Junko Morimoto, Ryuichiro Miyazawa, Minoru Matsumoto and Mitsuru Matsumoto : 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, Tokyo, Oct. 2020.
2.
Junko Morimoto, Ryuichiro Miyazawa, Minoru Matsumoto and Mitsuru Matsumoto : 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), HOKURYUKAN, Tokyo, Jul. 2020.
Academic Paper (Judged Full Paper):
1.
Hiroyuki Kondo, Kunihiro Otsuka, Junko Morimoto, Hideki Arimochi, Shin-ichi Tsukumo and Koji Yasutomo : Loss of Dmrta1 alters CD8+ T cell activation and resistance to influenza virus infection., ImmunoHorizons, 9, 11, 2025.
(Summary)
The generation and function of effector and memory CD8+ T cells are crucial for effective immune responses and long-term immunity. Using gene expression analysis, we found that doublesex- and mab-3-related transcription factor like family A1 (Dmrta1), a member of the DMRT family of transcription factors, is highly expressed in activated and memory CD8+ T cells. In this study, we investigated the role of Dmrta1 in the activation and differentiation of CD8+ T cells. The Dmrta1-deficient (Dmrta1-KO) mice showed an equivalent number of thymic and splenic T cells compared with wild-type mice. Dmrta1 deficiency in T cells resulted in impaired early activation of CD8+ but not CD4+ T cells and reduced expression of granzyme B in CD8+ T cells following influenza virus infection. Although virus-specific CD8+ T cell numbers and cytotoxicity in the lung were comparable between wild-type and Dmrta1-deficient mice during primary infection, Dmrta1-KO mice exhibited a transient accumulation of virus-specific CD8+ T cells in the spleen with reduced cytotoxic activity. Upon secondary challenge, memory CD8+ T cells from Dmrta1-KO mice showed persistent defects in granzyme B expression and cytotoxic function. These findings demonstrate that Dmrta1 modulates the early activation of naïve CD8+ T cells and supports the cytotoxic functionality of both effector and memory CD8+ T cells, particularly in secondary lymphoid organs, with significant implications for antiviral immunity.
Erkhembayar Shinebaatar, Junko Morimoto, Rinna Koga, Nam Thanh Nguyen, Yuki Sasaki, Shigenobu Yonemura, Hidetaka Kosako and Koji Yasutomo : Proteasome dysfunction in T cells causes immunodeficiency via cell cycle disruption and apoptosis., International Immunology, 37, 8, 493-505, 2025.
(Summary)
Proteasomes are essential molecular complexes that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in proteasome subunits lead to proteasome-associated autoinflammatory syndromes (PRAAS) characterized by autoinflammation, partial progressive lipodystrophy, and, in certain cases, immunodeficiency. However, the molecular mechanisms by which proteasome dysfunction results in these phenotypes remain unclear. Here, we established a mouse model carrying a mutation in β5i (encoded by Psmb8) along with T-cell-specific β5 (encoded by Psmb5) deficiency (KIKO mice). The KIKO mice presented severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity leading to the accumulation of ubiquitinated proteins. The CD4+ T cells of KIKO mice presented impaired proliferative activity with cell cycle arrest in the G0/G1 phase following T cell receptor (TCR) engagement. T cells from KIKO mice underwent rapid cell death through apoptosis, as treatment of T cells with the caspase inhibitor Z-Val-Ala-Asp(Ome)-fluoromethylketone (Z-VAD-FMK) rescued cell viability. Moreover, proteasome dysfunction induced apoptosis in T cells without affecting either mitochondrial functions or endoplasmic reticulum (ER) stress responses. Thus, our data provide insight into the molecular mechanisms underlying not only immunodeficiency in PRAAS patients but also T-cell deficiency associated with other disorders.
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.
(Summary)
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.
