"paper_title":{"en":"Endogenous CCL21-Ser deficiency reduces B16-F10 melanoma growth by enhanced antitumor immunity","ja":"Endogenous CCL21-Ser deficiency reduces B16-F10 melanoma growth by enhanced antitumor immunity"},"authors":{"en":[{"name":"Ryonosuke Fujie"},{"name":"Kaoru Kurowarabe"},{"name":"Yuki Yamada"},{"name":"Kakeru Fujiwara"},{"name":"Hayata Nakatani"},{"name":"Kenta Tsutsumi"},{"name":"Ryota Hayashi"},{"name":"Hinami Kawahata"},{"name":"Megumi Miyamoto"},{"name":"Madoka Ozawa"},{"name":"Tomoya Katakai"},{"name":"Takahama Yousuke"},{"name":"Ohigashi Izumi"},{"name":"Haruko Hayasaka"}],"ja":[{"name":"Ryonosuke Fujie"},{"name":"Kaoru Kurowarabe"},{"name":"Yuki Yamada"},{"name":"Kakeru Fujiwara"},{"name":"Hayata Nakatani"},{"name":"Kenta Tsutsumi"},{"name":"Ryota Hayashi"},{"name":"Hinami Kawahata"},{"name":"Megumi Miyamoto"},{"name":"Madoka Ozawa"},{"name":"Tomoya Katakai"},{"name":"高浜 洋介"},{"name":"大東 いずみ"},{"name":"Haruko Hayasaka"}]},"publication_date":"2023-08-19","publication_name":{"en":"Heliyon","ja":"Heliyon"},"volume":"Vol.9","number":"No.8","languages":["eng"],"referee":true,"identifiers":{"issn":["2405-8440"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:3, {"insert":{"user_id":"B000340639","type":"published_papers","id":"42163202"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118927","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/37045811","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=395715","label":"url"}],"paper_title":{"en":"Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla","ja":"Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla"},"authors":{"en":[{"name":"Lucas B"},{"name":"White AJ"},{"name":"Klein F"},{"name":"Veiga-Villauriz C"},{"name":"Handel A"},{"name":"Bacon A"},{"name":"Cosway EJ"},{"name":"James KD"},{"name":"Parnell SM"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"},{"name":"Jenkinson WE"},{"name":"Hollander GA"},{"name":"Lu WY"},{"name":"Anderson G"}],"ja":[{"name":"Lucas B"},{"name":"White AJ"},{"name":"Klein F"},{"name":"Veiga-Villauriz C"},{"name":"Handel A"},{"name":"Bacon A"},{"name":"Cosway EJ"},{"name":"James KD"},{"name":"Parnell SM"},{"name":"大東 いずみ"},{"name":"高浜 洋介"},{"name":"Jenkinson WE"},{"name":"Hollander GA"},{"name":"Lu WY"},{"name":"Anderson G"}]},"description":{"en":"The thymus medulla is a key site for immunoregulation and tolerance, and its functional specialisation is achieved through the complexity of medullary thymic epithelial cells (mTEC). While the importance of the medulla for thymus function is clear, the production and maintenance of mTEC diversity remains poorly understood. Here, using ontogenetic and inducible fate-mapping approaches, we identify mTEC-restricted progenitors as a cytokeratin19 (K19) TEC subset that emerges in the embryonic thymus. Importantly, labelling of a single cohort of K19 TEC during embryogenesis sustains the production of multiple mTEC subsets into adulthood, including CCL21 mTEC, Aire mTEC and thymic tuft cells. We show K19 progenitors arise prior to the acquisition of multiple mTEC-defining features including RANK and CCL21 and are generated independently of the key mTEC regulator, Relb. In conclusion, we identify and define a multipotent mTEC progenitor that emerges during embryogenesis to support mTEC diversity into adult life.","ja":"The thymus medulla is a key site for immunoregulation and tolerance, and its functional specialisation is achieved through the complexity of medullary thymic epithelial cells (mTEC). While the importance of the medulla for thymus function is clear, the production and maintenance of mTEC diversity remains poorly understood. Here, using ontogenetic and inducible fate-mapping approaches, we identify mTEC-restricted progenitors as a cytokeratin19 (K19) TEC subset that emerges in the embryonic thymus. Importantly, labelling of a single cohort of K19 TEC during embryogenesis sustains the production of multiple mTEC subsets into adulthood, including CCL21 mTEC, Aire mTEC and thymic tuft cells. We show K19 progenitors arise prior to the acquisition of multiple mTEC-defining features including RANK and CCL21 and are generated independently of the key mTEC regulator, Relb. In conclusion, we identify and define a multipotent mTEC progenitor that emerges during embryogenesis to support mTEC diversity into adult life."},"publication_date":"2023-04-12","publication_name":{"en":"Nature Communications","ja":"Nature Communications"},"volume":"Vol.14","number":"No.1","starting_page":"2066","ending_page":"2066","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41467-023-37589-4"],"issn":["2041-1723"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:4, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/118941","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35513371","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=394963","label":"url"}],"paper_title":{"en":"Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift","ja":"Recycling of memory B cells between germinal center and lymph node subcapsular sinus supports affinity maturation to antigenic drift"},"authors":{"en":[{"name":"Zhang Y"},{"name":"Garcia-Ibanez L"},{"name":"Ulbricht C"},{"name":"Lok LSC"},{"name":"Pike JA"},{"name":"Mueller-Winkler J"},{"name":"Dennison TW"},{"name":"Ferdinand JR"},{"name":"Burnett CJM"},{"name":"Yam-Puc JC"},{"name":"Zhang L"},{"name":"Alfaro RM"},{"name":"Takahama Yousuke"},{"name":"Ohigashi Izumi"},{"name":"Brown G"},{"name":"Kurosaki T"},{"name":"Tybulewicz VLJ"},{"name":"Rot A"},{"name":"Hauser AE"},{"name":"Clatworthy MR"},{"name":"Toellner KM"}],"ja":[{"name":"Zhang Y"},{"name":"Garcia-Ibanez L"},{"name":"Ulbricht C"},{"name":"Lok LSC"},{"name":"Pike JA"},{"name":"Mueller-Winkler J"},{"name":"Dennison TW"},{"name":"Ferdinand JR"},{"name":"Burnett CJM"},{"name":"Yam-Puc JC"},{"name":"Zhang L"},{"name":"Alfaro RM"},{"name":"高浜 洋介"},{"name":"大東 いずみ"},{"name":"Brown G"},{"name":"Kurosaki T"},{"name":"Tybulewicz VLJ"},{"name":"Rot A"},{"name":"Hauser AE"},{"name":"Clatworthy MR"},{"name":"Toellner KM"}]},"description":{"en":"Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (B) and find that many B cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, B cells may exit the lymph node to enter distant tissues, while some B cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of B cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific B cells and transport of antigen back to GC may support affinity maturation to antigenic drift.","ja":"Infection or vaccination leads to the development of germinal centers (GC) where B cells evolve high affinity antigen receptors, eventually producing antibody-forming plasma cells or memory B cells. Here we follow the migratory pathways of B cells emerging from germinal centers (B) and find that many B cells migrate into the lymph node subcapsular sinus (SCS) guided by sphingosine-1-phosphate (S1P). From the SCS, B cells may exit the lymph node to enter distant tissues, while some B cells interact with and take up antigen from SCS macrophages, followed by CCL21-guided return towards the GC. Disruption of local CCL21 gradients inhibits the recycling of B cells and results in less efficient adaption to antigenic variation. Our findings thus suggest that the recycling of antigen variant-specific B cells and transport of antigen back to GC may support affinity maturation to antigenic drift."},"publication_date":"2022-05-05","publication_name":{"en":"Nature Communications","ja":"Nature Communications"},"volume":"Vol.13","number":"No.1","starting_page":"2460","ending_page":"2460","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41467-022-29978-y"],"issn":["2041-1723"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:5, {"insert":{"user_id":"B000340639","type":"published_papers","id":"36183952"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116664","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/35042581","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=383730","label":"url"}],"paper_title":{"en":"Fine-tuning of β-catenin in mouse thymic epithelial cells is required for postnatal T-cell development","ja":"Fine-tuning of β-catenin in mouse thymic epithelial cells is required for postnatal T-cell development"},"authors":{"en":[{"name":"Fujimori Sayumi"},{"name":"Ohigashi Izumi"},{"name":"Abe Hayato"},{"name":"Matsushita Yosuke"},{"name":"Katagiri Toyomasa"},{"name":"Makoto M. Taketo"},{"name":"Yousuke Takahama"},{"name":"Shinji Takada"}],"ja":[{"name":"藤森 さゆ美"},{"name":"大東 いずみ"},{"name":"阿部 勇人"},{"name":"松下 洋輔"},{"name":"片桐 豊雅"},{"name":"Makoto M. Taketo"},{"name":"Yousuke Takahama"},{"name":"Shinji Takada"}]},"description":{"en":"In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in mouse thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T-cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of β-catenin highly specific in mouse TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T-cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T-cell development.","ja":"In the thymus, the thymic epithelium provides a microenvironment essential for the development of functionally competent and self-tolerant T cells. Previous findings showed that modulation of Wnt/β-catenin signaling in mouse thymic epithelial cells (TECs) disrupts embryonic thymus organogenesis. However, the role of β-catenin in TECs for postnatal T-cell development remains to be elucidated. Here, we analyzed gain-of-function (GOF) and loss-of-function (LOF) of β-catenin highly specific in mouse TECs. We found that GOF of β-catenin in TECs results in severe thymic dysplasia and T-cell deficiency beginning from the embryonic period. By contrast, LOF of β-catenin in TECs reduces the number of cortical TECs and thymocytes modestly and only postnatally. These results indicate that fine-tuning of β-catenin expression within a permissive range is required for TECs to generate an optimal microenvironment to support postnatal T-cell development."},"publication_date":"2022-01-19","publication_name":{"en":"eLife","ja":"eLife"},"volume":"Vol.11","starting_page":"e69088","ending_page":"e69088","languages":["eng"],"referee":true,"identifiers":{"doi":["10.7554/eLife.69088"],"issn":["2050-084X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:6, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116884","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34561276","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85117018419&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=384892","label":"url"}],"paper_title":{"en":"Intrathymic Plasmablasts Are Affected in Patients With Myasthenia Gravis With Active Disease.","ja":"Intrathymic Plasmablasts Are Affected in Patients With Myasthenia Gravis With Active Disease."},"authors":{"en":[{"name":"Yamamoto Yohei"},{"name":"Matsui Naoko"},{"name":"Uzawa Akiyuki"},{"name":"Ozawa Yukiko"},{"name":"Kanai Tetsuya"},{"name":"Oda Fumiko"},{"name":"Kondo Hiroyuki"},{"name":"Ohigashi Izumi"},{"name":"Takizawa Hiromitsu"},{"name":"Kondo Kazuya"},{"name":"Sugano Mikio"},{"name":"Kitaichi Takashi"},{"name":"Hata Hiroki"},{"name":"Kaji Ryuji"},{"name":"Kuwabara Satoshi"},{"name":"Yamamura Takashi"},{"name":"Izumi Yuishin"}],"ja":[{"name":"Yamamoto Yohei"},{"name":"松井 尚子"},{"name":"Uzawa Akiyuki"},{"name":"Ozawa Yukiko"},{"name":"Kanai Tetsuya"},{"name":"Oda Fumiko"},{"name":"近藤 博之"},{"name":"大東 いずみ"},{"name":"滝沢 宏光"},{"name":"Kondo Kazuya"},{"name":"菅野 幹雄"},{"name":"北市 隆"},{"name":"Hata Hiroki"},{"name":"Kaji Ryuji"},{"name":"Kuwabara Satoshi"},{"name":"Yamamura Takashi"},{"name":"和泉 唯信"}]},"description":{"en":"Our findings confirmed a correlation between increased frequency of intrathymic plasmablasts and disease activity before thymectomy. We postulate that activated intrathymic plasmablasts endow pathogenic capacity in MG.","ja":"Our findings confirmed a correlation between increased frequency of intrathymic plasmablasts and disease activity before thymectomy. We postulate that activated intrathymic plasmablasts endow pathogenic capacity in MG."},"publication_date":"2021-09-24","publication_name":{"en":"Neurology® Neuroimmunology & Neuroinflammation","ja":"Neurology® Neuroimmunology & Neuroinflammation"},"volume":"Vol.8","number":"No.6","starting_page":"e1087","ending_page":"e1087","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1212/NXI.0000000000001087"],"issn":["2332-7812"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:7, {"insert":{"user_id":"B000340639","type":"published_papers","id":"36716005"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/117033","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34636707","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85116882945&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=385107","label":"url"}],"paper_title":{"en":"Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells","ja":"Identification of protease serine S1 family member 53 as a mitochondrial protein in murine islet beta cells"},"authors":{"en":[{"name":"Mizusawa Noriko"},{"name":"Harada Nagakatsu"},{"name":"Iwata Takeo"},{"name":"Ohigashi Izumi"},{"name":"Itakura Mitsuo"},{"name":"Yoshimoto Katsuhiko"}],"ja":[{"name":"水澤 典子"},{"name":"原田 永勝"},{"name":"岩田 武男"},{"name":"大東 いずみ"},{"name":"板倉 光夫"},{"name":"吉本 勝彦"}]},"publication_date":"2021-09-13","publication_name":{"en":"Islets","ja":"Islets"},"volume":"Vol.14","number":"No.1","starting_page":"1","ending_page":"13","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1080/19382014.2021.1982325"],"issn":["1938-2014"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:8, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116723","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/34496235","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85114237730&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=382607","label":"url"}],"paper_title":{"en":"Specific impact of β5t on proteasome subunit composition in cortical thymic epithelial cells","ja":"Specific impact of β5t on proteasome subunit composition in cortical thymic epithelial cells"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"β5t is a cortical thymic epithelial cell (cTEC)-specific component of the thymoproteasome, which is essential for the optimal production of functionally competent CD8 T cells. Our recent analysis showed a specific impact of β5t on proteasome subunit composition in cTECs, supporting the possibility that the thymoproteasome optimizes CD8 T cell development through the production of MHC-I-associated unique self-peptides in cTECs. However, a recent article reports that β5t regulates the expression of hundreds of cTEC genes and affects both CD4 and CD8 thymocytes by causing oxidative stress in thymocytes. The authors further analyze our published data and describe that they confirm their conclusions. Here, we examine the issues that they raise and conclude that, rather than regulating hundreds of genes in cTECs, β5t has a highly specific impact in cTECs on proteasome subunit composition. This Matters Arising Response article addresses the Apavaloaei et al. (2021) Matters Arising paper, published concurrently in Cell Reports.","ja":"β5t is a cortical thymic epithelial cell (cTEC)-specific component of the thymoproteasome, which is essential for the optimal production of functionally competent CD8 T cells. Our recent analysis showed a specific impact of β5t on proteasome subunit composition in cTECs, supporting the possibility that the thymoproteasome optimizes CD8 T cell development through the production of MHC-I-associated unique self-peptides in cTECs. However, a recent article reports that β5t regulates the expression of hundreds of cTEC genes and affects both CD4 and CD8 thymocytes by causing oxidative stress in thymocytes. The authors further analyze our published data and describe that they confirm their conclusions. Here, we examine the issues that they raise and conclude that, rather than regulating hundreds of genes in cTECs, β5t has a highly specific impact in cTECs on proteasome subunit composition. This Matters Arising Response article addresses the Apavaloaei et al. (2021) Matters Arising paper, published concurrently in Cell Reports."},"publication_date":"2021-09-07","publication_name":{"en":"Cell Reports","ja":"Cell Reports"},"volume":"Vol.36","number":"No.10","starting_page":"109657","ending_page":"109657","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.celrep.2021.109657"],"issn":["2211-1247"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:9, {"insert":{"user_id":"B000340639","type":"published_papers","id":"31627940"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116455","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/33555295","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=373644","label":"url"}],"paper_title":{"en":"The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection.","ja":"The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection."