徳島大学 / 教育研究者総覧 --- 森本純子

専門分野

研究テーマ

著書・論文

著書:

1.	森本純子, 宮澤龍一郎, 松本穣, 松本満 : 胸腺上皮細胞を対象とする自己免疫疾患への橋渡し研究の可能性, 北隆館 Precision Medicine 第3巻第12号, 東京, 2020年10月.
2.	森本純子, 宮澤龍一郎, 松本穣, 松本満 : 自己免疫疾患(別冊 BIO Clinica 慢性炎症と疾患通巻24号第9巻第1巻), --- Aireを基軸とする自己免疫疾患の病態解明 ---, 北隆館, 東京, 2020年7月.

学術論文(審査論文):

1.	Junko Morimoto, Minoru Matsumoto, Takeshi Oya, Koichi Tsuneyama and Mitsuru Matsumoto : Cooperative but Distinct Role of Medullary Thymic Epithelial Cells and Dendritic Cells in the Production of Regulatory T Cells in the Thymus., The Journal of Immunology, 2023. (要約) Regulatory T cells (Tregs) are produced in the thymus to establish self-tolerance, and agonistic stimuli by self-Ags play a pivotal role in this process. Although two types of APCs, medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), are responsible for presenting self-Ags together with costimulatory/cytokine signals, the distinct role of each APC in producing Tregs remains enigmatic. We have approached this issue by depleting the mTECs and DCs using mice expressing diphtheria toxin receptors driven by Aire and CD11c promoters, respectively. Depletion of mTECs showed an effect on Treg production quantitatively and qualitatively more profound than that of DCs followed by the development of distinct organ-specific autoimmune lesions in the hosts. Because self-Ags produced by mTECs are transferable to DCs through a process known as Ag transfer, we monitored the process of Ag transfer using mice expressing GFP from TECs. Although GFP expressed from total TECs was effectively transferred to DCs, GFP expressed from cortical TECs was not, suggesting that mTECs are the predominant source of self-Ags. We also found that GFP expressed not only from mature mTECs but also from immature mTECs was transferred to DCs, suggesting that a broad spectrum of molecules were subjected to Ag transfer during mTEC development. Interestingly, the numbers of recirculating non-Tregs producing IL-2, an important source for Treg expansion in the thymus, were reduced only in the mTEC-depleted mice. These results suggested the cooperative but distinct role of mTECs and DCs in the production of Tregs to avoid autoimmunity. (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.2200780 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37067332 ● CiNii @ 国立情報学研究所 (CRID): 1360298757409567232 ● Search Scopus @ Elsevier (PMID): 37067332 ● Search Scopus @ Elsevier (DOI): 10.4049/jimmunol.2200780 (DOI: 10.4049/jimmunol.2200780, PubMed: 37067332, CiNii: 1360298757409567232)
2.	Ryuichiro Miyazawa, Jun-Ichi Nagao, Ken-Ichi Arita-Morioka, Minoru Matsumoto, Junko Morimoto, Yoshida Masaki, Takeshi Oya, Koichi Tsuneyama, Hedeyuki Yoshida, Yoshihiko Tanaka and Mitsuru Matsumoto : Dispensable Role of Aire in CD11c+ Conventional Dendritic Cells for Antigen Presentation and Shaping the Transcriptome., ImmunoHorizons, Vol.7, No.1, 140-158, 2023. (要約) Aire, the defect of which is responsible for the development of autoimmunity, is predominantly expressed in medullary thymic epithelial cells, and it controls a wide variety of genes, including those of tissue-restricted Ags, for establishing thymic tolerance. Aire is also expressed from APCs in the periphery, called extrathymic Aire-expressing cells (eTACs), and their complementing role to thymic tolerance has been suggested. eTACs are composed of two distinct classes of APCs, conventional dendritic cell (cDC)-type and group 3 innate lymphoid cell (ILC3)-like-type expressing retinoic acid receptor-related orphan receptor γt (RORγt). Although the essential role of Aire in the latter in the Th17-mediated immune response against Candida albicans has been reported, the role of Aire in the cDC-type eTACs for this action has not been examined. Furthermore, the significance of Aire in the production of the transcriptome of the cDC-type eTACs remains unknown. We have approached these issues using a high-fidelity Aire-reporter mouse strain. We found that although the cDC-type eTACs dominated ILC3-like-type eTACs in number and they served as efficient APCs for the immune response against an exogenous Ag as well as for the C. albicans-specific Th17 immune response, loss of Aire in cDC-type eTACs showed no clear effect on these functions. Furthermore, loss of Aire showed no major impact on the transcriptome from cDC-type eTACs. These results suggested that Aire in cDC-type eTACs may not have a cell-intrinsic role in the immune response in contrast to the role of Aire in ILC3-like-type eTACs. (徳島大学機関リポジトリ) ● Metadata: 118793 (出版サイトへのリンク) ● Publication site (DOI): 10.4049/immunohorizons.2200103 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.4049/immunohorizons.2200103 (徳島大学機関リポジトリ: 118793, DOI: 10.4049/immunohorizons.2200103)