Ryuichiro Miyazawa, Jun-Ichi Nagao, Ken-Ichi Arita-Morioka, Minoru Matsumoto, Junko Morimoto, Masaki Yoshida, 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, 7, 1, 140-158, 2023.
(Summary)
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.
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, 100, 5, 371-377, 2022.
(Summary)
cells expressing AIRE in the peripheral blood before the treatment but not during the remission phase treated with immunosuppressive drugs. Thus, not only loss of function of AIRE/Aire but also augmented and/or dysregulated expression of AIRE/Aire should be considered for the pathogenesis of organ-specific autoimmunity. We suggest that further analyses should be pursued to establish a novel link between organ-specific autoimmune disease and dysregulated AIRE expression in clinical settings.
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, 6, 3, 202-210, 2022.
(Summary)
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.
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, 38, 7, 110384, 2022.
(Summary)
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.
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, 208, 2, 303-320, 2022.
(Summary)
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.
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, 51, 2, 311-318, 2021.
(Summary)
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.
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, 32, 2, 117-131, 2020.
(Summary)
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.
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, 201, 11, 3244-3257, 2018.
(Summary)
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.
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, 86, 75-92, 2018.
(Summary)
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.
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, 195, 11, 5149-5158, 2015.
(Summary)
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.
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, 195, 10, 4641-4649, 2015.
(Summary)
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.
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, 193, 9, 4356-4367, 2014.
(Summary)
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.
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, 192, 6, 2585-2592, 2014.
(Summary)
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.
Interleukin(IL)-17A, an inflammatory cytokine, has been implicated in atherosclerosis, in which inflammatory cells within atherosclerotic plaques express IL-17A. However, its role in the development of atheroscelrosis remains to be controversial.To directly examine the role of IL-17A in atherosclerosis, we generated apolipoprotein E (ApoE)/IL-17A double-deficient (ApoE(-/-)IL-17A(-/-)) mice. Mice were fed with high-fat diet (HFD) for either 8 or 16 weeks, both starting at ages of 6 to 8 weeks. We found that splenic CD4(+) T-cells produced high amounts of IL-17A in ApoE(-/-) mice after HFD feeding for 8 weeks. Atherosclerosis was significantly accelerated in HFD-fed ApoE(-/-)IL-17A(-/-) mice compared with ApoE(-/-) mice. Splenic CD4(+) T-cells of ApoE(-/-)IL-17A(-/-) mice after HFD feeding for 8 weeks, but not for 16 weeks, exhibited increased interferon gamma and decreased IL-5 production. Importantly, formation of vulnerable plaque as evidenced by reduced numbers of vascular smooth muscle cells and reduced type I collagen deposition in the plaque was detected in ApoE(-/-)IL-17A(-/-) mice after HFD feeding for 8 weeks.These results suggest that IL-17A regulates the early phase of atherosclerosis development after HFD feeding and plaque stability, at least partly if not all by modulating interferon gamma and IL-5 production from CD4(+) T-cells.
Masashi Kanayama, Junko Morimoto, Yutaka Matsui, Masahiro Ikesue, Keiko Danzaki, Daisuke Kurotaki, Koyu Ito, Toshimichi Yoshida and Toshimitsu Uede : α9β1 integrin-mediated signaling serves as an intrinsic regulator of pathogenic Th17 cell generation., The Journal of Immunology, 187, 11, 5851-5864, 2011.
(Summary)
The interaction between matricellular proteins such as tenascin-C (TN-C) and osteopontin (OPN) and integrins has been implicated in the pathology of rheumatoid arthritis in which Th17 cells are recognized as primary pathogenic cells. The differentiation of Th17 cells is tightly regulated by cytokines derived from APCs, receiving various signals including TLR stimuli. In this study, we used a collagen-induced arthritis model and found that increased numbers of α(9) integrin-positive conventional dendritic cells and macrophage were detectable in the draining lymph node (dLN) shortly following first immunization, and these cells produced both TN-C and OPN, ligands for α(9) integrin. α(9) integrin-mediated signaling, induced by TN-C and OPN, promoted the production of Th17-related cytokines by conventional dendritic cells and macrophages in synergy with TLR2 and 4 signaling. This led to the Th17 cell differentiation and arthritis development. Moreover, Th17 cells generated under blocking of α(9) integrin-mediated signaling showed low level of CCR6 expression and impaired migration ability toward CCL20. Thus, we have identified α(9) integrin-mediated signaling by TN-C and OPN as a novel intrinsic regulator of pathogenic Th17 cell generation that contributes to the development of rheumatoid arthritis.
