Elucidating the molecular basis of regulatory T cell differentiation and function

• Project/Area Number: 20689012
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: HORI Shohei The Institute of Physical and Chemical Research, 免疫恒常性研究ユニット, ユニットリーダー (50392113)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥25,350,000 (Direct Cost: ¥19,500,000、Indirect Cost: ¥5,850,000); Fiscal Year 2010: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2009: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000); Fiscal Year 2008: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: 自己免疫疾患 / 免疫寛容 / 免疫制御 / 制御性T細胞 / 遺伝子発現制御 / 分化可塑性 / 免疫抑制 / 免疫疾患 / 転写因子 / 網羅的遺伝子発現解析 / 細胞分化

Research Abstract

We conducted two lines of research, which aim at elucidating the mechanisms of regulatory T cell (Treg) differentiation and function. First, we asked whether and how naturally occurring Foxp3 gene mutations identified in human IPEX affect Treg differentiation and function by generating knock-in mice. We found that one of the mutations resulted in the development of autoimmune diseases similar to human IPEX, which was associated with a selective deficiency of a "tissue-seeking" subset of Treg cells. These results suggest that Foxp3+ Treg cells consist of functionally distinct subsets, each of which may play non-redundant roles in the establishment and maintenance of self-tolerance. Second, we found that Foxp3^+ T cells are heterogeneous in that they contain a minor, functionally uncommitted, plastic subpopulation that loses Foxp3 expression and converts to helper T cells in response to environmental perturbations.