3.	Hitoshi Nishijima, Mizuki Sugita, Natsuka Umezawa, Naoki Kimura, Hirokazu Sasaki, Hiroshi Kawano, Yasuhiko Nishioka, Minoru Matsumoto, Takeshi Oya, Koichi Tsuneyama, Junko Morimoto and Mitsuru Matsumoto : Development of organ-specific autoimmunity by dysregulated Aire expression., Immunology and Cell Biology, Vol.100, No.5, 371-377, 2022. (要約) Deficiency for AIRE/Aire in both humans and mice results in the development of organ-specific autoimmune disease. We tested whether augmented and/or dysregulated AIRE/Aire expression might be also prone to the breakdown of self-tolerance. To define the effect of augmented Aire expression on the development of autoimmunity, antigen-specific clonal deletion and production of clonotypic regulatory T cells (Tregs) in the thymus were examined using mice expressing two additional copies of Aire in a heterozygous state (3xAire-knockin mice: 3xAire-KI). We found that both clonal deletion of autoreactive T cells and production of clonotypic Tregs in the thymus from 3xAire-KI were impaired in a T-cell receptor-transgenic system. Furthermore, 3xAire-KI females showed higher scores of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein than wild-type littermates, suggesting that augmented Aire expression exacerbates organ-specific autoimmunity under disease-prone conditions. In humans, we found that one patient with amyopathic dermatomyositis showed CD3 (キーワード) Animals / 自己免疫 (autoimmunity) / Clonal Deletion / Encephalomyelitis, Autoimmune, Experimental / 女性 (female) / Humans / Immune Tolerance / Mice / Myelin-Oligodendrocyte Glycoprotein / Thymus Gland (徳島大学機関リポジトリ) ● Metadata: 117817 (出版サイトへのリンク) ● Publication site (DOI): 10.1111/imcb.12546 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35313042 ● Search Scopus @ Elsevier (PMID): 35313042 ● Search Scopus @ Elsevier (DOI): 10.1111/imcb.12546 (徳島大学機関リポジトリ: 117817, DOI: 10.1111/imcb.12546, PubMed: 35313042)
4.	Junko Morimoto, Minoru Matsumoto, Ryuichiro Miyazawa, Takeshi Oya, Koichi Tsuneyama and Mitsuru Matsumoto : No Major Impact of Two Homologous Proteins Ly6C1 and Ly6C2 on Immune Homeostasis., ImmunoHorizons, Vol.6, No.3, 202-210, 2022. (要約) Ly6C comprises two homologous components of Ly6C1 and Ly6C2, and the expression of either of the Ly6C molecules defines unique functional subsets of monocytes. Ly6C is also expressed by other immune cell types, including Aire-expressing medullary thymic epithelial cells. Because the role of Ly6C expression in determining the functional subsets remains unclear, we generated mice deficient for both Ly6C1 and Ly6C2 with CRISPR-Cas9mediated deletion. Mice deficient for Ly6C1/Ly6C2 showed no major alterations in the subsets and function of monocyte and other immune cells, including the cells involved in the dextran sulfate sodium saltinduced colitis model. By generating the mice deficient for Ly6C1 alone, we have also investigated the expression pattern of Ly6C1 and Ly6C2 in immune cells. Except for medullary thymic epithelial cells and CD4 single-positive T cells, immune cells predominantly expressed Ly6C2. Thus, despite the importance as a marker with a unique differential expression pattern, the Ly6C molecules have no major impact on determining the functional subsets and maintaining immune homeostasis. (徳島大学機関リポジトリ) ● Metadata: 117315 (出版サイトへのリンク) ● Publication site (DOI): 10.4049/immunohorizons.2100114 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.4049/immunohorizons.2100114 (徳島大学機関リポジトリ: 117315, DOI: 10.4049/immunohorizons.2100114)
5.	Junko Morimoto, Minoru Matsumoto, Ryuichiro Miyazawa, Hideyuki Yoshida, Koichi Tsuneyama and Mitsuru Matsumoto : Aire suppresses CTLA-4 expression from the thymic stroma to control autoimmunity., Cell Reports, Vol.38, No.7, 110384, 2022. (要約) Impaired production of thymic regulatory T cells (Tregs) is implicated in the development of Aire-dependent autoimmunity. Because Tregs require agonistic T cell receptor stimuli by self-antigens to develop, reduced expression of self-antigens from medullary thymic epithelial cells (mTECs) has been considered to play a major role in the reduced Treg production in Aire deficiency. Here, we show that mTECs abnormally express co-inhibitory receptor CTLA-4 if Aire is non-functional. Upon binding with CD80/CD86 ligands expressed on thymic dendritic cells (DCs), the ectopically expressed CTLA-4 from Aire-deficient mTECs removes the CD80/CD86 ligands from the DCs. This attenuates the ability of DCs to provide co-stimulatory signals and to present self-antigens transferred from mTECs, both of which are required for Treg production. Accordingly, impaired production of Tregs and organ-specific autoimmunity in Aire-deficient mice are rescued by the depletion of CTLA-4 expression from mTECs. Our studies illuminate the significance of mTEC-DC interaction coordinated by Aire for the establishment of thymic tolerance. (キーワード) Animals / Antigens, CD / Autoantigens / Autoimmunity / CTLA-4 Antigen / Epithelial Cells / Ligands / Mice, Inbred BALB C / Mice, Inbred C57BL / Organ Specificity / Stromal Cells / T-Lymphocytes, Regulatory / Thymus Gland / Transcription Factors (徳島大学機関リポジトリ) ● Metadata: 117194 (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.celrep.2022.110384 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35172142 ● Search Scopus @ Elsevier (PMID): 35172142 ● Search Scopus @ Elsevier (DOI): 10.1016/j.celrep.2022.110384 (徳島大学機関リポジトリ: 117194, DOI: 10.1016/j.celrep.2022.110384, PubMed: 35172142)