Masahiro Ikesue, Yutaka Matsui, Daichi Ohta, Keiko Danzaki, Koyu Ito, Masashi Kanayama, Daisuke Kurotaki, Junko Morimoto, Tetsuhito Kojima, Hiroyuki Tsutsui and Toshimitsu Uede : Syndecan-4 deficiency limits neointimal formation after vascular injury by regulating vascular smooth muscle cell proliferation and vascular progenitor cell mobilization., Arteriosclerosis, Thrombosis, and Vascular Biology, 31, 5, 1066-1074, 2011.
(Summary)
Syndecan-4 (Syn4) is a heparan sulfate proteoglycan and works as a coreceptor for various growth factors. We examined whether Syn4 could be involved in the development of neointimal formation in vivo.Wild-type (WT) and Syn4-deficient (Syn4-/-) mice were subjected to wire-induced femoral artery injury. Syn4 mRNA was upregulated after vascular injury in WT mice. Neointimal formation was attenuated in Syn4-/- mice, concomitantly with the reduction of Ki67-positive vascular smooth muscle cells (VSMCs). Basic-fibroblast growth factor- or platelet-derived growth factor-BB-induced proliferation, extracellular signal-regulated kinase activation, and expression of cyclin D1 and Bcl-2 were impaired in VSMCs from Syn4-/- mice. To examine the role of Syn4 in bone marrow (BM)-derived vascular progenitor cells (VPCs) and vascular walls, we generated chimeric mice by replacing the BM cells of WT and Syn4-/- mice with those of WT or Syn4-/- mice. Syn4 expressed by both vascular walls and VPCs contributed to the neointimal formation after vascular injury. Although the numbers of VPCs were compatible between WT and Syn4-/- mice, mobilization of VPCs from BM after vascular injury was defective in Syn4-/- mice.Syn4 deficiency limits neointimal formation after vascular injury by regulating VSMC proliferation and VPC mobilization. Therefore, Syn4 may be a novel therapeutic target for preventing arterial restenosis after angioplasty.
Daisuke Kurotaki, Shigeyuki Kon, Kyeonghwa Bae, Koyu Ito, Yutaka Matsui, Yosuke Nakayama, Masashi Kanayama, Chiemi Kimura, Yoshinori Narita, Takashi Nishimura, Kazuya Iwabuchi, Matthias Mack, Nico Rooijen van, Shimon Sakaguchi, Toshimitsu Uede and Junko Morimoto : CSF-1-dependent red pulp macrophages regulate CD4 T cell responses., The Journal of Immunology, 186, 4, 2229-2237, 2011.