Research Products

• [Journal Article] Enhanced murine contact hypersensitivity by depletion of endogenous regulatory T cells in the sensitization phase. (2011)
  • Author(s): Honda, T., Otsuka, A., Tanizaki, H., Minegaki, Y., Nagao, K., Waldmann, H., Tomura, M., Hori, S., Miyachi, Y., Kabashima, K.
  • Journal Title: J.Dermatol.Sci. 61 Pages: 144-147
  • NAID: 10030890224
  • Peer Reviewed
• [Journal Article] Induction of colonic regulatory T cells by indigenous Clostridium species. (2011)
  • Author(s): Atarashi, K., Tanoue, T., Shima, T., Imaoka, A., Kuwahara, T., Momose, Y., Cheng, G., Yamasaki, S., Saito, T., Ohba, Y., Taniguchi, T., Takeda, K., Hori, S., Ivanov, I.I., Umesaki, Y., Itoh, K., Honda, K.
  • Journal Title: Science 331 Pages: 337-341
  • Peer Reviewed
• [Journal Article] Enhanced murine contact hypersensitivity by depletion of endogenous regulatory T cells in the sensitization phase. (2011)
  • Author(s): Honda, T., et al.
  • Journal Title: Journal of Dermatological Science Volume: 61 Pages: 144-147
  • Peer Reviewed
• [Journal Article] Induction of colonic regulatory T cells by indigenous Clostridium species (2011)
  • Author(s): Atarashi, K., et al.
  • Journal Title: Science Volume: 331 Pages: 337-341
  • Peer Reviewed
• [Journal Article] Developmental plasticity of Foxp3^+ regulatory T cells. (2010)
  • Author(s): Hori, S.
  • Journal Title: Curr.Opin.Immunol.y 22 Pages: 575-582
  • Peer Reviewed
• [Journal Article] Activated regulatory T cells are the major T cell type emigrating from sensitized skin. (2010)
  • Author(s): Tomura, M., Honda, T., Tanizaki, H., Otsuka, A., Egawa, G., Tokura, Y., Waldmann, H., Hori, S., Cyster, J.G., Watanabe, T., Miyachi, Y., Kanagawa, O., Kabashima, K.
  • Journal Title: J.Clin.Invest. 120 Pages: 883-893
  • Peer Reviewed
• [Journal Article] Exacerbation of delayed-type hypersensitivity responses in EBV-induced gene-3 (EBI-3)-deficient mice. (2010)
  • Author(s): Tong, H., Miyazaki, Y., Yamazaki, M., Hara, H., Waldmann, H., Hori, S., Yoshida, H.
  • Journal Title: Immunol.Lett. 128 Pages: 108-115
  • Peer Reviewed
• [Journal Article] c-Rel : A pioneer in directing regulatory T cell lineage commitment? (2010)
  • Author(s): Hori, S.
  • Journal Title: Eur.J.Immunol. 40 Pages: 664-667
  • Peer Reviewed
• [Journal Article] Developmental plasticity of Foxp3^+ regulatory T cells (2010)
  • Author(s): Hori, S.
  • Journal Title: Current Opinion in Immunology Volume: 22 Pages: 575-582
  • Peer Reviewed
• [Journal Article] c-Rel : A pioneer in directing regulatory T cell lineage commitment? (2010)
  • Author(s): Hori, S.
  • Journal Title: European Journal of Immunology (印刷中)
  • Peer Reviewed
• [Journal Article] Exacerbation of delayed-type hypersensitivity responses in EBV-induced gene-3(EBI-3)-deficient mice (2010)
  • Author(s): Tong, H.et al.
  • Journal Title: Immunology Letters (印刷中)
  • Peer Reviewed
• [Journal Article] Activated regulatory T cells are the major T cell type emigrating from sensitizedskin (2010)
  • Author(s): Tomura, M.et al.
  • Journal Title: Journal of Clinical Investigation (印刷中)
  • Peer Reviewed
• [Journal Article] Cutting Edge : Depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. (2009)
  • Author(s): Kim, J., Lahl, K., Hori, S., Loddenkemper, C., Chaudhry A., deRoos, P., Rudensky, A., Sparwasser, T.
  • Journal Title: J.Immunol. 183 Pages: 7631-7634
  • Peer Reviewed
• [Journal Article] Preferential generation of follicular B helper T cells from Foxp3^+ T cells in gut Peyer's patches. (2009)
  • Author(s): Tsuji, M., Komatsu, N., Kawamoto, S., Kanagawa, O., Honjo, T., Hori, S., Fagarasan, S.
  • Journal Title: Science 323 Pages: 1488-1492
  • Peer Reviewed
• [Journal Article] Heterogeneity of natural Foxp3^+ T cells : a committed regulatory T cell lineage and an uncommitted minor population retaining plasticity. (2009)
  • Author(s): Komatsu, N., Mariotti-Ferrandiz, M.E., Wang, Y., Malissen, B., Waldmann, H., Hori, S.
  • Journal Title: PNAS 106 Pages: 1903-1908
  • Peer Reviewed
• [Journal Article] Cutting Edge : Depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice (2009)
  • Author(s): Kim, J.et al.
  • Journal Title: Journal of Immunology 183 Pages: 7631-7634
  • Peer Reviewed
• [Journal Article] Preferential generation of follicular B helper T (TFH) cells from Foxp3+ T cells in gut Peyer's patches (2009)
  • Author(s): Tsuji, M., et al
  • Journal Title: Science (in press)
  • Peer Reviewed
• [Journal Article] Heterogeneity of natural Foxp3+ T cell : a committed regulatory T cell lineage and an uncommitted minor population retaining plasticity (2009)
  • Author(s): Komatsu, N., et al
  • Journal Title: Proceedingd of the National Academy of Sciences of the United States of America (PNAS) 106 Pages: 1903-1908
  • Peer Reviewed
• [Journal Article] Protection of IFN-γ signaling deficient NOD mice from diabetes by cyclophosphamide. (2008)
  • Author(s): Mori, Y., Kato, T., Kodaka, T., Kanagawa E.M., Hori, S., Kanagawa, O.
  • Journal Title: Int.Immunol. 20 Pages: 1231-1237
  • NAID: 10022599696
  • Peer Reviewed
• [Journal Article] Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt. (2008)
  • Author(s): Ichiyama, K., Yoshida, H., Wakabayashi, Y., Chinen, T., Saeki, K., Nakaya, M., Takasu, G., Hori, S., Yoshimura, A., Kobayashi, T.
  • Journal Title: J.Biol.Chem. 283 Pages: 17003-17008
  • Peer Reviewed
• [Journal Article] Rethinking the molecular definition of regulatory T cells. (2008)
  • Author(s): Hori, S.
