徳島大学 / 教育研究者総覧 --- 藤森さゆ美

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徳島大学 ⟩ 先端酵素学研究所 ⟩ 重点研究部門 ⟩
徳島大学 ⟩ 先端酵素学研究所 ⟩

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○	ライフサイエンス (Life sciences) [免疫学 (Immunology)]

研究テーマ

著書・論文

学術論文(審査論文):

1.	Izumi Ohigashi, Andrea White, Mei-Ting Yang, Sayumi Fujimori, Yu Tanaka, Alison Jacques, Hiroshi Kiyonari, Yosuke Matsushita, Sevilay Turan, Michael Kelly, Graham Anderson and Yousuke Takahama : Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in embryonic thymus medulla epithelium., eLife, Vol.12, RP92552, 2024. (要約) 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. (徳島大学機関リポジトリ) ● Metadata: 119092 (出版サイトへのリンク) ● Publication site (DOI): 10.7554/eLife.92552 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38466627 ● CiNii @ 国立情報学研究所 (CRID): 1360581940738928512 ● Summary page in Scopus @ Elsevier: 2-s2.0-85187799485 (徳島大学機関リポジトリ: 119092, DOI: 10.7554/eLife.92552, PubMed: 38466627, CiNii: 1360581940738928512, Elsevier: Scopus)
2.	Sayumi Fujimori, Izumi Ohigashi, Hayato Abe, Yosuke Matsushita, Toyomasa Katagiri, Taketo M. Makoto, Takahama Yousuke and Takada Shinji : Fine-tuning of β-catenin in mouse thymic epithelial cells is required for postnatal T-cell development, eLife, Vol.11, e69088, 2022. (要約) 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. (キーワード) Animals / Epithelial Cells / Female / Mice / T-Lymphocytes / Thymus Gland / beta Catenin (徳島大学機関リポジトリ) ● Metadata: 116664 (出版サイトへのリンク) ● Publication site (DOI): 10.7554/eLife.69088 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35042581 ● Search Scopus @ Elsevier (PMID): 35042581 ● Search Scopus @ Elsevier (DOI): 10.7554/eLife.69088 (徳島大学機関リポジトリ: 116664, DOI: 10.7554/eLife.69088, PubMed: 35042581)
3.	Izumi Ohigashi, Melina Frantzeskakis, Alison Jacques, Sayumi Fujimori, Aya Ushio, Fusano Yamashita, Naozumi Ishimaru, Da Yin, Margaret Cam, C Michael Kelly, Parirokh Awasthi, Kensuke Takada and Yousuke Takahama : The thymoproteasome hardwires the TCR repertoire of CD8+ T cells in the cortex independent of negative selection., The Journal of Experimental Medicine, Vol.218, No.4, 2021. (要約) 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. (徳島大学機関リポジトリ) ● Metadata: 116455 (出版サイトへのリンク) ● Publication site (DOI): 10.1084/jem.20201904 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33555295 ● Search Scopus @ Elsevier (PMID): 33555295 ● Search Scopus @ Elsevier (DOI): 10.1084/jem.20201904 (徳島大学機関リポジトリ: 116455, DOI: 10.1084/jem.20201904, PubMed: 33555295)
4.	Izumi Ohigashi, Yu Tanaka, Kenta Kondou, Sayumi Fujimori, Hiroyuki Kondo, Amy Palin, Victoria Hoffmann, Mina Kozai, Yosuke Matsushita, Shinsuke Uda, Ryo Motosugi, Jun Hamazaki, Hiroyuki Kubota, Shigeo Murata, Keiji Tanaka, Toyomasa Katagiri, Hidetaka Kosako and Yousuke Takahama : Trans-omics Impact of Thymoproteasome in Cortical Thymic Epithelial Cells., Cell Reports, Vol.29, No.9, 2901-2916.e6, 2019. (徳島大学機関リポジトリ) ● Metadata: 115049 (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.celrep.2019.10.079 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31775054 ● Search Scopus @ Elsevier (PMID): 31775054 ● Search Scopus @ Elsevier (DOI): 10.1016/j.celrep.2019.10.079 (徳島大学機関リポジトリ: 115049, DOI: 10.1016/j.celrep.2019.10.079, PubMed: 31775054)