},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Frantzeskakis Melina"},{"name":"Jacques Alison"},{"name":"Fujimori Sayumi"},{"name":"Ushio Aya"},{"name":"Yamashita Fusano"},{"name":"Ishimaru Naozumi"},{"name":"Yin Da"},{"name":"Cam Margaret"},{"name":"Kelly Michael C"},{"name":"Awasthi Parirokh"},{"name":"Takada Kensuke"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Frantzeskakis Melina"},{"name":"Jacques Alison"},{"name":"藤森 さゆ美"},{"name":"牛尾 綾"},{"name":"Yamashita Fusano"},{"name":"石丸 直澄"},{"name":"Yin Da"},{"name":"Cam Margaret"},{"name":"Kelly Michael C"},{"name":"Awasthi Parirokh"},{"name":"高田 健介"},{"name":"高浜 洋介"}]},"description":{"en":"The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells; however, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here, we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla; independent of additional antigen-presenting cells, including medullary thymic epithelial cells and dendritic cells; and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus.","ja":"The thymoproteasome expressed specifically in thymic cortical epithelium optimizes the generation of CD8+ T cells; however, how the thymoproteasome contributes to CD8+ T cell development is unclear. Here, we show that the thymoproteasome shapes the TCR repertoire directly in cortical thymocytes before migration to the thymic medulla. We further show that the thymoproteasome optimizes CD8+ T cell production independent of the thymic medulla; independent of additional antigen-presenting cells, including medullary thymic epithelial cells and dendritic cells; and independent of apoptosis-mediated negative selection. These results indicate that the thymoproteasome hardwires the TCR repertoire of CD8+ T cells with cortical positive selection independent of negative selection in the thymus."},"publication_date":"2021-04-05","publication_name":{"en":"The Journal of Experimental Medicine","ja":"The Journal of Experimental Medicine"},"volume":"Vol.218","number":"No.4","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1084/jem.20201904"],"issn":["1540-9538"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:10, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116300","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32845012","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85090990353&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=374058","label":"url"}],"paper_title":{"en":"A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation","ja":"A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation"},"authors":{"en":[{"name":"Pedro Ferreirinha"},{"name":"Camila Ribeiro"},{"name":"Morimoto Junko"},{"name":"Jonathan J M Landry"},{"name":"Matsumoto Minoru"},{"name":"Catarina Meireles"},{"name":"Andrea J White"},{"name":"Ohigashi Izumi"},{"name":"Leonor Araújo"},{"name":"Vladimir Benes"},{"name":"Takahama Yousuke"},{"name":"Graham Anderson"},{"name":"Matsumoto Mitsuru"},{"name":"Nuno L Alves"}],"ja":[{"name":"Pedro Ferreirinha"},{"name":"Camila Ribeiro"},{"name":"森本 純子"},{"name":"Jonathan J M Landry"},{"name":"松本 穣"},{"name":"Catarina Meireles"},{"name":"Andrea J White"},{"name":"大東 いずみ"},{"name":"Leonor Araújo"},{"name":"Vladimir Benes"},{"name":"高浜 洋介"},{"name":"Graham Anderson"},{"name":"松本 満"},{"name":"Nuno L Alves"}]},"description":{"en":"Autoimmune regulator (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEC (MHCII CD80 ) compartment into mTEC (CD24 Sca1 ), mTEC (CD24 Sca1 ), and mTEC (CD24 Sca1 ). While mTEC included mostly Aire-expressing cells, mTEC contained Aire and Aire cells and mTEC were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTEC , mTEC , and mTEC sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTEC downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation.","ja":"Autoimmune regulator (Aire) medullary thymic epithelial cells (mTECs) play a critical role in tolerance induction. Several studies demonstrated that Aire mTECs differentiate further into Post-Aire cells. Yet, the identification of terminal stages of mTEC maturation depends on unique fate-mapping mouse models. Herein, we resolve this limitation by segmenting the mTEC (MHCII CD80 ) compartment into mTEC (CD24 Sca1 ), mTEC (CD24 Sca1 ), and mTEC (CD24 Sca1 ). While mTEC included mostly Aire-expressing cells, mTEC contained Aire and Aire cells and mTEC were mainly composed of cells lacking Aire. The differential expression pattern of Aire led us to investigate the precursor-product relationship between these subsets. Strikingly, transcriptomic analysis of mTEC , mTEC , and mTEC sequentially mirrored the specific genetic program of Early-, Late- and Post-Aire mTECs. Corroborating their Post-Aire nature, mTEC downregulated the expression of tissue-restricted antigens, acquired traits of differentiated keratinocytes, and were absent in Aire-deficient mice. Collectively, our findings reveal a new and simple blueprint to survey late stages of mTEC differentiation."},"publication_date":"2021-02","publication_name":{"en":"European Journal of Immunology","ja":"European Journal of Immunology"},"volume":"Vol.51","number":"No.2","starting_page":"311","ending_page":"318","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/eji.202048764"],"issn":["1521-4141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:11, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=373251","label":"url"}],"paper_title":{"en":"Medullary stromal cells synergize their production and capture of CCL21 for T-cell emigration from neonatal mouse thymus","ja":"Medullary stromal cells synergize their production and capture of CCL21 for T-cell emigration from neonatal mouse thymus"},"authors":{"en":[{"name":"James KD"},{"name":"Legler DF"},{"name":"Purvanov V"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"},{"name":"Parnell SM"},{"name":"White AJ"},{"name":"Jenkinson WE"},{"name":"Anderson G"}],"ja":[{"name":"James KD"},{"name":"Legler DF"},{"name":"Purvanov V"},{"name":"大東 いずみ"},{"name":"高浜 洋介"},{"name":"Parnell SM"},{"name":"White AJ"},{"name":"Jenkinson WE"},{"name":"Anderson G"}]},"publication_date":"2021-01-05","publication_name":{"en":"Blood Advances","ja":"Blood Advances"},"volume":"Vol.5","number":"No.1","starting_page":"99","ending_page":"112","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1182/bloodadvances.2020003192"],"issn":["2473-9529"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:12, {"insert":{"user_id":"B000340639","type":"published_papers","id":"31520770"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/116206","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/33185454","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85096567671&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=373250","label":"url"}],"paper_title":{"en":"Smelling the Dark Proteome: Functional Characterization of PITH Domain-Containing Protein 1 (C1orf128) in Olfactory Metabolism","ja":"Smelling the Dark Proteome: Functional Characterization of PITH Domain-Containing Protein 1 (C1orf128) in Olfactory Metabolism"},"authors":{"en":[{"name":"Lachén-Montes M"},{"name":"Mendizuri N"},{"name":"Ausín K"},{"name":"Pérez-Mediavilla A"},{"name":"Azkargorta M"},{"name":"Iloro I"},{"name":"Elortza F"},{"name":"Kondo Hiroyuki"},{"name":"Ohigashi Izumi"},{"name":"Ferrer I"},{"name":"de la Torre R"},{"name":"Robledo P"},{"name":"Fernández-Irigoyen J"},{"name":"Santamaría E"}],"ja":[{"name":"Lachén-Montes M"},{"name":"Mendizuri N"},{"name":"Ausín K"},{"name":"Pérez-Mediavilla A"},{"name":"Azkargorta M"},{"name":"Iloro I"},{"name":"Elortza F"},{"name":"近藤 博之"},{"name":"大東 いずみ"},{"name":"Ferrer I"},{"name":"de la Torre R"},{"name":"Robledo P"},{"name":"Fernández-Irigoyen J"},{"name":"Santamaría E"}]},"description":{"en":"The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer's disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1 mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHD1 is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634.","ja":"The Human Proteome Project (HPP) consortium aims to functionally characterize the dark proteome. On the basis of the relevance of olfaction in early neurodegeneration, we have analyzed the dark proteome using data mining in public resources and omics data sets derived from the human olfactory system. Multiple dark proteins localize at synaptic terminals and may be involved in amyloidopathies such as Alzheimer's disease (AD). We have characterized the dark PITH domain-containing protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics, in vitro and in vivo studies, and neuropathology. PITHD1 mice exhibit olfactory bulb (OB) proteome changes related to synaptic transmission, cognition, and memory. OB PITHD1 expression increases with age in wild-type (WT) mice and decreases in Tg2576 AD mice at late stages. The analysis across 6 neurological disorders reveals that olfactory tract (OT) PITHD1 is specifically upregulated in human AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1 alters the ON phosphoproteome, modifies the proliferation rate, and induces a pro-inflammatory phenotype. This workflow applied by the Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across the ON-OB-OT axis can be adapted as a guidance to decipher functional features of dark proteins. Data are available via ProteomeXchange with identifiers PXD018784 and PXD021634."},"publication_date":"2020-12-04","publication_name":{"en":"Journal of Proteome Research","ja":"Journal of Proteome Research"},"volume":"Vol.19","number":"No.12","starting_page":"4826","ending_page":"4843","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1021/acs.jproteome.0c00452"],"issn":["1535-3907"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:13, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115261","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32477366","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=366477","label":"url"}],"paper_title":{"en":"Postnatal involution and counter-involution of the thymus. Frontiers in Immunology","ja":"Postnatal involution and counter-involution of the thymus. Frontiers in Immunology"},"authors":{"en":[{"name":"Cowan JE"},{"name":"Takahama Yousuke"},{"name":"Bhandoola A"},{"name":"Ohigashi Izumi"}],"ja":[{"name":"Cowan JE"},{"name":"高浜 洋介"},{"name":"Bhandoola A"},{"name":"大東 いずみ"}]},"description":{"en":"Thymus involution occurs in all vertebrates. It is thought to impact on immune responses in the aged, and in other clinical circumstances such as bone marrow transplantation. Determinants of thymus growth and size are beginning to be identified. Ectopic expression of factors like cyclin D1 and Myc in thymic epithelial cells (TEC)s results in considerable increase in thymus size. These models provide useful experimental tools that allow thymus function to be understood. In future, understanding TEC-specific controllers of growth will provide new approaches to thymus regeneration.","ja":"Thymus involution occurs in all vertebrates. It is thought to impact on immune responses in the aged, and in other clinical circumstances such as bone marrow transplantation. Determinants of thymus growth and size are beginning to be identified. Ectopic expression of factors like cyclin D1 and Myc in thymic epithelial cells (TEC)s results in considerable increase in thymus size. These models provide useful experimental tools that allow thymus function to be understood. In future, understanding TEC-specific controllers of growth will provide new approaches to thymus regeneration."},"publication_date":"2020-05-12","publication_name":{"en":"Frontiers in Immunology","ja":"Frontiers in Immunology"},"volume":"Vol.11","number":"No.897","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3389/fimmu.2020.00897"],"issn":["1664-3224"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:14, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115596","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/32366944","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85084220247&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=366474","label":"url"}],"paper_title":{"en":"Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells","ja":"Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells"},"authors":{"en":[{"name":"Lucas B"},{"name":"White AJ"},{"name":"Cosway EJ"},{"name":"Parnell SM"},{"name":"James KD"},{"name":"Jones ND"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"},{"name":"Jenkinson WE"},{"name":"Anderson G"}],"ja":[{"name":"Lucas B"},{"name":"White AJ"},{"name":"Cosway EJ"},{"name":"Parnell SM"},{"name":"James KD"},{"name":"Jones ND"},{"name":"大東 いずみ"},{"name":"高浜 洋介"},{"name":"Jenkinson WE"},{"name":"Anderson G"}]},"description":{"en":"The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEC subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104CCL21 mTEC that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.","ja":"The thymus supports multiple αβ T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEC subsets distinguished by surface, intracellular and secreted molecules, and identify LTβR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTβR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTβR controls CD104CCL21 mTEC that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues."},"publication_date":"2020-05-04","publication_name":{"en":"Nature Communications","ja":"Nature Communications"},"volume":"Vol.11","number":"No.1","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41467-020-16041-x"],"issn":["2041-1723"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:15, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/114611","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31915251","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=362983","label":"url"}],"paper_title":{"en":"PITHD1 is a proteasome-interacting protein essential for male fertilization","ja":"PITHD1 is a proteasome-interacting protein essential for male fertilization"},"authors":{"en":[{"name":"Kondo Hiroyuki"},{"name":"Matsumura Takafumi"},{"name":"Kaneko Mari"},{"name":"Inoue Kenichi"},{"name":"Kosako Hidetaka"},{"name":"Ikawa Masahito"},{"name":"Takahama Yousuke"},{"name":"Ohigashi Izumi"}],"ja":[{"name":"近藤 博之"},{"name":"Matsumura Takafumi"},{"name":"Kaneko Mari"},{"name":"Inoue Kenichi"},{"name":"小迫 英尊"},{"name":"Ikawa Masahito"},{"name":"高浜 洋介"},{"name":"大東 いずみ"}]},"description":{"en":"The proteasome is a protein-degrading molecular complex that is necessary for protein homeostasis and various biological functions, including cell cycle regulation, signal transduction, and immune response. Proteasome activity is finely regulated by a variety of proteasome-interacting molecules. PITHD1 is a recently described molecule that has a domain putatively capable of interacting with the proteasome. However, it is unknown whether PITHD1 can actually bind to proteasomes and what it does Here we report that PITHD1 is detected specifically in the spermatids in the testis and the cortical thymic epithelium in the thymus. Interestingly, PITHD1 associates with immunoproteasomes in the testis, but not with thymoproteasomes in the thymus. Mice deficient in PITHD1 exhibit severe male infertility accompanied with morphological abnormalities and impaired motility of spermatozoa. Furthermore, PITHD1 deficiency reduces proteasome activity in the testis and alters the amount of proteins that are important for fertilization capability by the sperm. However, the PITHD1-deficient mice demonstrate no detectable defects in the thymus, including T cell development. Collectively, our results identify PITHD1 as a proteasome-interacting protein that plays a nonredundant role in the male reproductive system.","ja":"The proteasome is a protein-degrading molecular complex that is necessary for protein homeostasis and various biological functions, including cell cycle regulation, signal transduction, and immune response. Proteasome activity is finely regulated by a variety of proteasome-interacting molecules. PITHD1 is a recently described molecule that has a domain putatively capable of interacting with the proteasome. However, it is unknown whether PITHD1 can actually bind to proteasomes and what it does Here we report that PITHD1 is detected specifically in the spermatids in the testis and the cortical thymic epithelium in the thymus. Interestingly, PITHD1 associates with immunoproteasomes in the testis, but not with thymoproteasomes in the thymus. Mice deficient in PITHD1 exhibit severe male infertility accompanied with morphological abnormalities and impaired motility of spermatozoa. Furthermore, PITHD1 deficiency reduces proteasome activity in the testis and alters the amount of proteins that are important for fertilization capability by the sperm. However, the PITHD1-deficient mice demonstrate no detectable defects in the thymus, including T cell development. Collectively, our results identify PITHD1 as a proteasome-interacting protein that plays a nonredundant role in the male reproductive system."