6.	Hitoshi Nishijima, Minoru Matsumoto, Junko Morimoto, Kazuyoshi Hosomichi, Nobuko Akiyama, Taishin Akiyama, Takeshi Oya, Koichi Tsuneyama, Hideyuki Yoshida and Mitsuru Matsumoto : Aire Controls Heterogeneity of Medullary Thymic Epithelial Cells for the Expression of Self-Antigens., The Journal of Immunology, Vol.208, No.2, 303-320, 2022. (要約) The deficiency of Aire, a transcriptional regulator whose defect results in the development of autoimmunity, is associated with reduced expression of tissue-restricted self-Ags (TRAs) in medullary thymic epithelial cells (mTECs). Although the mechanisms underlying Aire-dependent expression of TRAs need to be explored, the physical identification of the target(s) of Aire has been hampered by the low and promiscuous expression of TRAs. We have tackled this issue by engineering mice with augmented Aire expression. Integration of the transcriptomic data from Aire-augmented and Aire-deficient mTECs revealed that a large proportion of so-called Aire-dependent genes, including those of TRAs, may not be direct transcriptional targets downstream of Aire. Rather, Aire induces TRA expression indirectly through controlling the heterogeneity of mTECs, as revealed by single-cell analyses. In contrast, Ccl25 emerged as a canonical target of Aire, and we verified this both in vitro and in vivo. Our approach has illuminated the Aire's primary targets while distinguishing them from the secondary targets. (キーワード) Animals / Autoantigens / Autoimmunity / Chemokines, CC / Epithelial Cells / Gene Expression Regulation / Gene Knock-In Techniques / Gene Knockout Techniques / Mice / Mice, Inbred C57BL / Mice, Inbred NOD / Mice, Transgenic / Thymus Gland / Transcription Factors / Transcription, Genetic (徳島大学機関リポジトリ) ● Metadata: 117482 (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.2100692 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34930780 ● Search Scopus @ Elsevier (PMID): 34930780 ● Search Scopus @ Elsevier (DOI): 10.4049/jimmunol.2100692 (徳島大学機関リポジトリ: 117482, DOI: 10.4049/jimmunol.2100692, PubMed: 34930780)
7.	Ferreirinha Pedro, Ribeiro Camila, Junko Morimoto, Landry J M Jonathan, Minoru Matsumoto, Meireles Catarina, White J Andrea, Izumi Ohigashi, Araújo Leonor, Benes Vladimir, Yousuke Takahama, Anderson Graham, Mitsuru Matsumoto and Alves L Nuno : A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation, European Journal of Immunology, Vol.51, No.2, 311-318, 2021. (要約) 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. (キーワード) Animals / Cell Differentiation / Down-Regulation / Epithelial Cells / Gene Expression Profiling / Gene Expression Regulation / Keratinocytes / Mice / Mice, Inbred C57BL / Thymus Gland / Transcription Factors (徳島大学機関リポジトリ) ● Metadata: 116300 (出版サイトへのリンク) ● Publication site (DOI): 10.1002/eji.202048764 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32845012 ● Summary page in Scopus @ Elsevier: 2-s2.0-85090990353 (徳島大学機関リポジトリ: 116300, DOI: 10.1002/eji.202048764, PubMed: 32845012, Elsevier: Scopus)
8.	Minoru Matsumoto, Koichi Tsuneyama, Junko Morimoto, Kazuyoshi Hosomichi, Mitsuru Matsumoto and Hitoshi Nishijima : Tissue-specific autoimmunity controlled by Aire in thymic and peripheral tolerance mechanisms., International Immunology, Vol.32, No.2, 117-131, 2020. (要約) Tissue-specific autoimmune diseases are assumed to arise through malfunction of two checkpoints for immune tolerance: defective elimination of autoreactive T cells in the thymus and activation of these T cells by corresponding autoantigens in the periphery. However, evidence for this model and the outcome of such alterations in each or both of the tolerance mechanisms have not been sufficiently investigated. We studied these issues by expressing human AIRE (huAIRE) as a modifier of tolerance function in NOD mice wherein the defects of thymic and peripheral tolerance together cause type I diabetes (T1D). Additive huAIRE expression in the thymic stroma had no major impact on the production of diabetogenic T cells in the thymus. In contrast, huAIRE expression in peripheral antigen-presenting cells (APCs) rendered the mice resistant to T1D, while maintaining other tissue-specific autoimmune responses and antibody production against an exogenous protein antigen, because of the loss of Xcr1+ dendritic cells, an essential component for activating diabetogenic T cells in the periphery. These results contrast with our recent demonstration that huAIRE expression in both the thymic stroma and peripheral APCs resulted in the paradoxical development of muscle-specific autoimmunity. Our results reveal that tissue-specific autoimmunity is differentially controlled by a combination of thymic function and peripheral tolerance, which can be manipulated by expression of huAIRE/Aire in each or both of the tolerance mechanisms. (徳島大学機関リポジトリ) ● Metadata: 114944 (出版サイトへのリンク) ● Publication site (DOI): 10.1093/intimm/dxz066 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31586207 ● Search Scopus @ Elsevier (PMID): 31586207 ● Search Scopus @ Elsevier (DOI): 10.1093/intimm/dxz066 (徳島大学機関リポジトリ: 114944, DOI: 10.1093/intimm/dxz066, PubMed: 31586207)
9.	Junko Morimoto, Yumiko Nishikawa, Takumi Kakimoto, Kohei Furutani, Naoki Kihara, Minoru Matsumoto, Koichi Tsuneyama, Yuko Kozono, Haruo Kozono, Katsuto Hozumi, Kazuyoshi Hosomichi, Hitoshi Nishijima and Mitsuru Matsumoto : Aire Controls in Trans the Production of Medullary Thymic Epithelial Cells Expressing Ly-6C/Ly-6G., The Journal of Immunology, Vol.201, No.11, 3244-3257, 2018. (要約) Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire+ mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire+ mTECs functioned in trans to maintain Ly-6C/Ly-6G+ mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale. (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.1800950 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30389776 ● Search Scopus @ Elsevier (PMID): 30389776 ● Search Scopus @ Elsevier (DOI): 10.4049/jimmunol.1800950 (DOI: 10.4049/jimmunol.1800950, PubMed: 30389776)