5.	Shahina Umme Khanom, Izumi Ohigashi, Sayumi Fujimori, Kenta Kondou, Kensuke Takada and Yousuke Takahama : TCR affinity for in vivo peptide-induced thymic positive selection fine-tunes TCR responsiveness of peripheral CD8⁺ T cells, The Journal of Immunology, Vol.203, No.4, 881-887, 2019. (要約) 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. (徳島大学機関リポジトリ) ● Metadata: 113696 (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.1900097 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31235550 ● Summary page in Scopus @ Elsevier: 2-s2.0-85070388863 (徳島大学機関リポジトリ: 113696, DOI: 10.4049/jimmunol.1900097, PubMed: 31235550, Elsevier: Scopus)
6.	Masayuki Furuya, Junichi Kikuta, Sayumi Fujimori, Shigeto Seno, Hiroki Maeda, Mai Shirazaki, Maki Uenaka, Hiroki Mizuno, Yoriko Iwamoto, Akito Morimoto, Kunihiko Hashimoto, Takeshi Ito, Yukihiro Isogai, Masafumi Kashii, Takashi Kaito, Shinsuke Ohba, Ung-Il Chung, Alexander C. Lichtler, Kazuya Kikuchi, Hideo Matsuda, Hideki Yoshikawa and Masaru Ishii : Direct cell-cell contact between mature osteoblasts and osteoclasts dynamically controls their functions in vivo., Nature Communications, Vol.9, No.1, 300, 2018. (要約) Bone homeostasis is regulated by communication between bone-forming mature osteoblasts (mOBs) and bone-resorptive mature osteoclasts (mOCs). However, the spatial-temporal relationship and mode of interaction in vivo remain elusive. Here we show, by using an intravital imaging technique, that mOB and mOC functions are regulated via direct cell-cell contact between these cell types. The mOBs and mOCs mainly occupy discrete territories in the steady state, although direct cell-cell contact is detected in spatiotemporally limited areas. In addition, a pH-sensing fluorescence probe reveals that mOCs secrete protons for bone resorption when they are not in contact with mOBs, whereas mOCs contacting mOBs are non-resorptive, suggesting that mOBs can inhibit bone resorption by direct contact. Intermittent administration of parathyroid hormone causes bone anabolic effects, which lead to a mixed distribution of mOBs and mOCs, and increase cell-cell contact. This study reveals spatiotemporal intercellular interactions between mOBs and mOCs affecting bone homeostasis in vivo. (キーワード) Animals / Bone Resorption / Cell Communication / Cell Differentiation / Female / Fluorescent Dyes / Gene Expression / Genes, Reporter / Green Fluorescent Proteins / Homeostasis / Hydrogen-Ion Concentration / Intravital Microscopy / Mice / Mice, Inbred C57BL / Mice, Transgenic / Osteoblasts / Osteoclasts / Osteogenesis / Parathyroid Hormone / Primary Cell Culture / Skull (徳島大学機関リポジトリ) ● Metadata: 114781 (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41467-017-02541-w (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29352112 ● Search Scopus @ Elsevier (PMID): 29352112 ● Search Scopus @ Elsevier (DOI): 10.1038/s41467-017-02541-w (徳島大学機関リポジトリ: 114781, DOI: 10.1038/s41467-017-02541-w, PubMed: 29352112)