},"publication_date":"2020-02-07","publication_name":{"en":"The Journal of Biological Chemistry","ja":"The Journal of Biological Chemistry"},"volume":"Vol.295","number":"No.6","starting_page":"1658","ending_page":"1672","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1074/jbc.RA119.011144"],"issn":["1083-351X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:16, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115228","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31792212","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85075969312&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=362361","label":"url"}],"paper_title":{"en":"Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth","ja":"Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth"},"authors":{"en":[{"name":"Cowan E. Jennifer"},{"name":"Malin Justin"},{"name":"Zhao Yongge"},{"name":"Seedhom O. Mina"},{"name":"Harly Christelle"},{"name":"Ohigashi Izumi"},{"name":"Kelly Michael"},{"name":"Takahama Yousuke"},{"name":"Yewdell W. Jonathan"},{"name":"Cam Maggie"},{"name":"Bhandoola Avinash"}],"ja":[{"name":"Cowan E. Jennifer"},{"name":"Malin Justin"},{"name":"Zhao Yongge"},{"name":"Seedhom O. Mina"},{"name":"Harly Christelle"},{"name":"大東 いずみ"},{"name":"Kelly Michael"},{"name":"高浜 洋介"},{"name":"Yewdell W. Jonathan"},{"name":"Cam Maggie"},{"name":"Bhandoola Avinash"}]},"description":{"en":"Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size.","ja":"Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size."},"publication_date":"2019-12-02","publication_name":{"en":"Nature Communications","ja":"Nature Communications"},"volume":"Vol.10","number":"No.1","starting_page":"5498","ending_page":"5498","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/s41467-019-13465-y"],"issn":["2041-1723"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:17, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/115049","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31775054","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=361076","label":"url"}],"paper_title":{"en":"Trans-omics Impact of Thymoproteasome in Cortical Thymic Epithelial Cells.","ja":"Trans-omics Impact of Thymoproteasome in Cortical Thymic Epithelial Cells."},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Tanaka Yu"},{"name":"Kondou Kenta"},{"name":"Fujimori Sayumi"},{"name":"Kondo Hiroyuki"},{"name":"Palin Amy"},{"name":"Hoffmann Victoria"},{"name":"Kozai Mina"},{"name":"Matsushita Yosuke"},{"name":"Uda Shinsuke"},{"name":"Motosugi Ryo"},{"name":"Hamazaki Jun"},{"name":"Kubota Hiroyuki"},{"name":"Murata Shigeo"},{"name":"Tanaka Keiji"},{"name":"Katagiri Toyomasa"},{"name":"Kosako Hidetaka"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Tanaka Yu"},{"name":"近藤 健太"},{"name":"藤森 さゆ美"},{"name":"近藤 博之"},{"name":"Palin Amy"},{"name":"Hoffmann Victoria"},{"name":"Kozai Mina"},{"name":"松下 洋輔"},{"name":"Uda Shinsuke"},{"name":"Motosugi Ryo"},{"name":"Hamazaki Jun"},{"name":"Kubota Hiroyuki"},{"name":"Murata Shigeo"},{"name":"Tanaka Keiji"},{"name":"片桐 豊雅"},{"name":"小迫 英尊"},{"name":"高浜 洋介"}]},"publication_date":"2019-11-26","publication_name":{"en":"Cell Reports","ja":"Cell Reports"},"volume":"Vol.29","number":"No.9","starting_page":"2901","ending_page":"2916.e6","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.celrep.2019.10.079"],"issn":["2211-1247"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:18, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113696","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/31235550","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85070388863&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=359947","label":"url"}],"paper_title":{"en":"TCR affinity for in vivo peptide-induced thymic positive selection fine-tunes TCR responsiveness of peripheral CD8+ T cells","ja":"TCR affinity for in vivo peptide-induced thymic positive selection fine-tunes TCR responsiveness of peripheral CD8+ T cells"},"authors":{"en":[{"name":"Khanom Umme Shahina"},{"name":"Ohigashi Izumi"},{"name":"Fujimori Sayumi"},{"name":"Kondou Kenta"},{"name":"Takada Kensuke"},{"name":"Takahama Yousuke"}],"ja":[{"name":"UMME KHANOM SHAHINA"},{"name":"大東 いずみ"},{"name":"藤森 さゆ美"},{"name":"近藤 健太"},{"name":"高田 健介"},{"name":"高浜 洋介"}]},"description":{"en":"The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4CD8 thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8 T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8 T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells.","ja":"The affinity for TCR interactions with self-peptide/MHC complexes (pMHC) in the thymus critically affects immature thymocytes that newly express TCRs. Previous fetal thymus organ culture experiments have indicated that difference in the affinity for thymic TCR/pMHC interactions not only determines thymocyte fate between positive and negative selection, but also affects Ag responsiveness of positively selected thymocytes. In the current study, we examined whether TCR/pMHC affinity during positive selection in the thymus would further affect Ag responsiveness of mature T cells in the periphery. To do so, OVA peptide variants were in vivo administered to TAP1-deficient OT-I/TCR-transgenic mice in which T cell development was otherwise arrested at CD4CD8 thymocytes because of the lack of self-pMHC presentation in thymic APCs. We found that a group of peptide variants induced the transient generation of OT-I CD8 T cells in the thymus and the periphery. We also noticed that the affinity threshold for positive and negative selection detected in adult mice in vivo was higher than that measured in fetal thymus organ culture experiments in vitro. Interestingly, we further found that the affinity for positively selecting peptides proportionally affected TCR responsiveness of peripheral naive CD8 T cells. These results indicate that in vivo administration of a peptide can promote T cell selection in the thymus and the affinity for TCR/pMHC interaction during positive selection fine-tunes Ag responsiveness of peripheral T cells."},"publication_date":"2019-08-15","publication_name":{"en":"The Journal of Immunology","ja":"The Journal of Immunology"},"volume":"Vol.203","number":"No.4","starting_page":"881","ending_page":"887","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4049/jimmunol.1900097"],"issn":["1550-6606"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:19, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30476234","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85060634138&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352964","label":"url"}],"paper_title":{"en":"Thymus machinery for T-cell selection","ja":"Thymus machinery for T-cell selection"},"authors":{"en":[{"name":"Kondou Kenta"},{"name":"Ohigashi Izumi"},{"name":"Takahama Y"}],"ja":[{"name":"近藤 健太"},{"name":"大東 いずみ"},{"name":"Takahama Y"}]},"description":{"en":"An immunocompetent and self-tolerant pool of naive T cells is formed in the thymus through the process of repertoire selection. T cells that are potentially capable of responding to foreign antigens are positively selected in the thymic cortex and are further selected in the thymic medulla to help prevent self-reactivity. The affinity between T-cell antigen receptors expressed by newly generated T cells and self-peptide-major histocompatibility complexes displayed in the thymic microenvironments plays a key role in determining the fate of developing T cells during thymic selection. Recent advances in our knowledge of the biology of thymic epithelial cells have revealed unique machinery that contributes to positive and negative selection in the thymus. In this article, we summarize recent findings on thymic T-cell selection, focusing on the machinery unique to thymic epithelial cells.","ja":"An immunocompetent and self-tolerant pool of naive T cells is formed in the thymus through the process of repertoire selection. T cells that are potentially capable of responding to foreign antigens are positively selected in the thymic cortex and are further selected in the thymic medulla to help prevent self-reactivity. The affinity between T-cell antigen receptors expressed by newly generated T cells and self-peptide-major histocompatibility complexes displayed in the thymic microenvironments plays a key role in determining the fate of developing T cells during thymic selection. Recent advances in our knowledge of the biology of thymic epithelial cells have revealed unique machinery that contributes to positive and negative selection in the thymus. In this article, we summarize recent findings on thymic T-cell selection, focusing on the machinery unique to thymic epithelial cells."},"publication_date":"2019-03-05","publication_name":{"en":"International Immunology","ja":"International Immunology"},"volume":"Vol.31","number":"No.3","starting_page":"119","ending_page":"125","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1093/intimm/dxy081"],"issn":["1460-2377"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:20, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458421"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30324237","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85060922217&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352963","label":"url"}],"paper_title":{"en":"Thymoproteasome and peptidic self","ja":"Thymoproteasome and peptidic self"},"authors":{"en":[{"name":"Takahama Yousuke"},{"name":"Ohigashi Izumi"},{"name":"Murata Shigeo"},{"name":"Tanaka Keiji"}],"ja":[{"name":"Takahama Yousuke"},{"name":"大東 いずみ"},{"name":"Murata Shigeo"},{"name":"Tanaka Keiji"}]},"description":{"en":"Positive selection of T cells in the thymus is induced by low-affinity TCR recognition of self-peptide-MHC complexes expressed by cortical thymic epithelial cells (cTECs). cTECs express a specialized type of proteasomes, the thymoproteasome, which generates a unique spectrum of MHC class I-associated peptides and plays a critical role in thymic positive selection of CD8 T cells. However, it remains unclear how the thymoproteasome contributes to the thymic positive selection. More than 30 years ago, the \"peptidic self\" hypothesis proposed that TCRs recognize MHC-presented peptides only, without interacting with MHC molecules, which turned out to be incorrect. Interestingly, however, by implying that a set of MHC-associated peptides forms immunological self, this hypothesis also predicted that positive selection in the thymus is the primary immune response to \"foreign epitope\" peptides during T cell development. The thymoproteasome-dependent unique self-peptides may create those foreign epitope peptides displayed in the thymus for positive selection of T cells.","ja":"Positive selection of T cells in the thymus is induced by low-affinity TCR recognition of self-peptide-MHC complexes expressed by cortical thymic epithelial cells (cTECs). cTECs express a specialized type of proteasomes, the thymoproteasome, which generates a unique spectrum of MHC class I-associated peptides and plays a critical role in thymic positive selection of CD8 T cells. However, it remains unclear how the thymoproteasome contributes to the thymic positive selection. More than 30 years ago, the \"peptidic self\" hypothesis proposed that TCRs recognize MHC-presented peptides only, without interacting with MHC molecules, which turned out to be incorrect. Interestingly, however, by implying that a set of MHC-associated peptides forms immunological self, this hypothesis also predicted that positive selection in the thymus is the primary immune response to \"foreign epitope\" peptides during T cell development. The thymoproteasome-dependent unique self-peptides may create those foreign epitope peptides displayed in the thymus for positive selection of T cells."},"publication_date":"2019-03","publication_name":{"en":"Immunogenetics","ja":"Immunogenetics"},"volume":"Vol.71","number":"No.3","starting_page":"217","ending_page":"221","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/s00251-018-1081-3"],"issn":["1432-1211"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:21, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/114469","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/30333825","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85055079381&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=352962","label":"url"}],"paper_title":{"en":"A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node","ja":"A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node"},"authors":{"en":[{"name":"Takeuchi, A"},{"name":"Ozawa M"},{"name":"Kanda Y"},{"name":"Kozai M"},{"name":"Ohigashi Izumi"},{"name":"Kurosawa Y"},{"name":"Rahman MA"},{"name":"Kawamura T"},{"name":"Shichida Y"},{"name":"Umemoto E"},{"name":"Miyasaka M"},{"name":"Ludewig B"},{"name":"Takahama Y"},{"name":"Nagasawa T"},{"name":"Katakai T"}],"ja":[{"name":"Takeuchi, A"},{"name":"Ozawa M"},{"name":"Kanda Y"},{"name":"Kozai M"},{"name":"大東 いずみ"},{"name":"Kurosawa Y"},{"name":"Rahman MA"},{"name":"Kawamura T"},{"name":"Shichida Y"},{"name":"Umemoto E"},{"name":"Miyasaka M"},{"name":"Ludewig B"},{"name":"Takahama Y"},{"name":"Nagasawa T"},{"name":"Katakai T"}]},"description":{"en":"The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12LepR FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN.","ja":"The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12LepR FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN."},"publication_date":"2018-10-02","publication_name":{"en":"Frontiers in Immunology","ja":"Frontiers in Immunology"},"volume":"Vol.9","starting_page":"2196","ending_page":"2196","languages":["eng"],"referee":true,"identifiers":{"doi":["10.3389/fimmu.2018.02196"],"issn":["1664-3224"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:22, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458422"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/114497","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29784760","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85049826137&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=340561","label":"url"}],"paper_title":{"en":"Formation of the intrathymic dendritic cell pool requires CCL21-mediated recruitment of CCR7+ progenitors to the thymus","ja":"Formation of the intrathymic dendritic cell pool requires CCL21-mediated recruitment of CCR7+ progenitors to the thymus"},"authors":{"en":[{"name":"Cosway J. Emilie"},{"name":"Ohigashi Izumi"},{"name":"Schauble Karin"},{"name":"Parnell M. Sonia"},{"name":"Jenkinson E. William"},{"name":"Luther Sanjiv"},{"name":"Takahama Yousuke"},{"name":"Anderson Graham"}],"ja":[{"name":"Cosway J. Emilie"},{"name":"大東 いずみ"},{"name":"Schauble Karin"},{"name":"Parnell M. Sonia"},{"name":"Jenkinson E. William"},{"name":"Luther Sanjiv"},{"name":"高浜 洋介"},{"name":"Anderson Graham"}]},"description":{"en":"During αβ T cell development in the thymus, migration of newly selected CD4 and CD8 thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2. In contrast, although Sirpα conventional DC type 1 (cDC1) are known to arise intrathymically from immature progenitors, the precise nature of such thymus-colonizing progenitors and the mechanisms controlling their thymus entry are unclear. In this article, we report a selective reduction in thymic cDC1 in mice lacking the chemokine receptor CCR7. In addition, we show that the thymus contains a CD11cMHC class IISirpαFlt3 cDC progenitor population that expresses CCR7, and that migration of these cells to the thymus is impaired in mice. Moreover, thymic cDC1 defects in mice are mirrored in mice, with further analysis of mice individually lacking the CCR7 ligands CCL21Ser ( ) or CCL19 ( demonstrating an essential role for CCR7-CCL21Ser during intrathymic cDC1 development. Collectively, our data support a mechanism in which CCR7-CCL21Ser interactions guide the migration of cDC progenitors to the thymus for correct formation of the intrathymic cDC1 pool.","ja":"During αβ T cell development in the thymus, migration of newly selected CD4 and CD8 thymocytes into medullary areas enables tolerance mechanisms to purge the newly selected αβ TCR repertoire of autoreactive specificities. Thymic dendritic cells (DC) play key roles in this process and consist of three distinct subsets that differ in their developmental origins. Thus, plasmacytoid DC and Sirpα conventional DC type 2 are extrathymically derived and enter into the thymus via their respective expression of the chemokine receptors CCR9 and CCR2. In contrast, although Sirpα conventional DC type 1 (cDC1) are known to arise intrathymically from immature progenitors, the precise nature of such thymus-colonizing progenitors and the mechanisms controlling their thymus entry are unclear. In this article, we report a selective reduction in thymic cDC1 in mice lacking the chemokine receptor CCR7. In addition, we show that the thymus contains a CD11cMHC class IISirpαFlt3 cDC progenitor population that expresses CCR7, and that migration of these cells to the thymus is impaired in mice. Moreover, thymic cDC1 defects in mice are mirrored in mice, with further analysis of mice individually lacking the CCR7 ligands CCL21Ser ( ) or CCL19 ( demonstrating an essential role for CCR7-CCL21Ser during intrathymic cDC1 development. Collectively, our data support a mechanism in which CCR7-CCL21Ser interactions guide the migration of cDC progenitors to the thymus for correct formation of the intrathymic cDC1 pool."