2025/03/27 更新

写真a

クワハラ　マコト
桑原　誠
Kuwahara Makoto
所属
大学院医学系研究科 医学専攻 講師
職名
講師
連絡先
メールアドレス
外部リンク

学位

  • 医学博士 （ 千葉大学 ）

研究テーマ

  • 転写因子Bach2によるTh2細胞の自然免疫応答制御機構の解明

論文

  • Loss of Bach2 in T cells causes prolonged allergic inflammation through the accumulation of effector T cells and disruption of the epidermal barrier

    Miyuki Omori-Miyake, Ryosuke Kawakami, Makoto Kuwahara, Masataka Okabe, Jun Muto, Takeshi Imamura, Masakatsu Yamashita

    Journal of Allergy and Clinical Immunology   2025年2月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

    DOI： 10.1016/j.jaci.2025.01.036

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  • Suppressive effect of the anesthetic propofol on the T cell function and T cell-dependent immune responses. 国際誌

    Waichi Yamamoto, Taisuke Hamada, Junpei Suzuki, Yuko Matsuoka, Miyuki Omori-Miyake, Makoto Kuwahara, Akira Matsumoto, Shunsuke Nomura, Amane Konishi, Toshihiro Yorozuya, Masakatsu Yamashita

    Scientific reports   14 ( 1 )   19337 - 19337   2024年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    General anesthesia is thought to suppress the immune system and negatively affect postoperative infection and the long-term prognosis of cancer. However, the mechanism underlying immunosuppression induced by general anesthetics remains unclear. In this study, we focused on propofol, which is widely used for sedation under general anesthesia and intensive care and examined its effects on the T cell function and T cell-dependent immune responses. We found that propofol suppressed T cell glycolytic metabolism, differentiation into effector T cells, and cytokine production by effector T cells. CD8 T cells activated and differentiated into effector cells in the presence of propofol in vitro showed reduced antitumor activity. Furthermore, propofol treatment suppressed the increase in the number of antigen-specific CD8 T cells during Listeria infection. In contrast, the administration of propofol improved inflammatory conditions in mouse models of inflammatory diseases, such as OVA-induced allergic airway inflammation, hapten-induced contact dermatitis, and experimental allergic encephalomyelitis. These results suggest that propofol may reduce tumor and infectious immunity by suppressing the T cell function and T cell-dependent immune responses while improving the pathogenesis and prognosis of chronic inflammatory diseases by suppressing inflammation.

    DOI： 10.1038/s41598-024-69987-z

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  • The histone demethylase Utx controls CD8+ T-cell-dependent antitumor immunity via epigenetic regulation of the effector function. 国際誌

    Haruna Noda, Junpei Suzuki, Yuko Matsuoka, Akira Matsumoto, Makoto Kuwahara, Yoshiaki Kamei, Yasutsugu Takada, Masakatsu Yamashita

    Cancer science   2023年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    CD8+ T cells play a central role in antitumor immune responses. Epigenetic gene regulation is essential to acquire the effector function of CD8+ T cells. However, the role of Utx, a demethylase of histone H3K27, in antitumor immunity remains unclear. In this study, we examined the roles of Utx in effector CD8+ T-cell differentiation and the antitumor immune response. In a murine tumor-bearing model, an increased tumor size and decreased survival rate were observed in T-cell-specific Utx KO (Utx KO) mice compared with wild-type (WT) mice. The number of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) was significantly decreased in Utx KO mice. We found that the acquisition of effector function was delayed and attenuated in Utx KO CD8+ T cells. RNA sequencing revealed that the expression of effector signature genes was decreased in Utx KO effector CD8+ T cells, while the expression of naïve or memory signature genes was increased. Furthermore, the expression of Cxcr3, which is required for the migration of effector CD8+ T cells to tumor sites, was substantially decreased in Utx KO CD8+ T cells. These findings suggest that Utx promotes CD8+ T-cell-dependent antitumor immune responses partially through epigenetic regulation of the effector function.

