所属
大学院医学系研究科 医学専攻 講師
職名
講師
連絡先
外部リンク
クワハラ マコト
桑原 誠
Kuwahara Makoto
学位
学位
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医学博士 （ 千葉大学 ）
研究テーマ
研究テーマ
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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
論文
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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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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.
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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.
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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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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.
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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.
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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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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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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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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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.
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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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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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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.
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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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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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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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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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MISC
MISC
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イムノメタボリズムとT細胞の疲弊・老化 グルタミン代謝によるT細胞老化のエピジェネティック制御とがん免疫
鈴木淳平, 桑原誠, 山下政克
実験医学 38 ( 19 ) 2020年
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エピゲノムおよび転写制御による免疫リプログラミング T細胞老化のエピジェネティック制御
鈴木淳平, 桑原誠, 山下政克
医学のあゆみ 275 ( 1 ) 2020年
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グルタミン代謝調節を介したT細胞老化制御
鈴木淳平, 桑原誠, 山下政克
愛媛医学 39 ( 1 ) 2020年
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井上卓, 井上卓, 丸山砂穂, 桑原誠, 三浦裕正, 山下政克
日本整形外科学会雑誌 92 ( 8 ) S1805 2018年8月
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腫瘍抑制因子Meninはグルタミン代謝調節を介してCD8 T細胞の老化を制御する
鈴木淳平, 鈴木淳平, 桑原誠, 山田武司, 安川正貴, 山下政克
日本抗加齢医学会総会プログラム・抄録集 18th 189 2018年
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山下政克, 鈴木淳平, 桑原誠
日本抗加齢医学会総会プログラム・抄録集 18th 99 2018年
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山下政克, 桑原誠, 鈴木淳平
アンチ・エイジング医学 13 ( 3 ) 344‐350 2017年6月
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ヘルパーT細胞の制御と代謝 転写抑制因子Bach2によるタイプ2免疫反応の制御
山下政克, 桑原誠
月刊臨床免疫・アレルギー科 67 ( 2 ) 140‐146 2017年2月
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腫瘍抑制因子MeninはmTORC1シグナルの調節を介して腫瘍免疫を制御する
鈴木淳平, 鈴木淳平, 鈴木淳平, 桑原誠, 桑原誠, 山田武司, 松本哲, 安川正貴, 安川正貴, 山下政克, 山下政克
日本がん免疫学会総会プログラム・抄録集 21st 140 2017年
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慢性炎症疾患の新たな展開 慢性炎症のメカニズム 転写抑制因子Bach2によるT細胞SASPと慢性アレルギー性炎症の制御
山下政克, 桑原誠
最新医学 71 2211‐2216 2016年11月
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Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop
M. Yamashita, M. Ochi, T. Sawasaki, M. Kuwahara