},"publication_date":"2018-07","publication_name":{"en":"The Journal of Immunology","ja":"The Journal of Immunology"},"volume":"Vol.201","number":"No.2","starting_page":"516","ending_page":"523","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4049/jimmunol.1800348"],"issn":["1550-6606"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:23, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/29298829","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85044773413&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=336399","label":"url"}],"paper_title":{"en":"Cellularity of Thymic Epithelial Cells in the Postnatal Mouse.","ja":"Cellularity of Thymic Epithelial Cells in the Postnatal Mouse."},"authors":{"en":[{"name":"Sakata Mie"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"坂田 三恵"},{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"The molecular and cellular biology of thymic epithelial cells (TECs) often relies on the analysis of TECs isolated in enzymatically digested single-cell suspensions derived from mouse thymus. Many independent studies have reported that the estimated cellularity of total TECs isolated from one adult mouse is on the order of up to 10 However, these numbers appear extremely small given that the cellularity of total thymocytes exceeds 10 and that TECs play multiple roles in thymocyte development and repertoire formation. In the present study, we aimed to measure the numbers of β5t-expressing cortical TECs and Aire-expressing medullary TECs in postnatal mouse thymus in situ without enzymatic digestion. The numbers of these TECs were manually counted in individual thymic sections and were three-dimensionally summed throughout the entire thymic lobes. The results show that the cellularity of total TECs in one 5-wk-old female mouse exceeds 10, containing 9 × 10 β5t cortical TECs and 1.1 × 10 Aire medullary TECs. These results suggest that the use of conventional enzymatic digestion methods for the isolation of TECs may have resulted in the underestimation of the cellularity, and possibly the biology, of TECs.","ja":"The molecular and cellular biology of thymic epithelial cells (TECs) often relies on the analysis of TECs isolated in enzymatically digested single-cell suspensions derived from mouse thymus. Many independent studies have reported that the estimated cellularity of total TECs isolated from one adult mouse is on the order of up to 10 However, these numbers appear extremely small given that the cellularity of total thymocytes exceeds 10 and that TECs play multiple roles in thymocyte development and repertoire formation. In the present study, we aimed to measure the numbers of β5t-expressing cortical TECs and Aire-expressing medullary TECs in postnatal mouse thymus in situ without enzymatic digestion. The numbers of these TECs were manually counted in individual thymic sections and were three-dimensionally summed throughout the entire thymic lobes. The results show that the cellularity of total TECs in one 5-wk-old female mouse exceeds 10, containing 9 × 10 β5t cortical TECs and 1.1 × 10 Aire medullary TECs. These results suggest that the use of conventional enzymatic digestion methods for the isolation of TECs may have resulted in the underestimation of the cellularity, and possibly the biology, of TECs."},"publication_date":"2018-02-15","publication_name":{"en":"The Journal of Immunology","ja":"The Journal of Immunology"},"volume":"Vol.200","number":"No.4","starting_page":"1382","ending_page":"1388","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4049/jimmunol.1701235"],"issn":["1550-6606"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:24, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458423"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/110168","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28611158","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325872","label":"url"}],"paper_title":{"en":"Essential role of CCL21 in establishment of central self-tolerance in T cells","ja":"Essential role of CCL21 in establishment of central self-tolerance in T cells"},"authors":{"en":[{"name":"Kozai Mina"},{"name":"Kubo Yuki"},{"name":"Katakai Tomoya"},{"name":"Kondo Hiroyuki"},{"name":"Kiyonari Hiroshi"},{"name":"Schaeuble Karin"},{"name":"Luther A. Sanjiv"},{"name":"Ishimaru Naozumi"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"Kozai Mina"},{"name":"Kubo Yuki"},{"name":"Katakai Tomoya"},{"name":"近藤 博之"},{"name":"Kiyonari Hiroshi"},{"name":"Schaeuble Karin"},{"name":"Luther A. Sanjiv"},{"name":"石丸 直澄"},{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo.","ja":"The chemokine receptor CCR7 directs T cell relocation into and within lymphoid organs, including the migration of developing thymocytes into the thymic medulla. However, how three functional CCR7 ligands in mouse, CCL19, CCL21Ser, and CCL21Leu, divide their roles in immune organs is unclear. By producing mice specifically deficient in CCL21Ser, we show that CCL21Ser is essential for the accumulation of positively selected thymocytes in the thymic medulla. CCL21Ser-deficient mice were impaired in the medullary deletion of self-reactive thymocytes and developed autoimmune dacryoadenitis. T cell accumulation in the lymph nodes was also defective. These results indicate a nonredundant role of CCL21Ser in the establishment of self-tolerance in T cells in the thymic medulla, and reveal a functional inequality among CCR7 ligands in vivo."},"publication_date":"2017-07-03","publication_name":{"en":"The Journal of Experimental Medicine","ja":"The Journal of Experimental Medicine"},"volume":"Vol.214","number":"No.7","starting_page":"1925","ending_page":"1935","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1084/jem.20161864"],"issn":["1540-9538"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:25, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113736","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28515360","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=325871","label":"url"}],"paper_title":{"en":"A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production","ja":"A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Ohte Yuki"},{"name":"Setoh Kazuya"},{"name":"Nakase Hiroshi"},{"name":"Maekawa Akiko"},{"name":"Kiyonari Hiroshi"},{"name":"Hamazaki Yoko"},{"name":"Sekai Miho"},{"name":"Sudo Tetsuo"},{"name":"Tabara Yasuharu"},{"name":"Sawai Hiromi"},{"name":"Omae Yosuke"},{"name":"Yuliwulandari Rika"},{"name":"Tanaka Yasuhito"},{"name":"Mizokami Masashi"},{"name":"Inoue Hiroshi"},{"name":"Kasahara Masanori"},{"name":"Minato Nagahiro"},{"name":"Tokunaga Katsushi"},{"name":"Tanaka Keiji"},{"name":"Matsuda Fumihiko"},{"name":"Murata Shigeo"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Ohte Yuki"},{"name":"Setoh Kazuya"},{"name":"Nakase Hiroshi"},{"name":"前川 明子"},{"name":"Kiyonari Hiroshi"},{"name":"Hamazaki Yoko"},{"name":"Sekai Miho"},{"name":"Sudo Tetsuo"},{"name":"Tabara Yasuharu"},{"name":"Sawai Hiromi"},{"name":"Omae Yosuke"},{"name":"Yuliwulandari Rika"},{"name":"Tanaka Yasuhito"},{"name":"Mizokami Masashi"},{"name":"井上 寛"},{"name":"Kasahara Masanori"},{"name":"Minato Nagahiro"},{"name":"Tokunaga Katsushi"},{"name":"Tanaka Keiji"},{"name":"Matsuda Fumihiko"},{"name":"Murata Shigeo"},{"name":"高浜 洋介"}]},"description":{"en":"The Psmb11-encoded β5t subunit of the thymoproteasome, which is specifically expressed in cortical thymic epithelial cells (cTECs), is essential for the optimal positive selection of functionally competent CD8+ T cells in mice. Here, we report that a human genomic PSMB11 variation, which is detectable at an appreciable allele frequency in human populations, alters the β5t amino acid sequence that affects the processing of catalytically active β5t proteins. The introduction of this variation in the mouse genome revealed that the heterozygotes showed reduced β5t expression in cTECs and the homozygotes further exhibited reduction in the cellularity of CD8+ T cells. No severe health problems were noticed in many heterozygous and 5 homozygous human individuals. Long-term analysis of health status, particularly in the homozygotes, is expected to improve our understanding of the role of the thymoproteasome-dependent positive selection of CD8+ T cells in humans.","ja":"The Psmb11-encoded β5t subunit of the thymoproteasome, which is specifically expressed in cortical thymic epithelial cells (cTECs), is essential for the optimal positive selection of functionally competent CD8+ T cells in mice. Here, we report that a human genomic PSMB11 variation, which is detectable at an appreciable allele frequency in human populations, alters the β5t amino acid sequence that affects the processing of catalytically active β5t proteins. The introduction of this variation in the mouse genome revealed that the heterozygotes showed reduced β5t expression in cTECs and the homozygotes further exhibited reduction in the cellularity of CD8+ T cells. No severe health problems were noticed in many heterozygous and 5 homozygous human individuals. Long-term analysis of health status, particularly in the homozygotes, is expected to improve our understanding of the role of the thymoproteasome-dependent positive selection of CD8+ T cells in humans."},"publication_date":"2017-05-18","publication_name":{"en":"JCI Insight","ja":"JCI Insight"},"volume":"Vol.2","number":"No.10","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1172/jci.insight.93664"],"issn":["2379-3708"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:26, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/110920","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/28176764","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85012009599&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=324605","label":"url"}],"paper_title":{"en":"Foxn1-5t transcriptional axis controls CD8+ T-cell production in the thymus.","ja":"Foxn1-5t transcriptional axis controls CD8+ T-cell production in the thymus."},"authors":{"en":[{"name":"Muhammad Myn Uddin"},{"name":"Ohigashi Izumi"},{"name":"Motosugi Ryo"},{"name":"Nakayama Tomomi"},{"name":"Sakata Mie"},{"name":"Hamazaki Jun"},{"name":"Nishito Yasumasa"},{"name":"Rode Immanuel"},{"name":"Tanaka Keiji"},{"name":"Takemoto Tatsuya"},{"name":"Murata Shigeo"},{"name":"Takahama Yousuke"}],"ja":[{"name":"Muhammad Myn Uddin"},{"name":"大東 いずみ"},{"name":"Motosugi Ryo"},{"name":"Nakayama Tomomi"},{"name":"Sakata Mie"},{"name":"Hamazaki Jun"},{"name":"Nishito Yasumasa"},{"name":"Rode Immanuel"},{"name":"Tanaka Keiji"},{"name":"竹本 龍也"},{"name":"Murata Shigeo"},{"name":"高浜 洋介"}]},"description":{"en":"The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies. Foxn1 is a transcription factor that is essential for thymus organogenesis; however, the direct target for Foxn1 to actuate thymic T-cell production is unknown. Here we show that a Foxn1-binding cis-regulatory element promotes the transcription of β5t, which has an essential role in cortical thymic epithelial cells to induce positive selection of functionally competent CD8(+) T cells. A point mutation in this genome element results in a defect in β5t expression and CD8(+) T-cell production in mice. The results reveal a Foxn1-β5t transcriptional axis that governs CD8(+) T-cell production in the thymus.","ja":"The thymus is an organ that produces functionally competent T cells that protect us from pathogens and malignancies. Foxn1 is a transcription factor that is essential for thymus organogenesis; however, the direct target for Foxn1 to actuate thymic T-cell production is unknown. Here we show that a Foxn1-binding cis-regulatory element promotes the transcription of β5t, which has an essential role in cortical thymic epithelial cells to induce positive selection of functionally competent CD8(+) T cells. A point mutation in this genome element results in a defect in β5t expression and CD8(+) T-cell production in mice. The results reveal a Foxn1-β5t transcriptional axis that governs CD8(+) T-cell production in the thymus."},"publication_date":"2017-02-08","publication_name":{"en":"Nature Communications","ja":"Nature Communications"},"volume":"Vol.8","starting_page":"14419","ending_page":"14419","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1038/ncomms14419"],"issn":["2041-1723"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:27, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113737","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/27088904","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84963556553&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=315890","label":"url"}],"paper_title":{"en":"Development and developmental potential of cortical thymic epithelial cells","ja":"Development and developmental potential of cortical thymic epithelial cells"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Kozai Mina"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Kozai Mina"},{"name":"高浜 洋介"}]},"description":{"en":"The thymic cortex provides a microenvironment for the development and positive selection of immature T cells. Cortical thymic epithelial cells (cTECs), which structurally and functionally support the thymic cortical microenvironment, originate from endodermal epithelial progenitors that arise in the third pharyngeal pouch. Recent studies have revealed that thymic epithelial progenitors pass through a stage where the cells express cTEC-associated molecules prior to lineage separation into cTECs and medullary TECs (mTECs). Here, we review the molecular signatures of cTECs and highlight the development and developmental potential of cTECs.","ja":"The thymic cortex provides a microenvironment for the development and positive selection of immature T cells. Cortical thymic epithelial cells (cTECs), which structurally and functionally support the thymic cortical microenvironment, originate from endodermal epithelial progenitors that arise in the third pharyngeal pouch. Recent studies have revealed that thymic epithelial progenitors pass through a stage where the cells express cTEC-associated molecules prior to lineage separation into cTECs and medullary TECs (mTECs). Here, we review the molecular signatures of cTECs and highlight the development and developmental potential of cTECs."},"publication_date":"2016-05","publication_name":{"en":"Immunological Reviews","ja":"Immunological Reviews"},"volume":"Vol.271","number":"No.1","starting_page":"10","ending_page":"22","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1111/imr.12404"],"issn":["1600-065X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:28, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458424"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26694097","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=315888","label":"url"}],"paper_title":{"en":"Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla","ja":"Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla"},"authors":{"en":[{"name":"Mayer CE"},{"name":"Zuklys S"},{"name":"Zhanybekova S"},{"name":"Ohigashi Izumi"},{"name":"Teh HY"},{"name":"Sansom SN"},{"name":"Shikama-Dorn N"},{"name":"Hafen K"},{"name":"Macaulay IC"},{"name":"Deadman ME"},{"name":"Ponting CP"},{"name":"Takahama Yousuke"},{"name":"Hollander GA"}],"ja":[{"name":"Mayer CE"},{"name":"Zuklys S"},{"name":"Zhanybekova S"},{"name":"大東 いずみ"},{"name":"Teh HY"},{"name":"Sansom SN"},{"name":"Shikama-Dorn N"},{"name":"Hafen K"},{"name":"Macaulay IC"},{"name":"Deadman ME"},{"name":"Ponting CP"},{"name":"高浜 洋介"},{"name":"Hollander GA"}]},"description":{"en":"Intrathymic T-cell development is critically dependent on cortical and medullary thymic epithelial cells (TECs). Both epithelial subsets originate during early thymus organogenesis from progenitor cells that express the thymoproteasome subunit β5t, a typical feature of cortical TECs. Using in vivo lineage fate mapping, we demonstrate in mice that β5t(+) TEC progenitors give rise to the medullary TEC compartment early in life but significantly limit their contribution once the medulla has completely formed. Lineage-tracing studies at single cell resolution demonstrate for young mice that the postnatal medulla is expanded from individual β5t(+) cortical progenitors located at the cortico-medullary junction. These results therefore not only define a developmental window during which the expansion of medulla is efficiently enabled by progenitors resident in the thymic cortex, but also reveal the spatio-temporal dynamics that control the growth of the thymic medulla.","ja":"Intrathymic T-cell development is critically dependent on cortical and medullary thymic epithelial cells (TECs). Both epithelial subsets originate during early thymus organogenesis from progenitor cells that express the thymoproteasome subunit β5t, a typical feature of cortical TECs. Using in vivo lineage fate mapping, we demonstrate in mice that β5t(+) TEC progenitors give rise to the medullary TEC compartment early in life but significantly limit their contribution once the medulla has completely formed. Lineage-tracing studies at single cell resolution demonstrate for young mice that the postnatal medulla is expanded from individual β5t(+) cortical progenitors located at the cortico-medullary junction. These results therefore not only define a developmental window during which the expansion of medulla is efficiently enabled by progenitors resident in the thymic cortex, but also reveal the spatio-temporal dynamics that control the growth of the thymic medulla."