(Summary)
The balance between immune activation and suppression must be regulated to maintain immune homeostasis. Tissue macrophages (MΦs) constitute the major cellular subsets of APCs within the body; however, how and what types of resident MΦs are involved in the regulation of immune homeostasis in the peripheral lymphoid tissues are poorly understood. Splenic red pulp MΦ (RPMs) remove self-Ags, such as blood-borne particulates and aged erythrocytes, from the blood. Although many scattered T cells exist in the red pulp of the spleen, little attention has been given to how RPMs prevent harmful T cell immune responses against self-Ags. In this study, we found that murine splenic F4/80(hi)Mac-1(low) MΦs residing in the red pulp showed different expression patterns of surface markers compared with F4/80(+)Mac-1(hi) monocytes/MΦs. Studies with purified cell populations demonstrated that F4/80(hi)Mac-1(low) MΦs regulated CD4(+) T cell responses by producing soluble suppressive factors, including TGF-β and IL-10. Moreover, F4/80(hi)Mac-1(low) MΦs induced the differentiation of naive CD4(+) T cells into functional Foxp3(+) regulatory T cells. Additionally, we found that the differentiation of F4/80(hi)Mac-1(low) MΦs was critically regulated by CSF-1, and in vitro-generated bone marrow-derived MΦs induced by CSF-1 suppressed CD4(+) T cell responses and induced the generation of Foxp3(+) regulatory T cells in vivo. These results suggested that splenic CSF-1-dependent F4/80(hi)Mac-1(low) MΦs are a subpopulation of RPMs and regulate peripheral immune homeostasis.
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, 4, 1-4, Jul. 2013.
(Summary)
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.
Erkhembayar Shinebaatar, Junko Morimoto, Rinna Koga, (名) Nguyen and Koji Yasutomo : Dysfunction of immunoproteasome subunit Psmb8 in T cells induces rapid cell death dependent of TCR engagement, 19th International Congress of Immunology, Aug. 2025.
2.
Junko Morimoto, Rinna Koga, (名) Nguyen and Koji Yasutomo : Dysfunction of the proteasome subunit PSMB5 in adipocytes induces lipodystrophy with autoinflammation, 19th International Congress of Immunology, Wien, Aug. 2025.
3.
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.
4.
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.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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.
11.
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.
12.
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.
13.
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.
14.
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.
15.
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.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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.
21.
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.
22.
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.
23.
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.
Proceeding of Domestic Conference:
1.
Nguyen Nam, Junko Morimoto and Koji Yasutomo : Proteasome dysfunction in adipocytes causes lipodystrophy with autoinflammation, 第54回日本免疫学会学術集会, Dec. 2025.
2.
一ノ瀬 尊之, 福中 彩子, Junko Morimoto, Koji Yasutomo, 志村 まり and 坂口 晃一 : 微少量生体試料のICP-MS高感度測定に向けた取り組み, 日本分析化学会第74年会, Sep. 2025.
3.
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.
4.
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.
5.
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.
6.
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.
7.
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.
8.
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.
9.
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.
10.
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.
11.
Hitoshi Nishijima, Mizuki Sugita, Junko Morimoto, Minoru Matsumoto and Mitsuru Matsumoto : Functional and transcriptomic analysis of medullary thymic epithelial cells with augmented Aire expression, 第42回日本分子生物学会年会, Dec. 2019.
12.
Junko Morimoto, Hitoshi Nishijima, 松本 稔 and Mitsuru Matsumoto : 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, Dec. 2019.
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.
15.
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.
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.
18.
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.
19.
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.
20.
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.
21.
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.
22.
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.
23.
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.
Et cetera, Workshop:
1.
Junko Morimoto and Mitsuru Matsumoto : 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, Oct. 2021.
2.
Junko Morimoto and Mitsuru Matsumoto : 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, Feb. 2021.
identification of molecules involved in autoimmune responses caused by Aire dysfunction (Project/Area Number: 22K07120 )
Analysis of two homologous proteins Ly6C1 and Ly6C2 on immune homeostasis (Project/Area Number: 19K07626 )
Elucidation of the pathogenesis of autoimmune diseases based on AIRE and development of novel therapies for the autoimmune diseases (Project/Area Number: 19H03699 )
Studies on the mechanisms underlying autoimmune ambivalence (Project/Area Number: 18K19564 )
Elucidation of the pathogenesis of autoimmune disease through the functional study of AIRE (Project/Area Number: 16H05342 )
Expression of Ly6C/6G defines a novel Aire-dependent subset of medullary thymic epithelial cells with tolerogenic function (Project/Area Number: 26460577 )