    DOI： 10.1111/cas.15814

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  • The Inhibition of Glycolysis in T Cells by a Jak Inhibitor Ameliorates the Pathogenesis of Allergic Contact Dermatitis in Mice. 国際誌

    Michiko Okamoto, Miyuki Omori-Miyake, Makoto Kuwahara, Masataka Okabe, Mariko Eguchi, Masakatsu Yamashita

    The Journal of investigative dermatology   2023年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4+ T cells, CD8+ T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.

    DOI： 10.1016/j.jid.2023.03.1667

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  • アレルギー疾患における免疫細胞による病態形成とその解明 T細胞における解糖経路の阻害はアレルギー性接触皮膚炎の病態を改善する

    岡本 典子, ミヤケ 深雪, 桑原 誠, 江口 真理子, 山下 政克

    アレルギー   71 ( 6-7 )   794 - 794   2022年8月

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    記述言語：日本語   出版者・発行元：(一社)日本アレルギー学会  

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  • Glucocorticoid imprints a low glucose metabolism onto CD8 T cells and induces the persistent suppression of the immune response. 国際誌

    Amane Konishi, Junpei Suzuki, Makoto Kuwahara, Akira Matsumoto, Shunsuke Nomura, Tomoyoshi Soga, Toshihiro Yorozuya, Masakatsu Yamashita

    Biochemical and biophysical research communications   588   34 - 40   2021年12月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Glucocorticoids (GCs), immunosuppressive, and anti-inflammatory agents have various effects on T cells. However, the long-term influence of GCs on the T cell-mediated immune response remain to be elucidated. We demonstrated that the administration of GC during the TCR-mediated activation phase induced long-lasting suppression of glycolysis, even after the withdrawal of GC. The acquisition of the effector functions was inhibited, while the expression of PD-1 was increased in CD8 T cells activated in the presence of GC. Furthermore, adoptive transfer experiments revealed that GC-treated CD8 T cells reduced memory T cell formation and anti-tumor activity. These findings reveal that GCs have long-lasting influence on the T cell-mediated immune response via modulation of T cell metabolism.

    DOI： 10.1016/j.bbrc.2021.12.050

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  • The Loss of H3K27 Histone Demethylase Utx in T Cells Aggravates Allergic Contact Dermatitis. 国際誌

    Takashi Inoue, Miyuki Omori-Miyake, Saho Maruyama, Masataka Okabe, Makoto Kuwahara, Hiroaki Honda, Hiromasa Miura, Masakatsu Yamashita

    Journal of immunology (Baltimore, Md. : 1950)   2021年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    The pathogenesis of allergic contact dermatitis (ACD) requires the activation of Ag-specific T cells, including effector and regulatory T cells. The differentiation and function of these T cells is epigenetically regulated through DNA methylation and histone modifications. However, the roles of altered histone H3K27 methylation in T cells in the development of ACD remain unknown. Two types of histone H3K27 demethylases, Utx and Jmjd3, have been reported in mammals. To determine the role of the histone H3K27 demethylase expression of T cells in the development of ACD, we generated T cell-specific, Utx-deficient (Utx KO) mice or Jmjd3-deficient (Jmjd3 KO) mice. Unlike control mice, Utx KO mice had severer symptoms of ACD, whereas Jmjd3 KO mice showed symptoms identical to those in control mice. In Utx KO mice with ACD, the massive infiltration of myeloid cells, including neutrophils and dendritic cells, has been observed. In addition, the expression of proinflammatory cytokines in CD4+ T cells of the draining lymph nodes (LNs) and in CD8+ T cells of the skin was increased in Utx KO mice, whereas the ratio of Foxp3+ regulatory CD4+ T cells to Foxp3- conventional CD4+ T cells was decreased in both the draining LNs and the skin of Utx KO mice with ACD. Furthermore, Foxp3+ regulatory CD4+ T cells of Utx KO mice with ACD expressed a decreased level of CCR4 (a skin-tropic chemokine receptor) in comparison with control. Thus, in CD4+ T cells, Utx could potentially be involved in the regulation of the pathogenesis of ACD.