},"publication_date":"2016-04","publication_name":{"en":"European Journal of Immunology","ja":"European Journal of Immunology"},"volume":"Vol.46","number":"No.4","starting_page":"846","ending_page":"856","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/eji.201545995"],"issn":["1521-4141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:29, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-85043262396&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=315889","label":"url"}],"paper_title":{"en":"Thymocyte-mTEC cross talk for self-tolerance in T cells","ja":"Thymocyte-mTEC cross talk for self-tolerance in T cells"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"publication_date":"2016","publication_name":{"en":"Encyclopedia of Immunology","ja":"Encyclopedia of Immunology"},"volume":"Vol.1","starting_page":"263","ending_page":"267","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/B978-0-12-374279-7.04014-5"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:30, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26294398","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84940213841&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=315887","label":"url"}],"paper_title":{"en":"Flow Cytometry Analysis of Thymic Epithelial Cells and Their Subpopulations","ja":"Flow Cytometry Analysis of Thymic Epithelial Cells and Their Subpopulations"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"The parenchyma of the thymus is compartmentalized into the cortex and the medulla, which are constructed by cortical thymic epithelial cells (cortical TECs, cTECs) and medullary thymic epithelial cells (mTECs), respectively. cTECs and mTECs essentially and differentially regulate the development and repertoire selection of T cells. Consequently, the biology of T cell development and selection includes the study of TECs in addition to the study of developing T cells and other hematopoietic cells including dendritic cells. In this chapter, we describe the methods for flow cytometric analysis and sorting of TECs and their subpopulations, including cTECs and mTECs.","ja":"The parenchyma of the thymus is compartmentalized into the cortex and the medulla, which are constructed by cortical thymic epithelial cells (cortical TECs, cTECs) and medullary thymic epithelial cells (mTECs), respectively. cTECs and mTECs essentially and differentially regulate the development and repertoire selection of T cells. Consequently, the biology of T cell development and selection includes the study of TECs in addition to the study of developing T cells and other hematopoietic cells including dendritic cells. In this chapter, we describe the methods for flow cytometric analysis and sorting of TECs and their subpopulations, including cTECs and mTECs."},"publication_date":"2016","publication_name":{"en":"Methods in Molecular Biology","ja":"Methods in Molecular Biology"},"volume":"Vol.1323","starting_page":"65","ending_page":"73","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/978-1-4939-2809-5_5"],"issn":["1940-6029"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:31, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/113738","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/26549457","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84947347108&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=315884","label":"url"}],"paper_title":{"en":"Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors","ja":"Adult thymic medullary epithelium is maintained and regenerated by lineage-restricted cells rather than bipotent progenitors"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Zuklys Saulius"},{"name":"Sakata Mie"},{"name":"Mayer E. Carlos"},{"name":"Hamazaki Yoko"},{"name":"Minato Nagahiro"},{"name":"Hollander A Georg"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Zuklys Saulius"},{"name":"Sakata Mie"},{"name":"Mayer E. Carlos"},{"name":"Hamazaki Yoko"},{"name":"Minato Nagahiro"},{"name":"Hollander A Georg"},{"name":"高浜 洋介"}]},"description":{"en":"Medullary thymic epithelial cells (mTECs) play an essential role in establishing self-tolerance in T cells. mTECs originate from bipotent TEC progenitors that generate both mTECs and cortical TECs (cTECs), although mTEC-restricted progenitors also have been reported. Here, we report in vivo fate-mapping analysis of cells that transcribe β5t, a cTEC trait expressed in bipotent progenitors, during a given period in mice. We show that, in adult mice, most mTECs are derived from progenitors that transcribe β5t during embryogenesis and the neonatal period up to 1 week of age. The contribution of adult β5t(+) progenitors was minor even during injury-triggered regeneration. Our results further demonstrate that adult mTEC-restricted progenitors are derived from perinatal β5t(+) progenitors. These results indicate that the adult thymic medullary epithelium is maintained and regenerated by mTEC-lineage cells that pass beyond the bipotent stage during early ontogeny.","ja":"Medullary thymic epithelial cells (mTECs) play an essential role in establishing self-tolerance in T cells. mTECs originate from bipotent TEC progenitors that generate both mTECs and cortical TECs (cTECs), although mTEC-restricted progenitors also have been reported. Here, we report in vivo fate-mapping analysis of cells that transcribe β5t, a cTEC trait expressed in bipotent progenitors, during a given period in mice. We show that, in adult mice, most mTECs are derived from progenitors that transcribe β5t during embryogenesis and the neonatal period up to 1 week of age. The contribution of adult β5t(+) progenitors was minor even during injury-triggered regeneration. Our results further demonstrate that adult mTEC-restricted progenitors are derived from perinatal β5t(+) progenitors. These results indicate that the adult thymic medullary epithelium is maintained and regenerated by mTEC-lineage cells that pass beyond the bipotent stage during early ontogeny."},"publication_date":"2015-11-17","publication_name":{"en":"Cell Reports","ja":"Cell Reports"},"volume":"Vol.13","number":"No.7","starting_page":"1432","ending_page":"1443","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.celrep.2015.10.012"],"issn":["2211-1247"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:32, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24214487","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84892472653&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=277214","label":"url"}],"paper_title":{"en":"Serial progression of cortical and medullary thymic epithelial microenvironments.","ja":"Serial progression of cortical and medullary thymic epithelial microenvironments."},"authors":{"en":[{"name":"Alves Nuno L"},{"name":"Takahama Yousuke"},{"name":"Ohigashi Izumi"},{"name":"Ribeiro Ana R"},{"name":"Baik Song"},{"name":"Anderson Graham"},{"name":"Jenkinson William E"}],"ja":[{"name":"Alves Nuno L"},{"name":"高浜 洋介"},{"name":"大東 いずみ"},{"name":"Ribeiro Ana R"},{"name":"Baik Song"},{"name":"Anderson Graham"},{"name":"Jenkinson William E"}]},"description":{"en":"Thymic epithelial cells (TECs) provide key instructive signals for T-cell differentiation. Thymic cortical (cTECs) and medullary (mTECs) epithelial cells constitute two functionally distinct microenvironments for T-cell development, which derive from a common bipotent TEC progenitor. While seminal studies have partially elucidated events downstream of bipotent TECs in relation to the emergence of mTECs and their progenitors, the control and timing of the emergence of the cTEC lineage, particularly in relation to that of mTEC progenitors, has remained elusive. In this review, we describe distinct models that explain cTEC/mTEC lineage divergence from common bipotent progenitors. In particular, we summarize recent studies in mice providing evidence that mTECs, including the auto-immune regulator(+) subset, derive from progenitors initially endowed with phenotypic properties typically associated with the cTEC lineage. These observations support a novel \"serial progression\" model of TEC development, in which progenitors serially acquire cTEC lineage markers, prior to their commitment to the mTEC differentiation pathway. Gaining a better understanding of the phenotypic properties of early stages in TEC progenitor development should help in determining the mechanisms regulating cTEC/mTEC lineage development, and in strategies aimed at thymus reconstitution involving TEC therapy.","ja":"Thymic epithelial cells (TECs) provide key instructive signals for T-cell differentiation. Thymic cortical (cTECs) and medullary (mTECs) epithelial cells constitute two functionally distinct microenvironments for T-cell development, which derive from a common bipotent TEC progenitor. While seminal studies have partially elucidated events downstream of bipotent TECs in relation to the emergence of mTECs and their progenitors, the control and timing of the emergence of the cTEC lineage, particularly in relation to that of mTEC progenitors, has remained elusive. In this review, we describe distinct models that explain cTEC/mTEC lineage divergence from common bipotent progenitors. In particular, we summarize recent studies in mice providing evidence that mTECs, including the auto-immune regulator(+) subset, derive from progenitors initially endowed with phenotypic properties typically associated with the cTEC lineage. These observations support a novel \"serial progression\" model of TEC development, in which progenitors serially acquire cTEC lineage markers, prior to their commitment to the mTEC differentiation pathway. Gaining a better understanding of the phenotypic properties of early stages in TEC progenitor development should help in determining the mechanisms regulating cTEC/mTEC lineage development, and in strategies aimed at thymus reconstitution involving TEC therapy."},"publication_date":"2014","publication_name":{"en":"European Journal of Immunology","ja":"European Journal of Immunology"},"volume":"Vol.44","number":"No.1","starting_page":"16","ending_page":"22","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/eji.201344110"],"issn":["1521-4141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:33, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23612989","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84892696131&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=269062","label":"url"}],"paper_title":{"en":"Development and function of cortical thymic epithelial cells.","ja":"Development and function of cortical thymic epithelial cells."},"authors":{"en":[{"name":"Takada Kensuke"},{"name":"Ohigashi Izumi"},{"name":"Kasai Michiyuki"},{"name":"Nakase Hiroshi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"高田 健介"},{"name":"大東 いずみ"},{"name":"笠井 道之"},{"name":"Nakase Hiroshi"},{"name":"高浜 洋介"}]},"description":{"en":"The thymic cortex provides a microenvironment that supports the generation and T cell antigen receptor (TCR)-mediated selection of CD4(+)CD8(+)TCR(+) thymocytes. Cortical thymic epithelial cells (cTECs) are the essential component that forms the architecture of the thymic cortex and induces the generation as well as the selection of newly generated T cells. Here we summarize current knowledge on the development, function, and heterogeneity of cTECs, focusing on the expression and function of 5t, a cTEC-specific subunit of the thymoproteasome.","ja":"The thymic cortex provides a microenvironment that supports the generation and T cell antigen receptor (TCR)-mediated selection of CD4(+)CD8(+)TCR(+) thymocytes. Cortical thymic epithelial cells (cTECs) are the essential component that forms the architecture of the thymic cortex and induces the generation as well as the selection of newly generated T cells. Here we summarize current knowledge on the development, function, and heterogeneity of cTECs, focusing on the expression and function of 5t, a cTEC-specific subunit of the thymoproteasome."},"publication_date":"2014","publication_name":{"en":"Current Topics in Microbiology and Immunology","ja":"Current Topics in Microbiology and Immunology"},"volume":"Vol.373","starting_page":"1","ending_page":"17","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/82_2013_322"],"issn":["0070-217X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:34, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/25216053","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84925236502&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=286947","label":"url"}],"paper_title":{"en":"CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells.","ja":"CCRL1 marks heterogeneity in cortical and medullary thymic epithelial cells."},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs), which play essential roles in the establishment of a functionally competent and self-tolerant repertoire of T cells, are derived from common thymic epithelial progenitor cells (pTECs). Recent findings indicate that mTECs are derived from cells that express molecules that are abundant in cTECs rather than mTECs, and provide fresh insight into the characteristics of pTECs and their diversification pathways into TEC subpopulations. In this issue of the European Journal of Immunology, Ribeiro et al. [Eur. J. Immunol. 2014. 44: 2918-2924] focus on CCRL1, an atypical chemokine receptor that is highly expressed by cTECs rather than mTECs, and show that CCRL1-expressing embryonic TECs can give rise to mTECs. Interestingly, Ribeiro et al. further report that a fraction of postnatal mTECs express CCRL1 at a low level, suggesting novel complexity in mTECs.","ja":"Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs), which play essential roles in the establishment of a functionally competent and self-tolerant repertoire of T cells, are derived from common thymic epithelial progenitor cells (pTECs). Recent findings indicate that mTECs are derived from cells that express molecules that are abundant in cTECs rather than mTECs, and provide fresh insight into the characteristics of pTECs and their diversification pathways into TEC subpopulations. In this issue of the European Journal of Immunology, Ribeiro et al. [Eur. J. Immunol. 2014. 44: 2918-2924] focus on CCRL1, an atypical chemokine receptor that is highly expressed by cTECs rather than mTECs, and show that CCRL1-expressing embryonic TECs can give rise to mTECs. Interestingly, Ribeiro et al. further report that a fraction of postnatal mTECs express CCRL1 at a low level, suggesting novel complexity in mTECs."},"publication_date":"2014-10","publication_name":{"en":"European Journal of Immunology","ja":"European Journal of Immunology"},"volume":"Vol.44","number":"No.10","starting_page":"2872","ending_page":"2875","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/eji.201445091"],"issn":["1521-4141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:35, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458425"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24556356","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84896393117&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=285940","label":"url"}],"paper_title":{"en":"Increased number of Hassall's corpuscles in myasthenia gravis patients with thymic hyperplasia.","ja":"Increased number of Hassall's corpuscles in myasthenia gravis patients with thymic hyperplasia."