  • Journal Title: Eur.J.Immunol. 38 Pages: 928-930
  • Peer Reviewed
• [Journal Article] Protection of IFN-γsignaling deficient NOD mice from diabetes by cyclophosphamide (2008)
  • Author(s): Mori, Y., et al.
  • Journal Title: International Immunology 20 Pages: 1231-1237
  • Peer Reviewed
• [Journal Article] T. Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt (2008)
  • Author(s): Ichiyama, K., et al.
  • Journal Title: Journal of Biological Chemistry 283 Pages: 17003-17008
  • Peer Reviewed
• [Journal Article] Rethinking the molecular definition of Treg (2008)
  • Author(s): Hori, S.
  • Journal Title: European Journal of Immunology 38 Pages: 928-930
  • Peer Reviewed
• [Journal Article] Foxp3+Treg. (2008)
  • Author(s): 小松紀子、堀昌平
  • Journal Title: 分子細胞治療 7(3) Pages: 115-120
• [Presentation] A high-throughput approach for immune repertoire analysis (2010)
  • Author(s): Mariotti-Ferrandiz, E., et al.
  • Organizer: 2^<nd> Synthetic Immunology Workshop
  • Place of Presentation: 京都
  • Year and Date: 2010-12-18
• [Presentation] 制御性T細胞の系列安定性と可塑性 (2010)
  • Author(s): 堀昌平
  • Organizer: 第60回日本アレルギー学会秋季学術大会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2010-11-25
• [Presentation] 制御性T細胞による免疫制御 (2010)
  • Author(s): 堀昌平
  • Organizer: 第62回日本皮膚科学会西日本支部学術大会
  • Place of Presentation: 倉敷(招待講演)
  • Year and Date: 2010-10-24
• [Presentation] 制御性T細胞による免疫制御 (2010)
  • Author(s): 堀昌平
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜(招待講演)
  • Year and Date: 2010-09-25
• [Presentation] Stability and plasticity in regulatory T cell differentiation (2010)
  • Author(s): Hori, S.
  • Organizer: 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸(招待講演)
  • Year and Date: 2010-08-25
• [Presentation] Impact of TCRβ diversity on regulatory T cell development (2010)
  • Author(s): Mariotti-Ferrandiz, E., et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] Impact of IPEX mutations on regulatory T cell development, homeostasis and function (2010)
  • Author(s): Tachibana, M., et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸
  • Year and Date: 2010-08-25
• [Presentation] 制御性T細胞の可塑性と適応 (2010)
  • Author(s): 堀昌平
  • Organizer: 第14回日本適応医学会学術集会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2010-07-02
• [Presentation] Stability and plasticity in regulatory T cell differentiation (2010)
  • Author(s): Hori, S
  • Organizer: The 14^<th> International Congress of Immunology
  • Place of Presentation: 神戸
• [Presentation] Stability and plasticity in regulatory T cell differentiation (2010)
  • Author(s): Hori, S
  • Organizer: Keystone Symposia "Tolerance and Autoimmunity"
  • Place of Presentation: Taos, New Mexico, USA
• [Presentation] Robustness and plasticity in regulatory T cell differentiation (2009)
  • Author(s): Hori, S.
  • Organizer: The 39^<th> Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2009-12-03
• [Presentation] Impact of IPEX mutations on regulatory T cell development and function (2009)
  • Author(s): Tachibana, M., Hori, S.
  • Organizer: The 39^<th> Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: Osaka, Japan
  • Year and Date: 2009-12-03
• [Presentation] Lineage stability and plasticity in regulatory T cell differentiation (2009)
  • Author(s): Hori, S
  • Organizer: The 12^<th> US-Japan Cellular and Gene Therapy Conference "Immune Regulation"
  • Place of Presentation: Bethesda, Maryland, USA
  • Year and Date: 2009-02-26
• [Presentation] Lineage stability and plasticity in regulatory T cell differentiation (2009)
  • Author(s): Hori, Shohei
  • Organizer: 第12回日米科学技術会議
  • Place of Presentation: ベテスダ, メリーランド州, 米国
  • Year and Date: 2009-02-26
• [Presentation] 免疫制御性T細胞による自己免疫制御 (2009)
  • Author(s): 堀 昌平
  • Organizer: 第5回宮崎サイエンスキャンプ
  • Place of Presentation: 宮崎
  • Year and Date: 2009-02-22
• [Presentation] Robustness and plasticity in regulatory T cell differentiation (2009)
  • Author(s): Hori, S
  • Organizer: The 39^<th> Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 大阪
• [Presentation] Elucidating regulatory T cell TCR specificity and repertoire : a new mouse model (2009)
  • Author(s): Mariotti-Ferrandiz, M.E.et al.
  • Organizer: Kyoto T Cell Conference
  • Place of Presentation: Kyoto, Japan
• [Presentation] 制御性T細胞による自己免疫制御 (2008)
  • Author(s): 堀 昌平
  • Organizer: 第32回阿蘇シンポジウム
  • Place of Presentation: 阿蘇
  • Year and Date: 2008-08-02
• [Presentation] Foxp3 and its essential function for T cell regulation (2008)
  • Author(s): Hori, Shohei
  • Organizer: International Symposium Frontiers in Allergy and Autoimmunity
  • Place of Presentation: マインツ, ドイツ
  • Year and Date: 2008-05-30
• [Presentation] Dissecting Foxp3-dependent molecular program of regulatory T cell differentiation and function (2008)
  • Author(s): Hori, S
  • Organizer: BMB2008
  • Place of Presentation: 神戸
• [Presentation] Foxp3 and its essential function for T cell regulation (2008)
  • Author(s): Hori, S
  • Organizer: International Symposium "Frontiers in Allergy and Autoimmunity"
  • Place of Presentation: Mainz, Germany
• [Presentation] Impact of IPEX mutations on regulatory T cell development and function. (2008)
  • Author(s): 立花雅史, 堀昌平
  • Organizer: 第38回日本免疫学会学術集会
  • Place of Presentation: 京都
• [Presentation] Two subsets of natural Foxp3+ regulatory T cells with distinct phenotypic and functional stability. (2008)
  • Author(s): 小松紀子, Maria Encarnita Mariotti-Ferrandiz, 堀昌平
  • Organizer: 第38回日本免疫学会学術集会
  • Place of Presentation: 京都
• [Remarks] ホームページ
  • URL: http://www.riken.jp/r-world/research/lab/rcai/home/index.html