10.	Hitoshi Nishijima, Tatsuya Kajimoto, Yoshiki Matsuoka, Yasuhiro Mouri, Junko Morimoto, Minoru Matsumoto, Hiroshi Kawano, Yasuhiko Nishioka, Hisanori Uehara, Keisuke Izumi, Koichi Tsuneyama, Il-mi Okazaki, Taku Okazaki, Kazuyoshi Hosomichi, Ayako Shiraki, Makoto Shibutani, Kunitoshi Mitsumori and Mitsuru Matsumoto : Paradoxical development of polymyositis-like autoimmunity through augmented expression of autoimmune regulator (AIRE)., Journal of Autoimmunity, Vol.86, 75-92, 2018. (要約) Autoimmunity is prevented by the function of the autoimmune regulator [AIRE (Aire in mice)], which promotes the expression of a wide variety of tissue-restricted antigens (TRAs) from medullary thymic epithelial cells (mTECs) and from a subset of peripheral antigen-presenting cells (APCs). We examined the effect of additive expression of human AIRE (huAIRE) in a model of autoimmune diabetes in NOD mice. Unexpectedly, we observed that mice expressing augmented AIRE/Aire developed muscle-specific autoimmunity associated with incomplete maturation of mTECs together with impaired expression of Aire-dependent TRAs. This led to failure of deletion of autoreactive T cells together with dramatically reduced production of regulatory T cells in the thymus. In peripheral APCs, expression of costimulatory molecules was augmented. We suggest that levels of Aire expression need to be tightly controlled for maintenance of immunological tolerance. Our results also highlight the importance of coordinated action between central tolerance and peripheral tolerance under the common control of Aire. (徳島大学機関リポジトリ) ● Metadata: 112347 (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.jaut.2017.09.006 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28931462 ● Search Scopus @ Elsevier (PMID): 28931462 ● Search Scopus @ Elsevier (DOI): 10.1016/j.jaut.2017.09.006 (徳島大学機関リポジトリ: 112347, DOI: 10.1016/j.jaut.2017.09.006, PubMed: 28931462)
11.	Hiroshi Kawano, Hitoshi Nishijima, Junko Morimoto, Fumiko Hirota, Ryoko Morita, Yasuhiro Mouri, Yasuhiko Nishioka and Mitsuru Matsumoto : Aire expression is inherent to most medullary thymic epithelial cells during their differentiation program., The Journal of Immunology, Vol.195, No.11, 5149-5158, 2015. (要約) Aire in medullary thymic epithelial cells (mTECs) plays an important role in the establishment of self-tolerance. Because Aire+ mTECs appear to be a limited subset, they may constitute a unique lineage(s) among mTECs. An alternative possibility is that all mTECs are committed to express Aire in principle, but Aire expression by individual mTECs is conditional. To investigate this issue, we established a novel Aire reporter strain in which endogenous Aire is replaced by the human AIRE-GFP-Flag tag (Aire/hAGF-knockin) fusion gene. The hAGF reporter protein was produced and retained very efficiently within mTECs as authentic Aire nuclear dot protein. Remarkably, snapshot analysis revealed that mTECs expressing hAGF accounted for >95% of mature mTECs, suggesting that Aire expression does not represent a particular mTEC lineage(s). We confirmed this by generating Aire/diphtheria toxin receptor knockin mice in which long-term ablation of Aire+ mTECs by diphtheria toxin treatment resulted in the loss of most mature mTECs beyond the proportion of those apparently expressing Aire. These results suggest that Aire expression is inherent to all mTECs but may occur at particular stage(s) and/or cellular states during their differentiation, thus accounting for the broad impact of Aire on the promiscuous gene expression of mTECs. (徳島大学機関リポジトリ) ● Metadata: 109688 (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.1501000 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26503950 ● Search Scopus @ Elsevier (PMID): 26503950 ● Search Scopus @ Elsevier (DOI): 10.4049/jimmunol.1501000 (徳島大学機関リポジトリ: 109688, DOI: 10.4049/jimmunol.1501000, PubMed: 26503950)
12.	Hitoshi Nishijima, Satsuki Kitano, Hitoshi Miyachi, Junko Morimoto, Hiroshi Kawano, Fumiko Hirota, Ryoko Morita, Yasuhiro Mouri, Kiyoshi Masuda, Issei Imoto, Koichi Ikuta and Mitsuru Matsumoto : Ectopic Aire expression in the thymic cortex reveals inherent properties of Aire as a tolerogenic factor within the medulla., The Journal of Immunology, Vol.195, No.10, 4641-4649, 2015. (要約) Cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells (mTECs) play essential roles in the positive and negative selection of developing thymocytes, respectively. Aire in mTECs plays an essential role in the latter process through expression of broad arrays of tissue-restricted Ags. To determine whether the location of Aire within the medulla is absolutely essential or whether Aire could also function within the cortex for establishment of self-tolerance, we used bacterial artificial chromosome technology to establish a semiknockin strain of NOD-background (β5t/Aire-transgenic) mice