    DOI： 10.4049/jimmunol.2001160

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  • T cell-specific deletion of Pgam1 reveals a critical role for glycolysis in T cell responses 査読

    Koji Toriyama, Makoto Kuwahara, Hiroshi Kondoh, Takumi Mikawa, Nobuaki Takemori, Amane Konishi, Toshihiro Yorozuya, Takeshi Yamada, Tomoyoshi Soga, Atsushi Shiraishi, Masakatsu Yamashita

    Communications Biology   3 ( 1 )   2020年12月

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    掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

    DOI： 10.1038/s42003-020-01122-w

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    その他リンク： http://www.nature.com/articles/s42003-020-01122-w

  • Glycolysis and subsequent mevalonate biosynthesis play an important role in Th2 cell differentiation. 国際誌

    Yuichiro Yagi, Makoto Kuwahara, Junpei Suzuki, Yasushi Imai, Masakatsu Yamashita

    Biochemical and biophysical research communications   530 ( 2 )   355 - 361   2020年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    Th2 cytokine such as IL-4, IL -5 and IL-13 are important therapeutic targets for Th2-type chronic inflammation. Several biologics targeting Th2 cytokine and its receptors are effective in clinical practice; however, the development of small-molecule compounds that inhibit Th2 cytokine productions is awaited. We found that an inhibitor for pyruvate dehydrogenase kinase (PDHK) suppresses the differentiation of IL-5/IL-13-producing Th2 cells. The expression of the Th2-related transcriptional factors Pparγ was decreased by treatment with inhibitor, whereas Gata3, a master regulator of Th2 cell differentiation, remained unchanged. The oxygen consumption rate was unaffected, whereas the level of farnesylated proteins was decreased by the PDHK inhibitor. Furthermore, the inhibitors for farnesyltransferase and hydroxymethylglutaryl-CoA reductase showed an inhibitory effect similar to that of the PDHK inhibitor. These results suggest that the mevalonate biosynthesis and subsequent protein prenylation may be novel therapeutic target for Th2 cell-dependent immune dysregulation, such as in allergic diseases.

    DOI： 10.1016/j.bbrc.2020.08.009

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  • Pyrrothiogatain acts as an inhibitor of GATA family proteins and inhibits Th2 cell differentiation in vitro. 査読

    Nomura S, Takahashi H, Suzuki J, Kuwahara M, Yamashita M, Sawasaki T

    Scientific reports   9 ( 1 )   17335   2019年11月

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  • BAtF-interacting proteins dictate specificity in th subset activity

    Yongyao Fu, Byunghee Koh, Makoto Kuwahara, Benjamin J. Ulrich, Rakshin Kharwadkar, Masakatsu Yamashita, Mark H. Kaplan

    Journal of Immunology   203 ( 7 )   1989 - 1998   2019年10月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Association of Immunologists  

    The basic leucine zipper (bZIP) transcription factor BATF is expressed in multiple Th subsets and cooperates with other factors to regulate gene transcription. BATF activates lineage-specific cytokines in Th subsets, activating IL-9 in Th9 cells and IL-17 in Th17 cells, but not IL-9 or IL-17 in the reciprocal subset. The mechanism for this restricted activity is unclear. In this report, we define BATF binding partners that contribute to Th subset–specific functions. Although BATF and IRF4 are expressed in greater amounts in Th9 than Th17, increased expression of both factors is not sufficient to induce IL-9 in Th17 cells. BATF also requires heterodimer formation with Jun family members to bind DNA and induce gene expression. Using primary mouse T cell culture, we observed that JunB and c-Jun, but not JunD, promote IL-9 production in Th9 cells. Ectopic expression of BATF with either JunB or c-Jun generates modest, but significant, increases in IL-9 production in Th17 cells, suggesting that the low expression of Jun family members is one factor limiting the ability of BATF to induce IL-9 in Th17 cells. We further identified that Bach2 positively regulates IL-9 production by directly binding to the Il9 gene and by increasing transcription factor expression in Th9 cells. Strikingly, cotransduction of Bach2 and BATF significantly induces IL-9 production in both Th9 and Th17 cells. Taken together, our results reveal that JunB, c-Jun, and Bach2 cooperate with BATF to contribute to the specificity of BATF-dependent cytokine induction in Th subsets.