},"authors":{"en":[{"name":"Matsui Naoko"},{"name":"Ohigashi Izumi"},{"name":"Tanaka Keijirou"},{"name":"Sakata Mie"},{"name":"Furukawa Takahiro"},{"name":"Nakagawa Yasushi"},{"name":"Kondo Kazuya"},{"name":"Kitagawa Tetsuya"},{"name":"Yamashita Sumimasa"},{"name":"Nomura Yoshiko"},{"name":"Takahama Yousuke"},{"name":"Kaji Ryuji"}],"ja":[{"name":"松井 尚子"},{"name":"大東 いずみ"},{"name":"Tanaka Keijirou"},{"name":"Sakata Mie"},{"name":"Furukawa Takahiro"},{"name":"中川 靖士"},{"name":"近藤 和也"},{"name":"北川 哲也"},{"name":"Yamashita Sumimasa"},{"name":"Nomura Yoshiko"},{"name":"高浜 洋介"},{"name":"梶 龍兒"}]},"description":{"en":"The thymus is implicated as an organ that contributes to autoimmunity in myasthenia gravis (MG) patients. Hassall's corpuscles (HCs) are assumed to represent the terminally differentiated stage of medullary thymic epithelial cells (mTECs). By using multicolor immunohistofluorescence analysis, we examined HCs in thymuses that were therapeutically excised from MG (+) and MG (-) patients. We found that the number of HCs per unit area of the thymic medulla was significantly elevated in the thymuses of MG (+) patients with thymic hyperplasia. CCL21 expression increased in the hyperplastic MG thymuses. We speculate that the altered differentiation of mTECs is associated with the thymic hyperplasia and the onset of MG.","ja":"The thymus is implicated as an organ that contributes to autoimmunity in myasthenia gravis (MG) patients. Hassall's corpuscles (HCs) are assumed to represent the terminally differentiated stage of medullary thymic epithelial cells (mTECs). By using multicolor immunohistofluorescence analysis, we examined HCs in thymuses that were therapeutically excised from MG (+) and MG (-) patients. We found that the number of HCs per unit area of the thymic medulla was significantly elevated in the thymuses of MG (+) patients with thymic hyperplasia. CCL21 expression increased in the hyperplastic MG thymuses. We speculate that the altered differentiation of mTECs is associated with the thymic hyperplasia and the onset of MG."},"publication_date":"2014-01-28","publication_name":{"en":"Journal of Neuroimmunology","ja":"Journal of Neuroimmunology"},"volume":"Vol.269","number":"No.1-2","starting_page":"56","ending_page":"61","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.jneuroim.2014.01.011"],"issn":["1872-8421"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:36, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458426"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24337745","label":"url"},{"@id":"https://www.scopus.com/record/display.url?eid=2-s2.0-84892741006&origin=inward","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=277212","label":"url"}],"paper_title":{"en":"Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways.","ja":"Thymic medullary epithelium and thymocyte self-tolerance require cooperation between CD28-CD80/86 and CD40-CD40L costimulatory pathways."},"authors":{"en":[{"name":"Williams Joy A"},{"name":"Zhang Jingjing"},{"name":"Jeon Hyein"},{"name":"Nitta Takeshi"},{"name":"Ohigashi Izumi"},{"name":"Klug David"},{"name":"Kruhlak Michael J"},{"name":"Choudhury Baishakhi"},{"name":"Sharrow Susan O"},{"name":"Granger Larry"},{"name":"Adams Anthony"},{"name":"Eckhaus Michael A"},{"name":"Jenkinson S Rhiannon"},{"name":"Richie Ellen R"},{"name":"Gress Ronald E"},{"name":"Takahama Yousuke"},{"name":"Hodes Richard J"}],"ja":[{"name":"Williams Joy A"},{"name":"Zhang Jingjing"},{"name":"Jeon Hyein"},{"name":"新田 剛"},{"name":"大東 いずみ"},{"name":"Klug David"},{"name":"Kruhlak Michael J"},{"name":"Choudhury Baishakhi"},{"name":"Sharrow Susan O"},{"name":"Granger Larry"},{"name":"Adams Anthony"},{"name":"Eckhaus Michael A"},{"name":"Jenkinson S Rhiannon"},{"name":"Richie Ellen R"},{"name":"Gress Ronald E"},{"name":"高浜 洋介"},{"name":"Hodes Richard J"}]},"description":{"en":"A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals from mature single-positive thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LT, LT, and receptor activator for NF-B in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of single-positive thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high-affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 knockout mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development.","ja":"A critical process during thymic development of the T cell repertoire is the induction of self-tolerance. Tolerance in developing T cells is highly dependent on medullary thymic epithelial cells (mTEC), and mTEC development in turn requires signals from mature single-positive thymocytes, a bidirectional relationship termed thymus crosstalk. We show that CD28-CD80/86 and CD40-CD40L costimulatory interactions, which mediate negative selection and self-tolerance, upregulate expression of LT, LT, and receptor activator for NF-B in the thymus and are necessary for medullary development. Combined absence of CD28-CD80/86 and CD40-CD40L results in profound deficiency in mTEC development comparable to that observed in the absence of single-positive thymocytes. This requirement for costimulatory signaling is maintained even in a TCR transgenic model of high-affinity TCR-ligand interactions. CD4 thymocytes maturing in the altered thymic epithelial environment of CD40/CD80/86 knockout mice are highly autoreactive in vitro and are lethal in congenic adoptive transfer in vivo, demonstrating a critical role for these costimulatory pathways in self-tolerance as well as thymic epithelial development. These findings demonstrate that cooperativity between CD28-CD80/86 and CD40-CD40L pathways is required for normal medullary epithelium and for maintenance of self-tolerance in thymocyte development."},"publication_date":"2014","publication_name":{"en":"The Journal of Immunology","ja":"The Journal of Immunology"},"volume":"Vol.192","number":"No.2","starting_page":"630","ending_page":"640","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4049/jimmunol.1302550"],"issn":["1550-6606"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:37, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458427"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/24324158","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=277218","label":"url"}],"paper_title":{"en":"TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development.","ja":"TRAF3 enforces the requirement for T cell cross-talk in thymic medullary epithelial development."},"authors":{"en":[{"name":"Jenkinson S Rhiannon"},{"name":"Williams Joy A"},{"name":"Jeon Hyein"},{"name":"Zhang Jingjing"},{"name":"Nitta Takeshi"},{"name":"Ohigashi Izumi"},{"name":"Kruhlak Michael"},{"name":"Zuklys Saulius"},{"name":"Sharrow Susan"},{"name":"Adams Anthony"},{"name":"Granger Larry"},{"name":"Choi Yongwon"},{"name":"Siebenlist Ulrich"},{"name":"Bishop Gail A"},{"name":"Hollander Georg A"},{"name":"Takahama Yousuke"},{"name":"Hodes Richard J"}],"ja":[{"name":"Jenkinson S Rhiannon"},{"name":"Williams Joy A"},{"name":"Jeon Hyein"},{"name":"Zhang Jingjing"},{"name":"新田 剛"},{"name":"大東 いずみ"},{"name":"Kruhlak Michael"},{"name":"Zuklys Saulius"},{"name":"Sharrow Susan"},{"name":"Adams Anthony"},{"name":"Granger Larry"},{"name":"Choi Yongwon"},{"name":"Siebenlist Ulrich"},{"name":"Bishop Gail A"},{"name":"Hollander Georg A"},{"name":"高浜 洋介"},{"name":"Hodes Richard J"}]},"description":{"en":"Induction of self-tolerance in developing T cells depends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals from single-positive (SP) thymocytes. Thus, the absence of SP thymocytes in Tcra(-/-) mice results in a profound deficiency in mTECs. Here, we have probed the mechanism that underlies this requirement for cross-talk with thymocytes in medullary development. Previous studies have implicated nonclassical NF-B as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKK, critical components of this pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology. We therefore assessed the effect of selective deletion in TEC of TNF receptor-associated factor 3 (TRAF3), an inhibitor of nonclassical NF-B signaling. Deletion of TRAF3 in thymic epithelial cells allowed RelB-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes. Thus, mTEC development can occur in the absence of cross-talk with SP thymocytes, and signals provided by SP T cells are needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical NF-B. We further observed that TRAF3 deletion is also capable of overcoming all requirements for LTR and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the requirement for RANKL, indicating a role for RANKL that is distinct from the signals provided by SP thymocytes. We conclude that TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells and costimulation-mediated cross-talk in generation of the medullary compartment.","ja":"Induction of self-tolerance in developing T cells depends on medullary thymic epithelial cells (mTECs), whose development, in turn, requires signals from single-positive (SP) thymocytes. Thus, the absence of SP thymocytes in Tcra(-/-) mice results in a profound deficiency in mTECs. Here, we have probed the mechanism that underlies this requirement for cross-talk with thymocytes in medullary development. Previous studies have implicated nonclassical NF-B as a pathway important in the development of mTECs, because mice lacking RelB, NIK, or IKK, critical components of this pathway, have an almost complete absence of mTECs, with resulting autoimmune pathology. We therefore assessed the effect of selective deletion in TEC of TNF receptor-associated factor 3 (TRAF3), an inhibitor of nonclassical NF-B signaling. Deletion of TRAF3 in thymic epithelial cells allowed RelB-dependent development of normal numbers of AIRE-expressing mTECs in the complete absence of SP thymocytes. Thus, mTEC development can occur in the absence of cross-talk with SP thymocytes, and signals provided by SP T cells are needed to overcome TRAF3-imposed arrest in mTEC development mediated by inhibition of nonclassical NF-B. We further observed that TRAF3 deletion is also capable of overcoming all requirements for LTR and CD40, which are otherwise necessary for mTEC development, but is not sufficient to overcome the requirement for RANKL, indicating a role for RANKL that is distinct from the signals provided by SP thymocytes. We conclude that TRAF3 plays a central role in regulation of mTEC development by imposing requirements for SP T cells and costimulation-mediated cross-talk in generation of the medullary compartment."},"publication_date":"2013-12-09","publication_name":{"en":"Proceedings of the National Academy of Sciences of the United States of America","ja":"Proceedings of the National Academy of Sciences of the United States of America"},"volume":"Vol.110","number":"No.52","starting_page":"21107","ending_page":"21112","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1073/pnas.1314859111"],"issn":["1091-6490"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:38, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458428"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23720310","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=282851","label":"url"}],"paper_title":{"en":"Aire-expressing thymic medullary epithelial cells originate from β5t-expressing progenitor cells.","ja":"Aire-expressing thymic medullary epithelial cells originate from β5t-expressing progenitor cells."},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Zuklys Saulius"},{"name":"Sakata Mie"},{"name":"Mayer Carlos E"},{"name":"Zhanybekova Saule"},{"name":"Murata Shigeo"},{"name":"Tanaka Keiji"},{"name":"Holländer Georg A"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Zuklys Saulius"},{"name":"Sakata Mie"},{"name":"Mayer Carlos E"},{"name":"Zhanybekova Saule"},{"name":"Murata Shigeo"},{"name":"Tanaka Keiji"},{"name":"Holländer Georg A"},{"name":"高浜 洋介"}]},"description":{"en":"The thymus provides multiple microenvironments that are essential for the development and repertoire selection of T lymphocytes. The thymic cortex induces the generation and positive selection of T lymphocytes, whereas the thymic medulla establishes self-tolerance among the positively selected T lymphocytes. Cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs) constitute the major stromal cells that structurally form and functionally characterize the cortex and the medulla, respectively. cTECs and mTECs are both derived from the endodermal epithelium of the third pharyngeal pouch. However, the molecular and cellular characteristics of the progenitor cells for the distinct TEC lineages are unclear. Here we report the preparation and characterization of mice that express the recombinase Cre instead of 5t, a proteasome subunit that is abundant in cTECs and not detected in other cell types, including mTECs. By crossing 5t-Cre knock-in mice with loxP-dependent GFP reporter mice, we found that 5t-Cre-mediated recombination occurs specifically in TECs but not in any other cell types in the mouse. Surprisingly, in addition to cTECs, 5t-Cre-loxP-mediated GFP expression was detected in almost all mTECs. These results indicate that the majority of mTECs, including autoimmune regulator-expressing mTECs, are derived from 5t-expressing progenitor cells.","ja":"The thymus provides multiple microenvironments that are essential for the development and repertoire selection of T lymphocytes. The thymic cortex induces the generation and positive selection of T lymphocytes, whereas the thymic medulla establishes self-tolerance among the positively selected T lymphocytes. Cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs) constitute the major stromal cells that structurally form and functionally characterize the cortex and the medulla, respectively. cTECs and mTECs are both derived from the endodermal epithelium of the third pharyngeal pouch. However, the molecular and cellular characteristics of the progenitor cells for the distinct TEC lineages are unclear. Here we report the preparation and characterization of mice that express the recombinase Cre instead of 5t, a proteasome subunit that is abundant in cTECs and not detected in other cell types, including mTECs. By crossing 5t-Cre knock-in mice with loxP-dependent GFP reporter mice, we found that 5t-Cre-mediated recombination occurs specifically in TECs but not in any other cell types in the mouse. Surprisingly, in addition to cTECs, 5t-Cre-loxP-mediated GFP expression was detected in almost all mTECs. These results indicate that the majority of mTECs, including autoimmune regulator-expressing mTECs, are derived from 5t-expressing progenitor cells."},"publication_date":"2013-05-29","publication_name":{"en":"Proceedings of the National Academy of Sciences of the United States of America","ja":"Proceedings of the National Academy of Sciences of the United States of America"},"volume":"Vol.110","number":"No.24","starting_page":"9885","ending_page":"9890","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1073/pnas.1301799110"],"issn":["1091-6490"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:39, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458429"},"force":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/105886","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23585674","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=265130","label":"url"}],"paper_title":{"en":"Lymphotoxin receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells.","ja":"Lymphotoxin receptor regulates the development of CCL21-expressing subset of postnatal medullary thymic epithelial cells."