expressing Aire under control of the promoter of β5t, a thymoproteasome expressed exclusively in the cortex. Although Aire was expressed in cTECs as typical nuclear dot protein in β5t/Aire-Tg mice, cTECs expressing Aire ectopically did not confer transcriptional expression of either Aire-dependent or Aire-independent tissue-restricted Ag genes. We then crossed β5t/Aire-Tg mice with Aire-deficient NOD mice, generating a strain in which Aire expression was confined to cTECs. Despite the presence of Aire(+) cTECs, these mice succumbed to autoimmunity, as did Aire-deficient NOD mice. The thymic microenvironment harboring Aire(+) cTECs, within which many Aire-activated genes were present, also showed no obvious alteration of positive selection, suggesting that Aire's unique property of generating a self-tolerant T cell repertoire is functional only in mTECs. (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.1501026 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26453754 ● Summary page in Scopus @ Elsevier: 2-s2.0-84951861488 (DOI: 10.4049/jimmunol.1501026, PubMed: 26453754, Elsevier: Scopus)
13.	Yasuhiro Mouri, Hitoshi Nishijima, Hiroshi Kawano, Fumiko Hirota, Nobuo Sakaguchi, Junko Morimoto and Mitsuru Matsumoto : NF-κB-Inducing Kinase in Thymic Stroma Establishes Central Tolerance by Orchestrating Cross-Talk with Not Only Thymocytes but Also Dendritic Cells., The Journal of Immunology, Vol.193, No.9, 4356-4367, 2014. (要約) Essential roles of NF-κB-inducing kinase (NIK) for the development of medullary thymic epithelial cells (mTECs) and regulatory T cells have been highlighted by studies using a strain of mouse bearing a natural mutation of the NIK gene (aly mice). However, the exact mechanisms underlying the defect in thymic cross-talk leading to the breakdown of self-tolerance in aly mice remain elusive. In this study, we demonstrated that production of regulatory T cells and the final maturation process of positively selected conventional αβ T cells are impaired in aly mice, partly because of a lack of mature mTECs. Of note, numbers of thymic dendritic cells and their expression of costimulatory molecules were also affected in aly mice in a thymic stroma-dependent manner. The results suggest a pivotal role of NIK in the thymic stroma in establishing self-tolerance by orchestrating cross-talk between mTECs and dendritic cells as well as thymocytes. In addition, we showed that negative selection was impaired in aly mice as a result of the stromal defect, which accounts for the development of organ-specific autoimmunity through a lack of normal NIK. (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.1400389 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25261487 ● Search Scopus @ Elsevier (PMID): 25261487 ● Search Scopus @ Elsevier (DOI): 10.4049/jimmunol.1400389 (DOI: 10.4049/jimmunol.1400389, PubMed: 25261487)
14.	Yumiko Nishikawa, Hitoshi Nishijima, Minoru Matsumoto, Junko Morimoto, Fumiko Hirota, Satoru Takahashi, Hervé Luche, Joerg Hans Fehring, Yasuhiro Mouri and Mitsuru Matsumoto : Temporal lineage tracing of Aire-expressing cells reveals a requirement for Aire in their maturation program., The Journal of Immunology, Vol.192, No.6, 2585-2592, 2014. (要約) Understanding the cellular dynamics of Aire-expressing lineage(s) among medullary thymic epithelial cells (AEL-mTECs) is essential for gaining insight into the roles of Aire in establishment of self-tolerance. In this study, we monitored the maturation program of AEL-mTECs by temporal lineage tracing, in which bacterial artificial chromosome transgenic mice expressing tamoxifen-inducible Cre recombinase under control of the Aire regulatory element were crossed with reporter strains. We estimated that the half-life of AEL-mTECs subsequent to Aire expression was ∼7-8 d, which was much longer than that reported previously, owing to the existence of a post-Aire stage. We found that loss of Aire did not alter the overall lifespan of AEL-mTECs, inconsistent with the previous notion that Aire expression in medullary thymic epithelial cells (mTECs) might result in their apoptosis for efficient cross-presentation of self-antigens expressed by AEL-mTECs. In contrast, Aire was required for the full maturation program of AEL-mTECs, as exemplified by the lack of physiological downregulation of CD80 during the post-Aire stage in Aire-deficient mice, thus accounting for the abnormally increased CD80(high) mTECs seen in such mice. Of interest, increased CD80(high) mTECs in Aire-deficient mice were not mTEC autonomous and were dependent on cross-talk with thymocytes. These results further support the roles of Aire in the differentiation program of AEL-mTECs. (キーワード) Animals / Antigens, CD80 / Apoptosis / Autoantigens / Cell Differentiation / Cell Lineage / Cells, Cultured / Cross-Priming / Epithelial Cells / Flow Cytometry / Immunohistochemistry / Kinetics / Luminescent Proteins / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Thymocytes / Thymus Gland / Time Factors / Transcription Factors (出版サイトへのリンク) ● Publication site (DOI): 10.4049/jimmunol.1302786 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24516201 ● Summary page in Scopus @ Elsevier: 2-s2.0-84897508383 (DOI: 10.4049/jimmunol.1302786, PubMed: 24516201, Elsevier: Scopus)