    DOI： 10.4049/jimmunol.1900128

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  • Reinforce the antitumor activity of CD8<sup>+</sup> T cells via glutamine restriction. 査読

    Nabe S, Yamada T, Suzuki J, Toriyama K, Yasuoka T, Kuwahara M, Shiraishi A, Takenaka K, Yasukawa M, Yamashita M

    Cancer science   109 ( 12 )   3737 - 3750   2018年12月

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  • The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation. 査読 国際誌

    Junpei Suzuki, Takeshi Yamada, Kazuki Inoue, Shogo Nabe, Makoto Kuwahara, Nobuaki Takemori, Ayako Takemori, Seiji Matsuda, Makoto Kanoh, Yuuki Imai, Masaki Yasukawa, Masakatsu Yamashita

    Nature communications   9 ( 1 )   3296 - 3296   2018年8月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    While menin plays an important role in preventing T-cell dysfunction, such as senescence and exhaustion, the regulatory mechanisms remain unclear. We found that menin prevents the induction of dysfunction in activated CD8 T cells by restricting the cellular metabolism. mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis are augmented by menin deficiency. Rapamycin treatment prevents CD8 T-cell dysfunction in menin-deficient CD8 T cells. Limited glutamine availability also prevents CD8 T-cell dysfunction induced by menin deficiency, and its inhibitory effect is antagonized by α-ketoglutarate (α-KG), an intermediate metabolite of glutaminolysis. α-KG-dependent histone H3K27 demethylation seems to be involved in the dysfunction in menin-deficient CD8 T cells. We also found that α-KG activates mTORC1-dependent central carbon metabolism. These findings suggest that menin maintains the T-cell functions by limiting mTORC 1 activity and subsequent cellular metabolism.

    DOI： 10.1038/s41467-018-05854-6

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  • The critical role of Bach2 in regulating type 2 chronic airway inflammation. 査読

    Yamashita M, Kuwahara M

    International immunology   30 ( 9 )   397 - 402   2018年8月

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  • The transcriptional repressor Bach2 controls Th2-type immune response via interaction with Batf 査読

    Kuwahara Makoto, Sawasaki Tatsuya, Yamashita Masakatsu

    CYTOKINE   100   34   2017年12月

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  • Inflammatory responses induce an identity crisis of alveolar macrophages, leading to pulmonary alveolar proteinosis 査読

    Risa Ebina-Shibuya, Mitsuyo Matsumoto, Makoto Kuwahara, Kyoung-Jin Jang, Manabu Sugai, Yoshiaki Ito, Ryo Funayama, Keiko Nakayama, Yuki Sato, Naoto Ishii, Yasunobu Okamura, Kengo Kinoshita, Kohei Kometani, Tomohiro Kurosaki, Akihiko Muto, Masakazu Ichinose, Masakatsu Yamashita, Kazuhiko Igarashi

    JOURNAL OF BIOLOGICAL CHEMISTRY   292 ( 44 )   18098 - 18112   2017年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    Pulmonary alveolar proteinosis (PAP) is a severe respiratory disease characterized by dyspnea caused by accumulation of surfactant protein. Dysfunction of alveolar macrophages (AMs), which regulate the homeostasis of surfactant protein, leads to the development of PAP; for example, in mice lacking BTB and CNC homology 2 (Bach2). However, how Bach2 helps prevent PAP is unknown, and the cell-specific effects of Bach2 are undefined. Using mice lacking Bach2 in specific cell types, we found that the PAP phenotype of Bach2-deficient mice is due to Bach2 deficiency in more than two types of immune cells. Depletion of hyperactivated T cells in Bach2-deficient mice restored normal function of AMs and ameliorated PAP. We also found that, in Bach2-deficient mice, hyperactivated T cells induced gene expression patterns that are specific to other tissue-resident macrophages and dendritic cells. Moreover, Bach2-deficient AMs exhibited a reduction in cell cycle progression. IFN- released from T cells induced Bach2 expression in AMs, in which Bach2 then bound to regulatory regions of inflammation-associated genes in myeloid cells. Of note, in AMs, Bach2 restricted aberrant responses to excessive T cell-induced inflammation, whereas, in T cells, Bach2 puts a brake on T cell activation. Moreover, Bach2 stimulated the expression of multiple histone genes in AMs, suggesting a role of Bach2 in proper histone expression. We conclude that Bach2 is critical for the maintenance of AM identity and self-renewal in inflammatory environments. Treatments targeting T cells may offer new therapeutic strategies for managing secondary PAP.