},"authors":{"en":[{"name":"Lkhagvasuren Enkhsaikhan"},{"name":"Sakata Mie"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"Lkhagvasuren Enkhsaikhan"},{"name":"Sakata Mie"},{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"Medullary thymic epithelial cells (mTECs) play a pivotal role in the establishment of self-tolerance in T cells by ectopically expressing various tissue-restricted self-Ags and by chemoattracting developing thymocytes. The nuclear protein Aire expressed by mTECs contributes to the promiscuous expression of self-Ags, whereas CCR7-ligand (CCR7L) chemokines expressed by mTECs are responsible for the attraction of positively selected thymocytes. It is known that lymphotoxin signals from the positively selected thymocytes preferentially promote the expression of CCR7L rather than Aire in postnatal mTECs. However, it is unknown how lymphotoxin signals differentially regulate the expression of CCR7L and Aire in mTECs and whether CCR7L-expressing mTECs and Aire-expressing mTECs are distinct populations. In this study, we show that the majority of postnatal mTECs that express CCL21, a CCR7L chemokine, represent an mTEC subpopulation distinct from the Aire-expressing mTEC subpopulation. Interestingly, the development of CCL21-expressing mTECs, but not Aire-expressing mTECs, is impaired in mice deficient in the lymphotoxin receptor. These results indicate that postnatal mTECs consist of heterogeneous subsets that differ in the expression of CCL21 and Aire, and that lymphotoxin receptor regulates the development of the CCL21-expressing subset rather than the Aire-expressing subset of postnatal mTECs.","ja":"Medullary thymic epithelial cells (mTECs) play a pivotal role in the establishment of self-tolerance in T cells by ectopically expressing various tissue-restricted self-Ags and by chemoattracting developing thymocytes. The nuclear protein Aire expressed by mTECs contributes to the promiscuous expression of self-Ags, whereas CCR7-ligand (CCR7L) chemokines expressed by mTECs are responsible for the attraction of positively selected thymocytes. It is known that lymphotoxin signals from the positively selected thymocytes preferentially promote the expression of CCR7L rather than Aire in postnatal mTECs. However, it is unknown how lymphotoxin signals differentially regulate the expression of CCR7L and Aire in mTECs and whether CCR7L-expressing mTECs and Aire-expressing mTECs are distinct populations. In this study, we show that the majority of postnatal mTECs that express CCL21, a CCR7L chemokine, represent an mTEC subpopulation distinct from the Aire-expressing mTEC subpopulation. Interestingly, the development of CCL21-expressing mTECs, but not Aire-expressing mTECs, is impaired in mice deficient in the lymphotoxin receptor. These results indicate that postnatal mTECs consist of heterogeneous subsets that differ in the expression of CCL21 and Aire, and that lymphotoxin receptor regulates the development of the CCL21-expressing subset rather than the Aire-expressing subset of postnatal mTECs."},"publication_date":"2013-04-12","publication_name":{"en":"The Journal of Immunology","ja":"The Journal of Immunology"},"volume":"Vol.190","number":"No.10","starting_page":"5110","ending_page":"5117","languages":["eng"],"referee":true,"identifiers":{"doi":["10.4049/jimmunol.1203203"],"issn":["1550-6606"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:40, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458430"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/23179827","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=265133","label":"url"}],"paper_title":{"en":"The development of T lymphocytes in fetal thymus organ culture.","ja":"The development of T lymphocytes in fetal thymus organ culture."},"authors":{"en":[{"name":"Nitta Takeshi"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"新田 剛"},{"name":"大東 いずみ"},{"name":"高浜 洋介"}]},"description":{"en":"Fetal thymus organ culture (FTOC) is a unique and powerful culture system that allows intrathymic T-lymphocyte development in vitro. T-cell development in FTOC well represents fetal thymocyte development in vivo. Here we describe the basic method for FTOC as well as several related techniques, including reconstitution of thymus lobes with T-lymphoid progenitor cells, high-oxygen submersion culture, reaggregation thymus organ culture, retrovirus-mediated gene transfer to developing thymocytes in FTOC, and coculture of progenitor cells with OP9-DL1 cells.","ja":"Fetal thymus organ culture (FTOC) is a unique and powerful culture system that allows intrathymic T-lymphocyte development in vitro. T-cell development in FTOC well represents fetal thymocyte development in vivo. Here we describe the basic method for FTOC as well as several related techniques, including reconstitution of thymus lobes with T-lymphoid progenitor cells, high-oxygen submersion culture, reaggregation thymus organ culture, retrovirus-mediated gene transfer to developing thymocytes in FTOC, and coculture of progenitor cells with OP9-DL1 cells."},"publication_date":"2013","publication_name":{"en":"Methods in Molecular Biology","ja":"Methods in Molecular Biology"},"volume":"Vol.946","starting_page":"85","ending_page":"102","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1007/978-1-62703-128-8_6"],"issn":["1940-6029"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:41, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458431"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/22425250","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=246341","label":"url"}],"paper_title":{"en":"Rank signaling links the development of invariant γδ T cell progenitors and Aire+ medullary epithelium.","ja":"Rank signaling links the development of invariant γδ T cell progenitors and Aire+ medullary epithelium."},"authors":{"en":[{"name":"Roberts NM"},{"name":"White AJ"},{"name":"Jenkinson WE"},{"name":"Turchinovich G"},{"name":"Nakamura K"},{"name":"Withers DR"},{"name":"McConnell FM"},{"name":"Desanti GE"},{"name":"Benezech C"},{"name":"Parnell SM"},{"name":"Cunningham AF"},{"name":"Paolino M"},{"name":"Penninger J"},{"name":"Simon K"},{"name":"Nitta T"},{"name":"Ohigashi Izumi"},{"name":"Takahama Yousuke"},{"name":"Caamano JH"},{"name":"Hayday AC"},{"name":"Lane PJ"},{"name":"Jenkinson EJ"},{"name":"Anderson G"}],"ja":[{"name":"Roberts NM"},{"name":"White AJ"},{"name":"Jenkinson WE"},{"name":"Turchinovich G"},{"name":"Nakamura K"},{"name":"Withers DR"},{"name":"McConnell FM"},{"name":"Desanti GE"},{"name":"Benezech C"},{"name":"Parnell SM"},{"name":"Cunningham AF"},{"name":"Paolino M"},{"name":"Penninger J"},{"name":"Simon K"},{"name":"Nitta T"},{"name":"大東 いずみ"},{"name":"高浜 洋介"},{"name":"Caamano JH"},{"name":"Hayday AC"},{"name":"Lane PJ"},{"name":"Jenkinson EJ"},{"name":"Anderson G"}]},"description":{"en":"The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.","ja":"The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation."},"publication_date":"2012-03-15","publication_name":{"en":"Immunity","ja":"Immunity"},"volume":"Vol.36","number":"No.3","starting_page":"427","ending_page":"437","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.immuni.2012.01.016"],"issn":["1097-4180"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:42, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458432"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21706487","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=232706","label":"url"}],"paper_title":{"en":"Effects of RANKL on the thymic medulla","ja":"Effects of RANKL on the thymic medulla"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Nitta Takeshi"},{"name":"Lkhagvasuren E"},{"name":"Yasuda H"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"新田 剛"},{"name":"Lkhagvasuren E"},{"name":"Yasuda H"},{"name":"高浜 洋介"}]},"description":{"en":"The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) contribute to the establishment of self-tolerance by the deletion of self-reactive T cells and the generation of regulatory T cells. The progression of thymocyte development critically regulates the optimum formation of the thymic medulla, as discussed in this article. Of note, it was recently identified that RANKL produced by positively selected thymocytes plays a major role in the thymocyte-mediated medulla formation. Indeed, transgenic expression of soluble RANKL increased the number of mTECs and enlarged the thymic medulla in mice. The effects of RANKL on the thymic medulla may be useful for the engineering of self-tolerance in T cells.","ja":"The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) contribute to the establishment of self-tolerance by the deletion of self-reactive T cells and the generation of regulatory T cells. The progression of thymocyte development critically regulates the optimum formation of the thymic medulla, as discussed in this article. Of note, it was recently identified that RANKL produced by positively selected thymocytes plays a major role in the thymocyte-mediated medulla formation. Indeed, transgenic expression of soluble RANKL increased the number of mTECs and enlarged the thymic medulla in mice. The effects of RANKL on the thymic medulla may be useful for the engineering of self-tolerance in T cells."},"publication_date":"2011-07","publication_name":{"en":"European Journal of Immunology","ja":"European Journal of Immunology"},"volume":"Vol.41","number":"No.7","starting_page":"1822","ending_page":"1827","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1002/eji.201141480"],"issn":["1521-4141"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:43, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21300913","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=224006","label":"url"}],"paper_title":{"en":"Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development","ja":"Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development"},"authors":{"en":[{"name":"Lei Yu"},{"name":"Ripen Mat Adiratna"},{"name":"Ishimaru Naozumi"},{"name":"Ohigashi Izumi"},{"name":"Nagasawa Takashi"},{"name":"Jeker T. Lukas"},{"name":"Bösl R. Michael"},{"name":"Holländer A. Georg"},{"name":"Hayashi Yoshio"},{"name":"Malefyt Waal de Rene"},{"name":"Nitta Takeshi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"Lei Yu"},{"name":"Ripen Mat Adiratna"},{"name":"石丸 直澄"},{"name":"大東 いずみ"},{"name":"Nagasawa Takashi"},{"name":"Jeker T. Lukas"},{"name":"Bösl R. Michael"},{"name":"Holländer A. Georg"},{"name":"林 良夫"},{"name":"Malefyt Waal de Rene"},{"name":"新田 剛"},{"name":"高浜 洋介"}]},"description":{"en":"Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire.","ja":"Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accumulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice. mTEC expression of XCL1, tDC medullary accumulation, and nT reg cell generation are diminished in Aire-deficient mice. These results indicate that the XCL1-mediated medullary accumulation of tDCs contributes to nT reg cell development and is regulated by Aire."},"publication_date":"2011-02-14","publication_name":{"en":"The Journal of Experimental Medicine","ja":"The Journal of Experimental Medicine"},"volume":"Vol.208","number":"No.2","starting_page":"383","ending_page":"394","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1084/jem.20102327"],"issn":["1540-9538"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:44, {"insert":{"user_id":"B000340639","type":"published_papers","id":"30458433"},"force":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21194915","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=232708","label":"url"}],"paper_title":{"en":"Cytokine crosstalk for thymic medulla formation","ja":"Cytokine crosstalk for thymic medulla formation"},"authors":{"en":[{"name":"Nitta Takeshi"},{"name":"Ohigashi Izumi"},{"name":"Nakagawa Yasushi"},{"name":"Takahama Yousuke"}],"ja":[{"name":"新田 剛"},{"name":"大東 いずみ"},{"name":"Nakagawa Yasushi"},{"name":"高浜 洋介"}]},"description":{"en":"The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. Recent studies have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL, CD40L, and lymphotoxin, produced by positively selected thymocytes and lymphoid tissue inducer cells promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance.","ja":"The medullary microenvironment of the thymus plays a crucial role in the establishment of self-tolerance through the deletion of self-reactive thymocytes and the generation of regulatory T cells. Crosstalk or bidirectional signal exchanges between developing thymocytes and medullary thymic epithelial cells (mTECs) contribute to the formation of the thymic medulla. Recent studies have identified the molecules that mediate thymic crosstalk. Tumor necrosis factor superfamily cytokines, including RANKL, CD40L, and lymphotoxin, produced by positively selected thymocytes and lymphoid tissue inducer cells promote the proliferation and differentiation of mTECs. In return, CCR7 ligand chemokines produced by mTECs facilitate the migration of positively selected thymocytes to the medulla. The cytokine crosstalk between developing thymocytes and mTECs nurtures the formation of the thymic medulla and thereby regulates the establishment of self-tolerance."},"publication_date":"2011","publication_name":{"en":"Current Opinion in Immunology","ja":"Current Opinion in Immunology"},"volume":"Vol.23","number":"No.2","starting_page":"190","ending_page":"197","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.coi.2010.12.002"],"issn":["1879-0372"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:45, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/21203507","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=224001","label":"url"}],"paper_title":{"en":"Identification of the Transgenic Integration Site in Immunodeficient tgϵ26 Human CD3ϵ Transgenic Mice","ja":"Identification of the Transgenic Integration Site in Immunodeficient tgϵ26 Human CD3ϵ Transgenic Mice"},"authors":{"en":[{"name":"Ohigashi Izumi"},{"name":"Yamasaki Yuki"},{"name":"Hirashima Tsukasa"},{"name":"Takahama Yousuke"}],"ja":[{"name":"大東 いずみ"},{"name":"Yamasaki Yuki"},{"name":"Hirashima Tsukasa"},{"name":"高浜 洋介"}]},"description":{"en":"A strain of human CD3ϵ transgenic mice, tgϵ26, exhibits severe immunodeficiency associated with early arrest of T cell development. Complete loss of T cells is observed in homozygous tgϵ26 mice, but not in heterozygotes, suggesting that genomic disruption due to transgenic integration may contribute to the arrest of T cell development. Here we report the identification of the transgenic integration site in tgϵ26 mice. We found that multiple copies of the human CD3ϵ transgene are inserted between the Sstr5 and Metrn loci on chromosome 17, and that this is accompanied by duplication of the neighboring genomic region spanning 323 kb. However, none of the genes in this region were abrogated. These results suggest that the severe immunodeficiency seen in tgϵ26 mice is not due to gene disruption resulting from transgenic integration.","ja":"A strain of human CD3ϵ transgenic mice, tgϵ26, exhibits severe immunodeficiency associated with early arrest of T cell development. Complete loss of T cells is observed in homozygous tgϵ26 mice, but not in heterozygotes, suggesting that genomic disruption due to transgenic integration may contribute to the arrest of T cell development. Here we report the identification of the transgenic integration site in tgϵ26 mice. We found that multiple copies of the human CD3ϵ transgene are inserted between the Sstr5 and Metrn loci on chromosome 17, and that this is accompanied by duplication of the neighboring genomic region spanning 323 kb. However, none of the genes in this region were abrogated. These results suggest that the severe immunodeficiency seen in tgϵ26 mice is not due to gene disruption resulting from transgenic integration."},"publication_date":"2010-12-22","publication_name":{"en":"PLoS ONE","ja":"PLoS ONE"},"volume":"Vol.5","number":"No.12","starting_page":"e14391","ending_page":"e14391","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1371/journal.pone.0014391"],"issn":["1932-6203"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:46, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/20211905","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=257217","label":"url"}],"paper_title":{"en":"Undiminished regulatory T cells in the thymus of myathenia gravis patients","ja":"Undiminished regulatory T cells in the thymus of myathenia gravis patients"},"authors":{"en":[{"name":"Matsui Naoko"},{"name":"Nakane Shunya"},{"name":"Saitou Fumi"},{"name":"Ohigashi Izumi"},{"name":"Nakagawa Yasushi"},{"name":"Kurobe Hirotsugu"},{"name":"Takizawa Hiromitsu"},{"name":"Mitsui Takao"},{"name":"Kondo Kazuya"},{"name":"Kitagawa Tetsuya"},{"name":"Takahama Yousuke"},{"name":"Kaji Ryuji"}],"ja":[{"name":"松井 尚子"},{"name":"中根 俊成"},{"name":"Saitou Fumi"},{"name":"大東 いずみ"},{"name":"中川 靖士"},{"name":"黒部 裕嗣"},{"name":"滝沢 宏光"},{"name":"三ツ井 貴夫"},{"name":"近藤 和也"},{"name":"北川 哲也"},{"name":"高浜 洋介"},{"name":"梶 龍兒"}]},"description":{"en":"The thymus has been implicated as a possible site of origin that triggers autoimmunity in myasthenia gravis (MG). Although several groups have suggested that the decrease in the number of regulatory T (Treg) cells contributes to the onset of MG, the exact role of Treg cells in MG remains unclear. To address this point, we examined the number and distribution of Treg cells in a large number of patients with MG. Immunohistofluorescence analysis of Foxp3 along with CD4 and CD8 was performed in thymic sections of MG (+) (n = 24) and MG (-) patients (n = 27). Circulating CD4(+)CD25(+) cells in the peripheral blood of patients with MG (n = 15) and age-matched healthy subjects (n = 15) were also analyzed. Foxp3(+)CD4(+)CD8(-) cells were predominantly found in the thymic medulla and their number declined with age. There was no significant difference in the number or the distribution of Foxp3(+)CD4(+)CD8(-) cells in the thymus between MG (+) and MG (-) patients. The number of circulating CD4(+)CD25(+) cells in the peripheral blood of patients with MG was not significantly altered compared to that in healthy subjects. The cellularity of Treg cells in the thymus and circulation is not diminished in patients with myasthenia gravis.","ja":"The thymus has been implicated as a possible site of origin that triggers autoimmunity in myasthenia gravis (MG). Although several groups have suggested that the decrease in the number of regulatory T (Treg) cells contributes to the onset of MG, the exact role of Treg cells in MG remains unclear. To address this point, we examined the number and distribution of Treg cells in a large number of patients with MG. Immunohistofluorescence analysis of Foxp3 along with CD4 and CD8 was performed in thymic sections of MG (+) (n = 24) and MG (-) patients (n = 27). Circulating CD4(+)CD25(+) cells in the peripheral blood of patients with MG (n = 15) and age-matched healthy subjects (n = 15) were also analyzed. Foxp3(+)CD4(+)CD8(-) cells were predominantly found in the thymic medulla and their number declined with age. There was no significant difference in the number or the distribution of Foxp3(+)CD4(+)CD8(-) cells in the thymus between MG (+) and MG (-) patients. The number of circulating CD4(+)CD25(+) cells in the peripheral blood of patients with MG was not significantly altered compared to that in healthy subjects. The cellularity of Treg cells in the thymus and circulation is not diminished in patients with myasthenia gravis."