総説・解説:

1.	Minoru Matsumoto, Hitoshi Nishijima, Junko Morimoto, Koichi Tsuneyama and Mitsuru Matsumoto : AIRE - The Autoimmune Regulator, eLS, Feb. 2019. (出版サイトへのリンク) ● Publication site (DOI): 10.1002/9780470015902.a0027281 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1002/9780470015902.a0027281 (DOI: 10.1002/9780470015902.a0027281)
2.	Mitsuru Matsumoto, Yumiko Nishikawa, Hitoshi Nishijima, Junko Morimoto, Minoru Matsumoto and Yasuhiro Mouri : Which model better fits the role of Aire in the establishment of self-tolerance: the transcription model or the maturation model?, Frontiers in Immunology, Vol.4, 1-4, Jul. 2013. (要約) The discovery of Aire-dependent transcriptional control of many tissue-restricted self-antigen (TRA) genes in thymic epithelial cells in the medulla (medullary thymic epithelial cells, mTECs) has raised the intriguing question of how the single Aire gene can influence the transcription of such a large number of TRA genes within mTECs. From a mechanistic viewpoint, there are two possible models to explain the function of Aire in this action. In the first model, TRAs are considered to be the direct target genes of Aire's transcriptional activity. In this scenario, the lack of Aire protein within cells would result in the defective TRA gene expression, while the maturation program of mTECs would be unaffected in principle. The second model hypothesizes that Aire is necessary for the maturation program of mTECs. In this case, we assume that the mTEC compartment does not mature normally in the absence of Aire. If acquisition of the properties of TRA gene expression depends on the maturation status of mTECs, a defect of such an Aire-dependent maturation program in Aire-deficient mTECs can also result in impaired TRA gene expression. In this brief review, we will focus on these two contrasting models for the roles of Aire in controlling the expression of TRAs within mTECs. (出版サイトへのリンク) ● Publication site (DOI): 10.3389/fimmu.2013.00210 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23885257 ● Summary page in Scopus @ Elsevier: 2-s2.0-84883679216 (DOI: 10.3389/fimmu.2013.00210, PubMed: 23885257, Elsevier: Scopus)