    DOI： 10.1074/jbc.M117.808535

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  • Menin Plays a Critical Role in the Regulation of the Antigen-Specific CD8(+) T Cell Response upon Listeria Infection 査読

    Takeshi Yamada, Makoto Kanoh, Shogo Nabe, Toshiaki Yasuoka, Junpei Suzuki, Akira Matsumoto, Makoto Kuwahara, Saho Maruyama, Takuya Fujimoto, Ryo Sakisuka, Masaki Yasukawa, Masakatsu Yamashita

    JOURNAL OF IMMUNOLOGY   197 ( 10 )   4079 - 4089   2016年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC IMMUNOLOGISTS  

    Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8(+) T cells remains unclear. We generated Menin(flox/flox) CD4-Cre (Menin-KO) mice by crossing Menin(flox/flox) mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8(+) T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8(+) T cells. Menin deficiency resulted in an impaired primary immune response by CD8+ T cells. On day 7, there were fewer Menin-KO OVA-specific CD8(+) T cells compared with WT cells. Next, we adoptively transferred WT and Menin-KO OT-1 Tg CD8(+) T cells into congenic recipient mice and infected them with L. monocytogenes expressing OVA to determine the CD8(+) T cell-intrinsic effect. Menin-KO OT-1 Tg CD8(+) T cells were outcompeted by the WT cells upon infection. Increased expression of Blimp-1 and T-bet, cell cycle inhibitors, and proapoptotic genes was observed in the Menin-KO OT-1 Tg CD8(+) T cells upon infection. These data suggest that menin inhibits differentiation into terminal effectors and positively controls proliferation and survival of Ag-specific CD8(+) T cells that are activated upon infection. Collectively, our study uncovered an important role for menin in the immune response of CD8(+) T cells to infection.

    DOI： 10.4049/jimmunol.1502295

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  • Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop 査読

    Makoto Kuwahara, Wataru Ise, Mizuki Ochi, Junpei Suzuki, Kohei Kometani, Saho Maruyama, Maya Izumoto, Akira Matsumoto, Nobuaki Takemori, Ayako Takemori, Kenta Shinoda, Toshinori Nakayama, Osamu Ohara, Masaki Yasukawa, Tatsuya Sawasaki, Tomohiro Kurosaki, Masakatsu Yamashita

    NATURE COMMUNICATIONS   7   12596   2016年9月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

    Although Bach2 has an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the Batf-Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we find that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2-Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf-Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2-Batf interactions are required to prevent an excessive Th2 response.

    DOI： 10.1038/ncomms12596

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  • The Transcriptional Repressor Gfi1 Plays a Critical Role in the Development of NKT1-and NKT2-Type iNKT Cells 査読

    Toshiaki Yasuoka, Makoto Kuwahara, Takeshi Yamada, Saho Maruyama, Junpei Suzuki, Masaru Taniguchi, Masaki Yasukawa, Masakatsu Yamashita

    PLOS ONE   11 ( 6 )   e0157395   2016年6月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

    Gfi1 plays an important role in the development and maintenance of many hematopoietic linage cells. However, the impact of Gfi1-deficiency on the iNKT cell differentiation remains unclear. We herein demonstrate a critical role of Gfi1 in regulating the development of iNKT cell subsets. In the thymus of T cell-specific Gfi1-deficient mice, iNKT cells normally developed up to stage 2, while the number of stage 3 NK1.1(pos) iNKT cells was significantly reduced. Furthermore, CD4(pos) iNKT cells were selectively reduced in the peripheral organs of T cell-specific Gfi1-deficient mice. The alpha-GalCer-dependent production of IFN-gamma and Th2 cytokines, but not IL-17A, was severely reduced in T cell-specific Gfi1-deficient mice. In addition, a reduction of the alpha-GalCer-induced anti-tumor activity was observed in Gfi1-deficient mice. These findings demonstrate the important role of Gfi1 in regulating the development and function of NKT1- and NKT2-type iNKT cell subsets.