総説・解説:

1.	藤森さゆ美, 大東いずみ : 胸腺髄質上皮細胞の多様性と分化経路, 臨床免疫·アレルギー科, Vol.81, No.4, 385-390, 2024年4月.
2.	Sayumi Fujimori and Izumi Ohigashi : The role of thymic epithelium in thymus development and age-related thymic involution., The Journal of Medical Investigation : JMI, Vol.71, No.1.2, 29-39, 2024. (要約) The establishment of an adaptive immune system is critical for protecting our bodies from neoplastic cancers and invading pathogens such as viruses and bacteria. As a primary lymphoid organ, the thymus generates lymphoid T cells that play a major role in the adaptive immune system. T cell generation in the thymus is controlled by interactions between thymocytes and other thymic cells, primarily thymic epithelial cells. Thus, the normal development and function of thymic epithelial cells are important for the generation of immunocompetent and self-tolerant T cells. On the other hand, the degeneration of the thymic epithelium due to thymic aging causes thymic involution, which is associated with the decline of adaptive immune function. Herein we summarize basic and current knowledge of the development and function of thymic epithelial cells and the mechanism of thymic involution. J. Med. Invest. 71 : 29-39, February, 2024. (キーワード) Thymus Gland / Humans / Aging / Animals / Epithelial Cells / Epithelium / T-Lymphocytes (徳島大学機関リポジトリ) ● Metadata: 119192 (出版サイトへのリンク) ● Publication site (DOI): 10.2152/jmi.71.29 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 38735722 ● Search Scopus @ Elsevier (PMID): 38735722 ● Search Scopus @ Elsevier (DOI): 10.2152/jmi.71.29 (徳島大学機関リポジトリ: 119192, DOI: 10.2152/jmi.71.29, PubMed: 38735722)
3.	藤森さゆ美, 大東いずみ : 胸腺上皮細胞の動態:胎生期での発生，成体での維持，加齢に伴う退縮, 炎症と免疫, Vol.29, No.6, 491-495, 2021年10月. (要約) 胸腺上皮細胞は，非自己に応答し，自己に寛容なT細胞レパトア形成をになう胸腺微小環境を構築する主要な細胞である．胸腺上皮細胞は，それぞれ皮質と髄質の微小環境を構成する胸腺皮質上皮細胞と胸腺髄質上皮細胞に分類され，これらの上皮細胞は，胎生期に，内胚葉由来の上皮共通前駆細胞から分化する．近年，胸腺上皮細胞の分化と維持，および，胸腺退縮における胸腺上皮細胞の変化について，そのメカニズムが明らかにされつつある．そこで本稿では，これらの胸腺上皮細胞の動態について，最新の知見を紹介する． (キーワード) 胸腺上皮細胞 / 胸腺退縮 / β5t (徳島大学機関リポジトリ) ● Metadata: 116705 (文献検索サイトへのリンク) ● CiNii @ 国立情報学研究所 (CRID): 1520294440710757504 (徳島大学機関リポジトリ: 116705, CiNii: 1520294440710757504)

国際会議:

1.	Sayumi Fujimori, Shinji Takada, Yousuke Takahama and Izumi Ohigashi : Role of β-catenin in mouse thymic epithelial cells for postnatal thymic development, The 18th International Symposium of the Institute Network for Biomedical Sciences, Oct. 2023.
2.	Sayumi Fujimori, Shinji Takada, Yousuke Takahama and Izumi Ohigashi : Role of β-catenin in thymic epithelial cells for postnatal thymic development and involution, ThymOz International Conference on T Cells: ThymOz 2023, Mar. 2023.
3.	Izumi Ohigashi, White J. Andrea, Yang Mei-Ting, Sayumi Fujimori, Anderson Graham and Yousuke Takahama : Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in thymus medulla epithelium, ThymOz International Conference on T Cells: ThymOz 2023, Mar. 2023.
4.	Sayumi Fujimori, Izumi Ohigashi, Takahama Yousuke and Takada Shinji : β-catenin in mouse thymic epithelial cells fine-tunes postnatal T-cell production, EMBO Workshop co-supported by The Company of Biologists and Yamada Science Foundation: Wnt 2022, Nov. 2022.
5.	Sayumi Fujimori, Izumi Ohigashi, Takahama Yousuke and Takada Shinji : Role of β-catenin in thymic epithelial progenies of β5t positive progenitors, ThymE: T cell and thymus biology, May 2019.
6.	Izumi Ohigashi, Yu Tanaka, Kenta Kondou, Sayumi Fujimori, Amy C. Palin, Hiroyuki Kondo, Hidetaka Kosako and Yousuke Takahama : Trans-omics impact of thymoproteasome in cortical thymic epithelial cells, ThymE: T cell and thymus biology, May 2019.
7.	Sayumi Fujimori, Izumi Ohigashi, Tatsuya Takemoto, Yousuke Takahama and Takada Shinji : Activation of Wnt/β-catenin signaling in thymic epithelial progenitors, 7th International Workshop of Kyoto T Cell Conference, Kyoto, Mar. 2017.