国際会議:

1.	Minoru Matsumoto, Mitsuru Matsumoto, Junko Morimoto and Hitoshi Nishijima : Tissue-specific Autoimmunity Controlled by Aire, a Gene Responsible for APECED, The 3rd International Congress on Rare Diseases, Berlin, Germany, Mar. 2020.
2.	Minoru Matsumoto, Hitoshi Nishijima, Ryuichiro Miyazawa, Junko Morimoto, Koichi Tsuneyama and Mitsuru Matsumoto : Characterization of Aire-expressing DCs with high-sensitivity and high-fidelity Aire-reporter strain, The 48th Annual Meeting of the Japanese Society for Immunology, Hamamatsu, Japan, Dec. 2019.
3.	Mitsuru Matsumoto, Junko Morimoto, Minoru Matsumoto, Koichi Tsuneyama, Ryuichiro Miyazawa and Hitoshi Nishijima : Aire-dependent establishment of self-tolerance, The 17th International Congress of Immunology, Beijing, Oct. 2019.
4.	Mitsuru Matsumoto, Junko Morimoto, Minoru Matsumoto, Koichi Tsuneyama, Ryuichiro Miyazawa and Hitoshi Nishijima : Aire-dependent establishment of self-tolerance studied by genetically modified mice, EMBO Workshop ThymE, Israel, May 2019.
5.	Minoru Matsumoto, Junko Morimoto, Mitsuru Matsumoto and Hitoshi Nishijima : Tissue-specific autoimmunity modified by Aire in thymic and peripheral tolerance, 5th International Congress on Controversies in Rheumatology and Autoimmunity (CORA), Italy, Mar. 2019.
6.	Mitsuru Matsumoto, Minoru Matsumoto, Junko Morimoto, Koichi Tsuneyama and Hitoshi Nishijima : Tissue-specific autoimmunity manipulated by Aire in thymic and peripheral tolerance, Immunology of Diabetes Society Congress 2018, London, Oct. 2018.
7.	Mitsuru Matsumoto, Junko Morimoto, Minoru Matsumoto and Hitoshi Nishijima : Aire controls in trans the production of medullary thymic epithelial cells expressing Ly6C/Ly6G, 5th European Congress of Immunology 2018, Amsterdam, Sep. 2018.
8.	Minoru Matsumoto, Hitoshi Nishijima, Junko Morimoto and Mitsuru Matsumoto : Distinct tissue-specific immune response revealed by manipulation of thymic and peripheral tolerance by Aire, 1st International Symposium for "Neo-self", Awaji, Japan, Jul. 2018.
9.	Minoru Matsumoto, Hitoshi Nishijima, Junko Morimoto, Koichi Tsuneyama and Mitsuru Matsumoto : Manipulation of thymic and peripheral tolerance by AIRE defines distinct tissue-specific autoimmunity, 11th International Congress on Autoimmunity, Lisbon, Portugal, May 2018.
10.	Junko Morimoto, Yumiko Nishikawa, Naoki Kihara, Kazuyoshi Hosomichi, Hitoshi Nishijima and Mitsuru Matsumoto : Expression of Ly6C/6G defines a novel subset of medullary thymic epithelial cells, Immunology 2018 - AAI Annual Meeting, Austin, Texas, May 2018.
11.	Mitsuru Matsumoto, Junko Morimoto, Minoru Matsumoto, Koichi Tsuneyama and Hitoshi Nishijima : A novel Aire-dependent subset of mTECs with tolerogenic functions is defined by Ly6 family protein expression, ThymOz8, Heron Island, Australia, Mar. 2018.
12.	Minoru Matsumoto, Hitoshi Nishijima, Junko Morimoto, Koichi Tsuneyama and Mitsuru Matsumoto : Acquisition of the resistance to autoimmune diabetes by the expression of human AIRE in BM-derived APCs in NOD, ThymOz8, Heron Island, Australia, Mar. 2018.
13.	Junko Morimoto, Yumiko Nishikawa, Naoki Kihara, Kazuyoshi Hosomichi, Hitoshi Nishijima and Mitsuru Matsumoto : Expression of Ly6C/6G defines a novel subset of medullary thymic epithelial cells, 5th Annual Meeting of the International Cytokine and Interferon Society, Kanazawa, Japan, Oct. 2017.
14.	Junko Morimoto, Yumiko Nishikawa, Hitoshi Nishijima and Mitsuru Matsumoto : Expression of Ly6C/6G defines a novel Aire-dependent subset of medullary thymic epithelial cells with tolerogenic function, 12th International Congress on SLE, Melbourne, Australia, Mar. 2017.
15.	Hitoshi Nishijima, Yasuhiro Mouri, Junko Morimoto and Mitsuru Matsumoto : Paradoxical development of polymyositis-like autoimmunity through augmented expression of AIRE, 7th International Workshop of Kyoto T Cell Conference, Kyoto, Japan, Mar. 2017.
16.	Hitoshi Nishijima, Yasuhiro Mouri, Junko Morimoto and Mitsuru Matsumoto : Paradoxical development of polymyositis-like autoimmunity through augmented expression of human AIRE in mice, Controversies in Rheumatology and Autoimmunity 2017, Bologna, Italy, Mar. 2017.
17.	Hiroshi Kawano, Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri and Mitsuru Matsumoto : Aire expression is inherent to all medullary thymic epithelial cells during their differentiation program, The 4th European Congress of Immunology, Vienna, Austria, Sep. 2015.
18.	Mitsuru Matsumoto, Hiroshi Kawano, Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri and Yasuhiko Nishioka : Aire expression is inherent properties of all medullary thymic epithelial cells during their differentiation program, Venice Thymus Meeting 2015, Venice, Italy, Apr. 2015.
19.	Hitoshi Nishijima, Junko Morimoto, Hiroshi Kawano, Yasuhiro Mouri, Koichi Ikuta and Mitsuru Matsumoto : Ectopic Aire expression in thymic cortex reveals inherent properties of Aire as a stromal factor for medullary thymic microenvironment, ThymOz 7, Heron Island, Australia, Apr. 2014.
20.	Mitsuru Matsumoto, Junko Morimoto, Hiroshi Kawano, Yasuhiro Mouri and Hitoshi Nishijima : Ectopic Aire expression in thymic cortex reveals inherent properties of Aire as a stromal factor for medullary microenvironment, 9th International Congress on Autoimmunity, Nice, France, Mar. 2014.
21.	Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri, Yumiko Nishikawa, Kouichi Ikuta and Mitsuru Matsumoto : Ectopic Aire expression in thymic cortex reveals inherent properties of Aire as a stromal factor within medullary microenvironment, 第3回眉山免疫シンポジウム, Tokushima, Feb. 2014.