    DOI： 10.1371/journal.pone.0157395

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  • Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells 査読

    Junpei Suzuki, Saho Maruyama, Hidekazu Tamauchi, Makoto Kuwahara, Mika Horiuchi, Masumi Mizuki, Mizuki Ochi, Tatsuya Sawasaki, Jinfang Zhu, Masaki Yasukawa, Masakatsu Yamashita

    IMMUNOLOGY   147 ( 4 )   476 - 487   2016年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

    A transcriptional repressor Gfi1 promotes T helper type 2 (Th2) cell development and inhibits Th17 and inducible regulatory T-cell differentiation. However, the role of Gfi1 in regulating Th1 cell differentiation and the Th1-type immune response remains to be investigated. We herein demonstrate that Gfi1 inhibits the induction of the Th1 programme in activated CD4 T cells. The activated Gfi1-deficient CD4 T cells spontaneously develop into Th1 cells in an interleukin-12-and interferon-gamma-independent manner. The increase of Th1-type immune responses was confirmed in vivo in Gfi1-deficient mice using a murine model of nickel allergy and delayed-type hypersensitivity (DTH). The expression levels of Th1-related transcription factors were found to increase in Gfi1-deficient activated CD4 T cells. Tbx21, Eomes and Runx2 were identified as possible direct targets of Gfi1. Gfi1 binds to the Tbx21, Eomes and Runx2 gene loci and reduces the histone H3K4 methylation levels in part by modulating Lsd1 recruitment. Together, these findings demonstrate a novel regulatory role of Gfi1 in the regulation of the Th1-type immune response.

    DOI： 10.1111/imm.12580

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  • A novel function of interferon regulatory factor-1: inhibition of T(h)2 cells by down-regulating the Il4 gene during Listeria infection 査読

    Saho Maruyama, Makoto Kanoh, Akira Matsumoto, Makoto Kuwahara, Masakatsu Yamashita, Yoshihiro Asano

    INTERNATIONAL IMMUNOLOGY   27 ( 3 )   143 - 152   2015年3月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：OXFORD UNIV PRESS  

    Infection with certain pathogens induces a shift of the T-h subset balance to a T(h)1 dominant state. This, in turn, results in the suppression of T(h)2 responses. We focused on the involvement of interferon regulatory factor-1 (IRF-1) in the suppression of T(h)2 cells during Listeria infection. We found that the inhibition of IL-4 production by T(h)2 cells is mediated by a soluble factor (LmSN) produced by Listeria-infected antigen-presenting cells. The inhibition is not observed with T cells from Irf1 gene-targeted mice. IRF-1 suppresses transcription of the Il4 gene in T(h)2 cells. Under the influence of the LmSN, IRF-1 binds to the 3 ' untranslated region (UTR) region of the Il4 gene and down-regulates Il4 gene transcription. Finally, we identified IL-1 alpha and IL-1 beta as the mediator of the LmSN activity. Signaling through IL-1R induces the stabilization and/or nuclear translocation of IRF-1. We propose that IRF-1 functions to induce the T-cell subset shift via a novel mechanism. Under the influence of IL-1, IRF-1 translocates into the nucleus and acts on the 3 ' UTR region of the Il4 gene, thus inhibiting its transcription in T(h)2 cells. As a result, the immune system shifts predominantly to a T(h)1 response during Listeria infection, resulting in effective protection of the host.