国内講演発表:

1.	大東いずみ, White J. Andrea, Yang Mei-Ting, 藤森さゆ美, Anderson Graham, 高浜洋介 : ケモカインCCL21を発現する胎仔期の胸腺髄質上皮細胞は自己抗原発現髄質上皮細胞への分化活性を有する, 第46回日本分子生物学会年会, 2023年12月.
2.	藤森さゆ美 : 出生後のT細胞産生を制御する胸腺上皮細胞におけるbeta-cateninの役割, 第46回日本分子生物学会年会, 2023年12月.
3.	大東いずみ, J. Andrea White, Mei-Ting Yang, 藤森さゆ美, Grahama Anderson, 高浜洋介 : ケモカインCCL21を発現する胸腺髄質上皮細胞は自己抗原発現髄質上皮細胞への分化活性を有する, 第32回 Kyoto T Cell Conference, 2023年6月.
4.	藤森さゆ美, 大東いずみ, 高浜洋介, 高田慎治 : 出生後マウスのT細胞産生には，胸腺上皮細胞におけるβ-catenin依存性経路の精緻な制御が必要である, 第45回日本分子生物学会年会, 2022年11月.
5.	藤森さゆ美, 高浜洋介, 高田慎治, 大東いずみ : 出生後T細胞の産生における胸腺上皮細胞のβ-cateninの役割, 第31回Kyoto T Cell Conference(KTCC), 2022年5月.
6.	藤森さゆ美, 大東いずみ, 高浜洋介, 高田慎治 : マウス胸腺上皮細胞の分化にはβ-catenin依存性経路の精緻な制御が必要である, 第42回日本分子生物学会年会, 2019年12月.
7.	Sayumi Fujimori, Izumi Ohigashi, Takada Shinji and Yousuke Takahama : Enforced activation of β-catenin signaling in mouse thymic epithelial cells induces thymic dysplasia, The 41st Annual Meeting of the Molecular Biology Society of Japan, Nov. 2018.
8.	藤森さゆ美, 大東いずみ, 竹本龍也, 高田慎治, 高浜洋介 : マウス胸腺皮質上皮細胞亜集団におけるWnt/β-cateninシグナル経路の活性化, 第40回日本分子生物学会年会, 2017年12月.
9.	藤森さゆ美, 大東いずみ, 竹本龍也, 高浜洋介, 高田慎治 : マウス胸腺上皮細胞におけるWnt/β-cateninシグナル経路の時空間的活性化, 第39回日本分子生物学会年会, 2016年12月.

その他・研究会:

1.	藤森さゆ美 : Fine-tuning of β-catenin expression level in thymic epithelial cells is required for thymic development, Wnt研究会, 2021年1月.
2.	藤森さゆ美, 大東いずみ, 高田慎治, 高浜洋介 : 胸腺上皮細胞特異的なWnt/β-cateninシグナル経路活性制御の影響, 第18回四国免疫フォーラム, 2019年6月.

科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

マウス胸腺微小環境を構成するWntシグナル活性化細胞の動態と機能の解析 (研究課題/領域番号: 17K15740 )
光変換型タンパク質を利用した生体イメージングによる骨代謝制御因子の同定 (研究課題/領域番号: 25670109 )
リンパ器官形成の分子機構と制御 (研究課題/領域番号: 24111002 )
生体イメージングによる骨代謝制御のダイナミクス解析法の開発 (研究課題/領域番号: 23790248 )
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