国内講演発表:

1.	Junko Morimoto, Hiroyuki Kondo, OKAHISA Rinka, RI Kei, 黒滝大翼 and Koji Yasutomo : The role of splenic CD8+CD103+ cDC1 in the maintenance of immune homeostasis, 第53回日本免疫学会学術集会, Dec. 2024.
2.	Rinna Koga, Junko Morimoto, Kunihiro Otsuka and Koji Yasutomo : Proteasome dysfunction in adipocytes induces lipodystrophy and autoinflammation, 第53回日本免疫学会学術集会, Dec. 2024.
3.	Erkhembayar Shinebaatar, Junko Morimoto, Rinna Koga and Koji Yasutomo : Dysfunction of proteasomes in T cells causes immunodeficiency, 第53回日本免疫学会学術集会, Dec. 2024.
4.	Erkhembayar Shinebaatar, Junko Morimoto, Rinna Koga and Koji Yasutomo : Dysfunction of proteasomes in T cells causes immunodeficiency, 第22回四国免疫フォーラム, Jun. 2024.
5.	Erkhembayar Shinebaatar, Junko Morimoto, Hiroyuki Kondo and Koji Yasutomo : Dysfunction of proteasomes in T cells causes immunodeficiency, 第52回日本免疫学会学術集会, Jan. 2024.
6.	Rinna Koga, Junko Morimoto, Kunihiro Otsuka and Koji Yasutomo : Proteasome dysfunction in adipocytes induces lipodystrophy and autoinflammation, 第52回日本免疫学会学術集会, Jan. 2024.
7.	Minoru Matsumoto, Hitoshi Nishijima, Junko Morimoto, Koichi Tsuneyama and Mitsuru Matsumoto : Aire controls heterogeneity of medullary thymic epithelial cells for the expression of self-antigens, 第50回日本免疫学会学術集会, Dec. 2021.
8.	Junko Morimoto, Minoru Matsumoto, Ryuichiro Miyazawa and Mitsuru Matsumoto : Aire suppresses CTLA-4 expression from medullary thymic epithelial cells to avoid autoimmunity., 第50回日本免疫学会学術集会, Dec. 2021.
9.	西嶋仁, 杉田瑞季, 森本純子, 松本穣, 松本満 : Aireを高発現する胸腺髄質上皮細胞の免疫学的機能とトランスクリプトーム解析, 第42回日本分子生物学会年会, 2019年12月.
10.	森本純子, 西嶋仁, 松本稔, 松本満 : Antigen Transfer from thymic epithelial cells to DCs contributes to the production of thymic Tregs., The 48th Annual meeting of the Japanese Society for Immunology, 2019年12月.
11.	森本純子, 西嶋仁, 松本稔, 松本満 : Treg誘導に関与する胸腺内樹状細胞サブセットとAireの機能解析, 第2回若手の会(新学術領域ネオセルフの生成・機能・構造)(静岡), 2019年1月.
12.	Hitoshi Nishijima, Junko Morimoto, Minoru Matsumoto and Mitsuru Matsumoto : Transcriptomic analysis of medullary thymic epithelial cells with augmented Aire expression, 第47回日本免疫学会学術集会, Dec. 2018.
13.	Junko Morimoto, Hitoshi Nishijima, Minoru Matsumoto and Mitsuru Matsumoto : Analysis of the role of thymic APCs and Aire in the production of thymic Tregs, 第47回日本免疫学会学術集会, Dec. 2018.
14.	西嶋仁, 森本純子, 松本穣, 松本満 : 胸腺髄質上皮細胞における Aire 発現レベルと組織特異的自己抗原遺伝子発現との関連性に関する検討, 28 Kyoto T cell Conference (KTCC), 2018年6月.
15.	Minoru Matsumoto, Hitoshi Nishijima, Junko Morimoto, Koichi Tsuneyama and Mitsuru Matsumoto : Transgenic human AIRE expression in NOD acquired resistance to the diabetes due to the impaired presentation of self-antigens in the pancreas, 第46回日本免疫学会学術集会, Dec. 2017.
16.	Hitoshi Nishijima, Yoshiki Matsuoka, Yasuhiro Mouri, Junko Morimoto and Mitsuru Matsumoto : Possible defect in the Treg production in mice overexpressing AIRE/Aire which exhibit muscle-specific autoimmunity, 第45回日本免疫学会学術集会, Dec. 2016.
17.	Junko Morimoto, Yumiko Nishikawa, Hiroshi Kawano, Yasuhiro Mouri, Hitoshi Nishijima and Mitsuru Matsumoto : A novel Aire-dependent subset of medullary thymic epithelial cells that express Ly6 family protein, 第44回日本免疫学会学術集会, Nov. 2015.
18.	Hitoshi Nishijima, Yasuhiro Mouri, Junko Morimoto, Hiroshi Kawano and Mitsuru Matsumoto : Paradoxical development of polymyositis-like autoimmunity by the additive expression of AIRE, 第44回日本免疫学会学術集会, Nov. 2015.
19.	Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri, Hiroshi Kawano, Koichi Ikuta and Mitsuru Matsumoto : Approaches to identify Aire-regulated non-tissue-restricted antigen genes by the ectopic expression of Aire in thymic cortex, 第43回日本免疫学会学術集会, Dec. 2014.
20.	Hiroshi Kawano, Junko Morimoto, Yasuhiro Mouri, Hitoshi Nishijima, Yasuhiko Nishioka and Mitsuru Matsumoto : Unexpected disturbance of the development of medullary thymic epithelial cells at immature stages by the long-term ablation of mature Aire-expressing cells, 第43回日本免疫学会学術集会, Dec. 2014.
21.	Hitoshi Nishijima, Junko Morimoto, Yasuhiro Mouri, Yumiko Nishikawa, Kouichi Ikuta and Mitsuru Matsumoto : Requirement of Aire expression within thymic medulla but not cortex for establishing self-tolerance, 第42回日本免疫学会総会, Dec. 2013.

その他・研究会:

1.	森本純子, 松本満 : Aire欠損mTECは異所性CTLA-4を発現することによって胸腺内DCの機能に影響を及ぼす．, 第30回KTCC, 2021年10月.
2.	森本純子, 松本満 : 胸腺髄質上皮細胞から樹状細胞への抗原転移におけるAireの役割, 日本胸腺研究会 2021年2月 on line 開催, 2021年2月.
3.	西嶋仁, 松岡慶樹, 毛利安宏, 森本純子, 松本満 : ヒトAIRE トランスジェニックマウスに誘導される多発性筋炎病態の解析, 第36回日本胸腺研究会, 2017年2月.
4.	西嶋仁, 梶本達也, 松岡慶樹, 毛利安宏, 森本純子, 河野弘, 松本満 : NOD系統特異的に多発性筋炎様症状をもたらすゲノム領域の解析, 第14回四国免疫フォーラム, 2015年6月.

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

Aire遺伝子の機能不全による自己免疫応答に関わる分子の探索と治療への応用 (研究課題/領域番号: 22K07120 )
GPIアンカー型タンパク質Ly6C分子による免疫応答調節機構の解明 (研究課題/領域番号: 19K07626 )
AIREを基軸とする自己免疫疾患の病態解明、ならびに新規治療法の開発 (研究課題/領域番号: 19H03699 )
自己免疫病態におけるアンビバレンス（両価性）の解読 (研究課題/領域番号: 18K19564 )
AIREの機能解析による自己免疫病態の解明 (研究課題/領域番号: 16H05342 )
胸腺微小環境の構築に対するAire機能の解明 (研究課題/領域番号: 26460577 )
新規マクロファージ亜群の同定とその生体内自己免疫反応制御における意義 (研究課題/領域番号: 22021003 )
免疫記憶CD8T細胞の形成および維持機構におけるオステオポンチンの機能解析 (研究課題/領域番号: 22790449 )
オステオポンチン機能制御による難治性炎症性疾患制御の分子基盤 (研究課題/領域番号: 21390113 )
ウイルス感染防御免疫応答におけるオステオポンチンおよびIL-17の機能解析 (研究課題/領域番号: 20790365 )
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科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

助教 : 森本 純子

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専門分野

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総説・解説:

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

助教 : 森本純子