    DOI： 10.1093/intimm/dxu092

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  • ヘルパーT細胞活性化と分化 Bach2-Blimp1 axisはアレルギー性気道炎症の調節に重要な役割を果たす(Regulatory T cells Bach2-Blimp1 axis plays an important role in the regulation of allergic airway inflammation)

    Izumoto Maya, Kuwahara Makoto, Kiyoi Takeshi, Shinoda Kenta, Nakayama Toshinori, Kurosaki Tomohiro, Yamashita Masakatsu

    日本免疫学会総会・学術集会記録   43 ( Proceedings )   180 - 180   2014年11月

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    記述言語：英語   出版者・発行元：(NPO)日本免疫学会  

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  • ヘルパーT細胞活性化と分化 Bach2はTh2細胞介在性免疫応答をglutaminolysisの調整を介して制御する(Regulatory T cells Bach2 controls Th2 cell-mediated immune responses through regulation of glutaminolysis)

    Kuwahara Makoto, Ochi Mizuki, Kiyoi Takeshi, Kurosaki Tomohiro, Yamashita Masakatsu

    日本免疫学会総会・学術集会記録   43 ( Proceedings )   178 - 178   2014年11月

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    記述言語：英語   出版者・発行元：(NPO)日本免疫学会  

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  • The Menin-Bach2 axis is critical for regulating CD4 T-cell senescence and cytokine homeostasis 査読

    Makoto Kuwahara, Junpei Suzuki, Soichi Tofukuji, Takeshi Yamada, Makoto Kanoh, Akira Matsumoto, Saho Maruyama, Kohei Kometani, Tomohiro Kurosaki, Osamu Ohara, Toshinori Nakayama, Masakatsu Yamashita

    NATURE COMMUNICATIONS   5   3555   2014年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

    Although CD4 T-cell senescence plays an important role in immunosenescence, the mechanism behind this process remains unclear. Here we show that T cell-specific Menin deficiency results in the premature senescence of CD4 T cells, which is accompanied by the senescence-associated secretory phenotype after antigenic stimulation and dysregulated cytokine production. Menin is required for the expansion and survival of antigen-stimulated CD4 T cells in vivo and acts by targeting Bach2, which is known to regulate immune homeostasis and cytokine production. Menin binds to the Bach2 locus and controls its expression through maintenance of histone acetylation. Menin binding at the Bach2 locus and the Bach2 expression are decreased in the senescent CD4 T cells. These findings reveal a critical role of the Menin-Bach2 pathway in regulating CD4 T-cell senescence and cytokine homeostasis, thus indicating the involvement of this pathway in the inhibition of immunosenescence.

    DOI： 10.1038/ncomms4555

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  • A Novel Small Compound SH-2251 Suppresses Th2 Cell-Dependent Airway Inflammation through Selective Modulation of Chromatin Status at the Il5 Gene Locus 査読

    Junpei Suzuki, Makoto Kuwahara, Soichi Tofukuji, Masashi Imamura, Fuminori Kato, Toshinori Nakayama, Osamu Ohara, Masakatsu Yamashita

    PLoS ONE   8 ( 4 )   e61785   2013年4月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    IL-5 is a key cytokine that plays an important role in the development of pathological conditions in allergic inflammation. Identifying strategies to inhibit IL-5 production is important in order to establish new therapies for treating allergic inflammation. We found that SH-2251, a novel thioamide-related small compound, selectively inhibits the differentiation of IL-5-producing Th2 cells. SH-2251 inhibited the induction of active histone marks at the Il5 gene locus during Th2 cell differentiation. The recruitment of RNA polymerase II, and following expression of the Th2 cell-specific intergenic transcripts around the Il5 gene locus was also inhibited. Furthermore, Th2 cell-dependent airway inflammation in mice was suppressed by the oral administration of SH-2251. Gfi1, a transcriptional repressor, was identified as a downstream target molecule of SH-2251 using a DNA microarray analysis. The Gfi1 expression dramatically decreased in SH-2251-treated Th2 cells, and the SH-2251-mediated inhibition of IL-5-producing Th2 cell differentiation was restored by transduction of Gfi1. Therefore, our study unearthed SH-2251 as a novel therapeutic candidate for allergic inflammation that selectively inhibits active histone marks at the Il5 gene locus. © 2013 Suzuki et al.