EUROPEAN JOURNAL OF IMMUNOLOGY 46 993 - 993 2016年8月
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A tumor suppressor Menin controls CD8 T cell senescence by regulating energy metabolism
J. Suzuki, M. Kuwahara, M. Yasukawa, M. Yamashita
EUROPEAN JOURNAL OF IMMUNOLOGY 46 1011 - 1012 2016年8月
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桑原誠, 桑原誠, 桑原誠, 井上和樹, 井上和樹, 今井祐記, 今井祐記, 山下政克, 山下政克, 山下政克
がんと代謝研究会プログラム&抄録集 4th 60 2016年7月
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山下政克, 山下政克, 鈴木淳平, 鈴木淳平, 鈴木淳平, 桑原誠, 桑原誠
日本老年医学会雑誌 53 27 2016年5月
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桑原誠, 桑原誠, 桑原誠, 鈴木淳平, 鈴木淳平, 鈴木淳平, 山下政克, 山下政克, 山下政克
日本抗加齢医学会総会プログラム・抄録集 16th 164 2016年
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コムギ無細胞サイトカイン関連プロテインアレイにより見出した新規カスパーゼ1基質の解析
増原有紀, 高橋宏隆, 桑原誠, 鈴木淳平, 山下政克, 澤崎達也
日本分子生物学会年会プログラム・要旨集(Web) 39th ROMBUNNO.1P‐0570 (WEB ONLY) 2016年
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臓器の記憶と血管代謝ニッシェ 7 T細胞老化に起因する炎症性記憶の形成機構
山下政克, 桑原誠
血管医学 16 ( 4 ) 365 - 371 2015年12月
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細胞内エネルギー代謝調節によるヘルパーT細胞分化とアレルギー性気道炎症の制御
桑原誠, 桑原誠, 山下政克, 山下政克
日本病態生理学会雑誌 24 ( 2 ) 23 2015年7月
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塩入幹汰, 桑原誠, 山下政克
アレルギー 64 ( 3/4 ) 462 2015年4月
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コムギ無細胞系を基盤としたサイトカイン関連プロテインアレイを用いたカスパーゼ1新規基質の探索と解析
増原有紀, 高橋宏隆, 桑原誠, 山下政克, 澤崎達也
日本生化学会大会(Web) 88th 3P0387 (WEB ONLY) 2015年
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腫瘍抑制因子Meninは代謝調節を介してCD8T細胞老化を制御する
鈴木淳平, 桑原誠, 桑原誠, 山田武司, 安川正貴, 山下政克, 山下政克
がんと代謝研究会プログラム&抄録集 3rd 55 2015年
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桑原誠, 桑原誠, 桑原誠, 鈴木淳平, 山下政克, 山下政克, 山下政克
日本生化学会大会(Web) 88th 2W19-6 (WEB ONLY) 2015年
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桑原誠, 山下政克
愛媛医学 33 ( 3 ) 107 - 112 2014年9月
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【炎症の抑制・終焉機構】 転写因子Sox4を介するTGF-βによるアレルギー炎症の抑制機構
桑原 誠, 山下 政克, 中山 俊憲
炎症と免疫 22 ( 2 ) 94 - 97 2014年2月
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記述言語：日本語 出版者・発行元：(株)先端医学社
抑制性サイトカインであるTGF-βはTh2分化や機能を阻害することが知られているが、その分子機構は完全には解明されていない。最近、筆者らは、TGF-βによって発現が制御され、Th2分化やその機能を抑制する分子として、転写因子Sox4を見出した。T細胞特異的なSox4トランスジェニックマウス、Sox4欠損マウスの解析から、Sox4はTh2分化および機能を抑制することがわかった。さらに、Sox4をノックダウンすることで、TGF-βによるTh2分化の抑制が部分的に解除されたことから、Sox4がTGF-βによるTh2分化抑制に関与することが明らかとなった。(著者抄録)
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Sox4、TGF-βとTh2分化
桑原 誠, 山下 政克, 中山 俊憲
感染・炎症・免疫 43 ( 2 ) 154 - 155 2013年7月
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免疫学 転写因子Sox4によるTh2細胞分化制御
桑原 誠, 山下 政克, 中山 俊憲
医学のあゆみ 245 ( 7 ) 602 - 603 2013年5月
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TGF‐βによるT<sub>H</sub>1/T<sub>H</sub>2細胞分化の新しい制御機構
桑原誠, 山下政克
月刊臨床免疫・アレルギー科 58 ( 5 ) 593 - 600 2012年11月
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山下政克, 東福寺聡一, 鈴木淳平, 桑原誠
日本小児アレルギー学会誌 26 ( 1 ) 30 - 36 2012年3月
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山下政克, 東福寺聡一, 鈴木淳平, 桑原誠
日本小児アレルギー学会誌 25 ( 3 ) 413 2011年8月
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Sox4によるTh1細胞分化制御の解析
東福寺 聡一, 桑原 誠, 鈴木 淳平, 小原 收, 中山 俊憲, 山下 政克
日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 83回・33回 3T11 - 1 2010年12月
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新規チオアミド系化合物SH-2251はTh2細胞分化に伴うIL-5遺伝子座のクロマチンリモデリングを阻害する
鈴木 淳平, 東福寺 聡一, 桑原 誠, 今村 匡志, 中山 俊憲, 小原 收, 加藤 文法, 山下 政克
日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 83回・33回 3P - 1032 2010年12月
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Gfi1はGATA3蛋白質の安定化を介してTh2細胞分化を制御する
山下政克, 新中須亮, 桑原誠, 中山俊憲
生化学 1T20-8 2008年
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Bmi1はNoxa遺伝子の発現調節を介してメモリーCD4T細胞の生存を制御する
山下政克, 桑原誠, 新中須亮, 細川裕之, 中山俊憲
生化学 4P-1041 2007年
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