},"publication_date":"2010-03-09","publication_name":{"en":"Neurology","ja":"Neurology"},"volume":"Vol.74","number":"No.10","starting_page":"816","ending_page":"820","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1212/WNL.0b013e3181d31e47"],"issn":["1526-632X"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:47, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/19164599","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=207761","label":"url"}],"paper_title":{"en":"Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development","ja":"Gene expression profile of the third pharyngeal pouch reveals role of mesenchymal MafB in embryonic thymus development"},"authors":{"en":[{"name":"Sultana DA"},{"name":"Tomita Shuhei"},{"name":"Hamada M"},{"name":"Iwanaga Y"},{"name":"Kitahama Y"},{"name":"Khang NV"},{"name":"Hirai S"},{"name":"Ohigashi Izumi"},{"name":"Nitta S"},{"name":"Amagai T"},{"name":"Takahashi S"},{"name":"Takahama Yousuke"}],"ja":[{"name":"Sultana DA"},{"name":"冨田 修平"},{"name":"Hamada M"},{"name":"Iwanaga Y"},{"name":"Kitahama Y"},{"name":"Khang NV"},{"name":"Hirai S"},{"name":"大東 いずみ"},{"name":"Nitta S"},{"name":"Amagai T"},{"name":"Takahashi S"},{"name":"高浜 洋介"}]},"description":{"en":"The thymus provides a microenvironment that induces the differentiation of T-progenitor cells into functional T cells and that establishes a diverse yet self-tolerant T-cell repertoire. However, the mechanisms that lead to the development of the thymus are incompletely understood. We report herein the results of screening for genes that are expressed in the third pharyngeal pouch, which contains thymic primordium. Polymerase chain reaction (PCR)-based cDNA subtraction screening for genes expressed in microdissected tissues of the third pharyngeal pouch rather than the second pharyngeal arch yielded one transcription factor, MafB, which was predominantly expressed in CD45(-)IA(-)PDGFRalpha(+) mesenchymal cells and was detectable even in the third pharyngeal pouch of FoxN1-deficient nude mice. Interestingly, the number of CD45(+) cells that initially accumulated in the embryonic thymus was significantly decreased in MafB-deficient mice. Alterations of gene expression in the embryonic thymi of MafB-deficient mice included the reduced expression of Wnt3 and BMP4 in mesenchymal cells and of CCL21 and CCL25 in epithelial cells. These results suggest that MafB expressed in third pharyngeal pouch mesenchymal cells critically regulates lymphocyte accumulation in the embryonic thymus.","ja":"The thymus provides a microenvironment that induces the differentiation of T-progenitor cells into functional T cells and that establishes a diverse yet self-tolerant T-cell repertoire. However, the mechanisms that lead to the development of the thymus are incompletely understood. We report herein the results of screening for genes that are expressed in the third pharyngeal pouch, which contains thymic primordium. Polymerase chain reaction (PCR)-based cDNA subtraction screening for genes expressed in microdissected tissues of the third pharyngeal pouch rather than the second pharyngeal arch yielded one transcription factor, MafB, which was predominantly expressed in CD45(-)IA(-)PDGFRalpha(+) mesenchymal cells and was detectable even in the third pharyngeal pouch of FoxN1-deficient nude mice. Interestingly, the number of CD45(+) cells that initially accumulated in the embryonic thymus was significantly decreased in MafB-deficient mice. Alterations of gene expression in the embryonic thymi of MafB-deficient mice included the reduced expression of Wnt3 and BMP4 in mesenchymal cells and of CCL21 and CCL25 in epithelial cells. These results suggest that MafB expressed in third pharyngeal pouch mesenchymal cells critically regulates lymphocyte accumulation in the embryonic thymus."},"publication_date":"2009-03","publication_name":{"en":"Blood","ja":"Blood"},"volume":"Vol.113","number":"No.13","starting_page":"2976","ending_page":"2987","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1182/blood-2008-06-164921"],"issn":["1528-0020"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:48, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/18799150","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=185187","label":"url"}],"paper_title":{"en":"The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator.","ja":"The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator."},"authors":{"en":[{"name":"Hikosaka Yu"},{"name":"Nitta Takeshi"},{"name":"Ohigashi Izumi"},{"name":"Yano Kouta"},{"name":"Ishimaru Naozumi"},{"name":"Hayashi Yoshio"},{"name":"Matsumoto Mitsuru"},{"name":"Matsuo Koichi"},{"name":"Penninger M Josef"},{"name":"Takayanagi Hiroshi"},{"name":"Yokota Yoshifumi"},{"name":"Yamada Hisakata"},{"name":"Yoshikai Yasunobu"},{"name":"Inoue Jun-ichiro"},{"name":"Akiyama Taishin"},{"name":"Takahama Yousuke"}],"ja":[{"name":"Hikosaka Yu"},{"name":"新田 剛"},{"name":"大東 いずみ"},{"name":"Yano Kouta"},{"name":"石丸 直澄"},{"name":"林 良夫"},{"name":"松本 満"},{"name":"Matsuo Koichi"},{"name":"Penninger M Josef"},{"name":"Takayanagi Hiroshi"},{"name":"Yokota Yoshifumi"},{"name":"Yamada Hisakata"},{"name":"Yoshikai Yasunobu"},{"name":"Inoue Jun-ichiro"},{"name":"Akiyama Taishin"},{"name":"高浜 洋介"}]},"description":{"en":"The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishing central tolerance.","ja":"The thymic medulla provides a microenvironment where medullary thymic epithelial cells (mTECs) express autoimmune regulator and diverse tissue-restricted genes, contributing to launching self-tolerance. Positive selection is essential for thymic medulla formation via a previously unknown mechanism. Here we show that the cytokine RANK ligand (RANKL) was produced by positively selected thymocytes and regulated the cellularity of mTEC by interacting with RANK and osteoprotegerin. Forced expression of RANKL restored thymic medulla in mice lacking positive selection, whereas RANKL perturbation impaired medulla formation. These results indicate that RANKL produced by positively selected thymocytes is responsible for fostering thymic medulla formation, thereby establishing central tolerance."},"publication_date":"2008-09-19","publication_name":{"en":"Immunity","ja":"Immunity"},"volume":"Vol.29","number":"No.3","starting_page":"438","ending_page":"450","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.immuni.2008.06.018"],"issn":["1097-4180"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:49, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/16509771","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=185198","label":"url"}],"paper_title":{"en":"IAN family critically regulates survival and development of T lymphocytes","ja":"IAN family critically regulates survival and development of T lymphocytes"},"authors":{"en":[{"name":"Nitta Takeshi"},{"name":"Nasreen Mariam"},{"name":"Seike Takafumi"},{"name":"Goji Atsushi"},{"name":"Ohigashi Izumi"},{"name":"Miyazaki Tadaaki"},{"name":"Ohta Tsutomu"},{"name":"Kanno Masamoto"},{"name":"Takahama Yousuke"}],"ja":[{"name":"新田 剛"},{"name":"Nasreen Mariam"},{"name":"Seike Takafumi"},{"name":"Goji Atsushi"},{"name":"大東 いずみ"},{"name":"Miyazaki Tadaaki"},{"name":"Ohta Tsutomu"},{"name":"Kanno Masamoto"},{"name":"高浜 洋介"}]},"description":{"en":"The IAN (immune-associated nucleotide-binding protein) family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins.","ja":"The IAN (immune-associated nucleotide-binding protein) family is a family of functionally uncharacterized GTP-binding proteins expressed in vertebrate immune cells and in plant cells during antibacterial responses. Here we show that all eight IAN family genes encoded in a single cluster of mouse genome are predominantly expressed in lymphocytes, and that the expression of IAN1, IAN4, and IAN5 is significantly elevated upon thymic selection of T lymphocytes. Gain-of-function experiments show that the premature overexpression of IAN1 kills immature thymocytes, whereas short hairpin RNA-mediated loss-of-function studies show that IAN4 supports positive selection. The knockdown of IAN5 perturbs the optimal generation of CD4/CD8 double-positive thymocytes and reduces the survival of mature T lymphocytes. We also show evidence suggesting that IAN4 and IAN5 are associated with anti-apoptotic proteins Bcl-2 and Bcl-xL, whereas IAN1 is associated with pro-apoptotic Bax. Thus, the IAN family is a novel family of T cell-receptor-responsive proteins that critically regulate thymic development and survival of T lymphocytes and that potentially exert regulatory functions through the association with Bcl-2 family proteins."},"publication_date":"2006-03-07","publication_name":{"en":"PLoS Biology","ja":"PLoS Biology"},"volume":"Vol.4","number":"No.4","starting_page":"e103","ending_page":"e115","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1371/journal.pbio.0040103"],"issn":["1545-7885"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
line:50, {"insert":{"user_id":"B000340639","type":"published_papers"},"similar_merge":{"see_also":[{"@id":"https://repo.lib.tokushima-u.ac.jp/ja/112035","label":"url"},{"@id":"https://www.ncbi.nlm.nih.gov/pubmed/15094191","label":"url"},{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=88061","label":"url"}],"paper_title":{"en":"Differentiation Penotypes of Pancreatic Islet β- and α-cells are Closely Related with Homeotic Genes and a Group of Differentially Expressed Genes.","ja":"Differentiation Penotypes of Pancreatic Islet β- and α-cells are Closely Related with Homeotic Genes and a Group of Differentially Expressed Genes."},"authors":{"en":[{"name":"Mizusawa Noriko"},{"name":"Hasegawa, Tomoko"},{"name":"Ohigashi Izumi"},{"name":"Kosugi Chisato"},{"name":"Harada Nagakatsu"},{"name":"Itakura Mitsuo"},{"name":"Yoshimoto Katsuhiko"}],"ja":[{"name":"水澤 典子"},{"name":"長谷川 朋子"},{"name":"大東 いずみ"},{"name":"小杉 知里"},{"name":"原田 永勝"},{"name":"板倉 光夫"},{"name":"吉本 勝彦"}]},"description":{"en":"To identify the genes that determine differentiation phenotypes, we compared gene expression of pancreatic islet beta- and alpha-cells, which are derived from the common precursor and secrete insulin and glucagon, respectively. The expression levels of homeotic genes including Hox genes known to determine region specificity in the antero-posterior (AP) body axis, tissue-specific homeobox genes, and other 8,734 genes were compared in a beta- and alpha-cell line of MIN6 and alpha TC1.6. The expression of homeotic genes were surveyed with reverse transcription-polymerase chain reaction (RT-PCR) using degenerate primers corresponding to invariant amino acid sequences within the homeodomain and subsequently with specific primers. Expression of Hoxc6, Hoxc9, Hoxc10, Pdx1, Cdx2, Gbx2, Pax4, and Hlxb9 genes in MIN6 was higher than those in alpha TC1.6, while expression of Hoxa2, Hoxa3, Hoxa5, Hoxa6, Hoxa7, Hoxa9, Hoxa10, Hoxa13, Hoxb3, Hoxb5, Hoxb6, Hoxb13, Hoxb8, and Brain4 genes in alpha TC1.6 was higher than those in MIN6. Out of 8,734 mouse genes screened with high-density mouse cDNA microarrays for MIN6- and alpha TC1.6-derived cDNA, 58 and 25 genes were differentially over- and under-expressed in MIN6, respectively. GLUTag, which is derived from a large bowel tumor and expresses the proglucagon gene, showed a comparatively similar expression profile to that of alpha TC1.6 in both homeotic and other genes analyzed in cDNA microarray. Our results are consistent with the interpretation that not only the tissue-specific homeotic genes, but also Hox genes are related to differentiation phenotypes of pancreatic beta- and alpha-cells rather than their regional specification of the body in vertebrates.","ja":"To identify the genes that determine differentiation phenotypes, we compared gene expression of pancreatic islet beta- and alpha-cells, which are derived from the common precursor and secrete insulin and glucagon, respectively. The expression levels of homeotic genes including Hox genes known to determine region specificity in the antero-posterior (AP) body axis, tissue-specific homeobox genes, and other 8,734 genes were compared in a beta- and alpha-cell line of MIN6 and alpha TC1.6. The expression of homeotic genes were surveyed with reverse transcription-polymerase chain reaction (RT-PCR) using degenerate primers corresponding to invariant amino acid sequences within the homeodomain and subsequently with specific primers. Expression of Hoxc6, Hoxc9, Hoxc10, Pdx1, Cdx2, Gbx2, Pax4, and Hlxb9 genes in MIN6 was higher than those in alpha TC1.6, while expression of Hoxa2, Hoxa3, Hoxa5, Hoxa6, Hoxa7, Hoxa9, Hoxa10, Hoxa13, Hoxb3, Hoxb5, Hoxb6, Hoxb13, Hoxb8, and Brain4 genes in alpha TC1.6 was higher than those in MIN6. Out of 8,734 mouse genes screened with high-density mouse cDNA microarrays for MIN6- and alpha TC1.6-derived cDNA, 58 and 25 genes were differentially over- and under-expressed in MIN6, respectively. GLUTag, which is derived from a large bowel tumor and expresses the proglucagon gene, showed a comparatively similar expression profile to that of alpha TC1.6 in both homeotic and other genes analyzed in cDNA microarray. Our results are consistent with the interpretation that not only the tissue-specific homeotic genes, but also Hox genes are related to differentiation phenotypes of pancreatic beta- and alpha-cells rather than their regional specification of the body in vertebrates."},"publication_date":"2004-04-28","publication_name":{"en":"Gene","ja":"Gene"},"volume":"Vol.331","number":"No.28","starting_page":"53","ending_page":"63","languages":["eng"],"referee":true,"identifiers":{"doi":["10.1016/j.gene.2004.01.016"],"issn":["0378-1119"]},"published_paper_type":"scientific_journal"},"priority":"input_data"}
==== end registerFile(/WWW/pub2/data/ERD/person/207340/researchmap/published_papers.jsonl, aMEv-I4B7kacV6CWi_a6) ====
==== begin registerFile(/WWW/pub2/data/ERD/person/207340/researchmap/misc.jsonl) ====
line:1, {"insert":{"user_id":"B000340639","type":"misc","id":"46003230"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=406017","label":"url"}],"paper_title":{"en":"Diversity and differentiation pathways of medullary thymic epithelial cells","ja":"胸腺髄質上皮細胞の多様性と分化経路"},"authors":{"en":[{"name":"Fujimori Sayumi"},{"name":"Ohigashi Izumi"}],"ja":[{"name":"藤森 さゆ美"},{"name":"大東 いずみ"}]},"publication_date":"2024-04","publication_name":{"en":"Clinical Immunology & Allergology","ja":"臨床免疫·アレルギー科"},"volume":"Vol.81","number":"No.4","languages":["jpn"],"identifiers":{"issn":["1881-1930"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
line:2, {"insert":{"user_id":"B000340639","type":"misc","id":"45943532"},"force":{"see_also":[{"@id":"https://web.db.tokushima-u.ac.jp/cgi-bin/edb_browse?EID=405845","label":"url"}],"paper_title":{"en":"The role of thymic epithelium in thymus development and age-related thymic involution","ja":"The role of thymic epithelium in thymus development and age-related thymic involution"},"authors":{"en":[{"name":"Fujimori Sayumi"},{"name":"Ohigashi Izumi"}],"ja":[{"name":"藤森 さゆ美"},{"name":"大東 いずみ"}]},"publication_date":"2024-02-26","publication_name":{"en":"The Journal of Medical Investigation : JMI","ja":"The Journal of Medical Investigation : JMI"},"volume":"Vol.71","number":"No.1,2","starting_page":"29","ending_page":"39","languages":["eng"],"identifiers":{"issn":["1343-1420"]},"misc_type":"introduction_scientific_journal"},"priority":"input_data"}
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