    DOI： 10.1371/journal.pone.0061785

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  • Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGF-β. 査読

    Tofukuji S, Kuwahara M, Suzuki J, Ohara O, Nakayama T, Yamashita M

    Journal of immunology (Baltimore, Md. : 1950)   188 ( 10 )   4846 - 4857   2012年5月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）  

    DOI： 10.4049/jimmunol.1103799

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  • The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses T(H)2 differentiation. 査読

    Kuwahara M, Yamashita M, Shinoda K, Tofukuji S, Onodera A, Shinnakasu R, Motohashi S, Hosokawa H, Tumes D, Iwamura C, Lefebvre V, Nakayama T

    Nature immunology   13 ( 8 )   778 - 786   2012年

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    掲載種別：研究論文（学術雑誌）  

    DOI： 10.1038/ni.2362

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  • Eomesodermin Controls Interleukin-5 Production in Memory T Helper 2 Cells through Inhibition of Activity of the Transcription Factor GATA3 査読

    Yusuke Endo, Chiaki Iwamura, Makoto Kuwahara, Akane Suzuki, Kaoru Sugaya, Damon J. Tumes, Koji Tokoyoda, Hiroyuki Hosokawa, Masakatsu Yamashita, Toshinori Nakayama

    IMMUNITY   35 ( 5 )   733 - 745   2011年11月

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    記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

    The regulation of memory CD4(+) helper T (Th) cell function, such as polarized cytokine production, remains unclear. Here we show that memory T helper 2 (Th2) cells are divided into four subpopulations by CD62L and CXCR3 expression. All four subpopulations produced interleukin-4 (IL-4) and IL-13, whereas only the CD62L(lo)CXCR3(lo) population produced IL-5 accompanied by increased H3-K4 methylation at the 115 gene locus. The transcription factor Eomesodermin (encoded by Eomes) was highly expressed in memory Th2 cells, whereas its expression was selectively downregulated in the IL-5-producing cells. 115 expression was enhanced in Eomes-deficient cells, and Eomesodermin was shown to interact with the transcription factor GATA3, preventing GATA3 binding to the 115 promoter. Memory Th2 cell-dependent airway inflammation was attenuated in the absence of the CD62L(lo)CXCR3(lo) population but was enhanced by Eomes-deficient memory Th2 cells. Thus, IL-5 production in memory Th2 cells is regulated by Eomesodermin via the inhibition of GATA3 activity.

    DOI： 10.1016/j.immuni.2011.08.017

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  • STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells 査読

    Onodera, A., Yamashita, M., Endo, Y., Kuwahara, M., Tofukuji, S., Hosokawa, H., Kanai, A., Suzuki, Y., Nakayama, T.

    Journal of Experimental Medicine   207 ( 11 )   2493 - 2506   2010年

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    掲載種別：研究論文（学術雑誌）  

    DOI： 10.1084/jem.20100760

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  • Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene 査読

    Yamashita, M., Kuwahara, M., Suzuki, A., Hirahara, K., Shinnaksu, R., Hosokawa, H., Hasegawa, A., Motohashi, S., Iwama, A., Nakayama, T.

    Journal of Experimental Medicine   205 ( 5 )   1109 - 1120   2008年

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    掲載種別：研究論文（学術雑誌）  

    DOI： 10.1084/jem.20072000

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  • Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation 査読

    Shinnakasu, R., Yamashita, M., Kuwahara, M., Hosokawa, H., Hasegawa, A., Motohashi, S., Nakayama, T.

    Journal of Biological Chemistry   283 ( 42 )   28216 - 28225   2008年

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    掲載種別：研究論文（学術雑誌）  

    DOI： 10.1074/jbc.M804174200

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  • Evaluating the immune responses stimulated by CpG oligodeoxynucleotides. 査読

    Hayashi M, Kuwahara M, Ogata M, Miyao-Kurosaki N, Abel T, Ueki R, Yano M, Fujii M, Hartmann G, Takaku H

    Nucleic acids research. Supplement (2001)   ( 3 )   323 - 324   2003年

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