Elucidating the molecular basis of regulatory T cell differentiation

• Project/Area Number: 23390123
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: HORI Shohei 独立行政法人理化学研究所, 統合生命医科学研究センター, チームリーダー (50392113)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000); Fiscal Year 2013: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2012: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: 細胞分化 / 細胞運命 / 分化可塑性 / 制御性T細胞 / 転写因子 / 自己免疫寛容 / 自己免疫 / 免疫制御 / 可塑性

Research Abstract

The emerging notion of environment-induced reprogramming of Foxp3+ regulatory T (Treg) cells into helper T (Th) cells remains controversial. By genetic fate mapping or adoptive transfers, we have identified a minor population of non-regulatory Foxp3+ T cells exhibiting promiscuous and transient Foxp3 expression, which gives rise to Foxp3- Th cells and selectively accumulates in inflammatory cytokine milieus or in lymphopenic environments including those in early ontogeny. In contrast, Treg cells do not undergo reprogramming under those conditions irrespectively of their thymic or peripheral origins. Moreover, while a few Treg cells transiently lose Foxp3 expression, such "latent" Treg cells retain memory of Foxp3 expression and suppressive function. Our study establishes that Treg cells constitute a stable cell lineage, whose committed state in a changing environment is ensured by DNA demethylation of the Foxp3 locus irrespectively of ongoing Foxp3 expression.

Research Products

• [Journal Article] Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells (2014)
  • Author(s): Hori, S.
  • Journal Title: Immunological Reviews Volume: 259 Issue: 1 Pages: 159-172
  • DOI: 10.1111/imr.12175
  • Peer Reviewed
• [Journal Article] Expansion of Foxp3(+) T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge (2014)
  • Author(s): Whibley, N., et al.
  • Journal Title: European Journal of Immunology Volume: 44 Issue: 4 Pages: 1069-1083
  • DOI: 10.1002/eji.201343604
  • Peer Reviewed
• [Journal Article] Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus (2013)
  • Author(s): Toker A, Engelbert D, Garg G, Polansky Geffers R, Giehr P, Schallenberg S, Kretschmer K, Olek S, Walter J, Weiss S, Hori S, Hamann A, Huehn J
  • Journal Title: J Immunol Volume: 190 Issue: 7 Pages: 3180-8
  • DOI: 10.4049/jimmunol.1203473
  • Peer Reviewed
• [Journal Article] Commensal microbe-derived butyrate induces colonic regulatory T cells (2013)
  • Author(s): Yukihiro Furusawa, Yuuki Obata, Shinji Fukuda, Takaho A. Endo, Gaku Nakato, Daisuke Takahashi, Yumiko Nakanishi, Chikako Uetake, Keiko Kato, Tamotsu Kato, Masumi Takahashi, Noriko N. Fukuda, Shinnosuke Murakami, Eiji Miyauchi, Shingo Hino, Koji Atarashi, Satoshi Onawa, Yumiko Fujimura, Trevor Lockett, Julie M. Clarke, David L. Topping, Masaru Tomita, Shohei Hori, Osamu Ohara, Tatsuya Morita, Haruhiko Koseki, J un Kikuchi, Kenya Honda, Koji Hase and Hiroshi Ohno
  • Journal Title: Nature Volume: 506 Issue: 7480 Pages: 446-450
  • DOI: 10.1038/nature12721
  • Peer Reviewed
• [Journal Article] Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. (2013)
  • Author(s): Oh-hora, M. et al.
  • Journal Title: Immunity Volume: in press
  • Peer Reviewed
• [Journal Article] Plasticity of Foxp3^+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells (2012)
  • Author(s): Miyao, T., et al
  • Journal Title: Immunity Volume: 36 Issue: 2 Pages: 262-275
  • DOI: 10.1016/j.immuni.2011.12.012
  • Peer Reviewed
• [Journal Article] The Foxp3 interactome: a network perspective of Treg cells (2012)
  • Author(s): Hori, S.
  • Journal Title: Nature Immunology Volume: 13 Issue: 10 Pages: 943-945
  • DOI: 10.1038/ni.2424
  • Peer Reviewed
• [Journal Article] Stability of regulatory T-cell lineage (2011)
  • Author(s): Hori S
  • Journal Title: Adv Immunol Volume: 112 Pages: 1-24
  • DOI: 10.1016/b978-0-12-387827-4.00001-2
  • NAID: 40019769824
  • ISBN: 9780123878274
  • Peer Reviewed
• [Journal Article] Regulatory T cell plasticity : beyond the controversies (2011)
  • Author(s): Hori, S.
  • Journal Title: Trends in Immunology Volume: 32 Issue: 7 Pages: 295-300
  • DOI: 10.1016/j.it.2011.04.004
  • Peer Reviewed
• [Journal Article] Sustained suppression by Foxp3^+ regulatory T cells is vital for infectious transplantation tolerance (2011)
  • Author(s): Kendal, A.R., et al
  • Journal Title: Journal of Experimental Medicine Volume: 208 Issue: 10 Pages: 2043-2053
  • DOI: 10.1084/jem.20110767
  • Peer Reviewed
• [Journal Article] The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells (2011)
  • Author(s): Motomura, Y., et al
  • Journal Title: Nature Immunology Volume: 12 Issue: 5 Pages: 450-459
  • DOI: 10.1038/ni.2020
  • Peer Reviewed
• [Journal Article] Prostaglandin E2-prostoglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression (2011)
  • Author(s): Kitipong Soontrapa, Tetsuya Honda, Daiji Sakata, Chengcan Yao, Takako Hirata, Shohei Hori, Toshiyuki Matsuoka, Yoshihiro Kita, Takao Shimizu, Kenji Kabashima, Shuh Narumiya
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Issue: 16 Pages: 668-667
  • DOI: 10.1073/pnas.1018625108
  • Peer Reviewed
• [Journal Article] The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells (2011)
  • Author(s): Sekiya, T., et al
  • Journal Title: Nature Communications Volume: 2 Issue: 1 Pages: 269-269
  • DOI: 10.1038/ncomms1272
  • Peer Reviewed
• [Journal Article] TRAF6 directs commitment to regulatory T cells in thymocytes (2011)
  • Author(s): Shimo, Y., et al
  • Journal Title: Genes to Cells Volume: 16 Issue: 4 Pages: 437-447
  • DOI: 10.1111/j.1365-2443.2011.01500.x
  • Peer Reviewed
• [Presentation] Genetic control of regulatory T cell fitness in tissues (2013)
  • Author(s): Hori S
  • Organizer: The 7th International Leukocyte Signal Transduction Conference
  • Place of Presentation: Kos Island, Greece
  • Year and Date: 2013-09-10
• [Presentation] Stability and adaptability of regulatory T cells (2013)
  • Author(s): Hori S
  • Organizer: The 7th International Symposium on Cellular Therapy 2013
  • Place of Presentation: Erlangen, Germany
• [Presentation] Stability and adaptability of regulatory T cells. (2013)
  • Author(s): Hori, S.
  • Organizer: The 7th International Symposium on Cellular Therapy 2013
  • Place of Presentation: Erlangen, Germany
  • Invited
• [Presentation] Genetic and environmental control of regulatory T cell fitness in peripheral tissues. (2013)
  • Author(s): Hori, S.
  • Organizer: The 2nd New Zealand-Japan Joint Immunology Workshop
  • Place of Presentation: Aukland, New Zealand
  • Invited
• [Presentation] Genetic and environmental control of regulatory T cell fitness in peripheral tissues (2012)
  • Author(s): Hori, S.
  • Organizer: The 4^<th> RCAI-LIAI Joint Workshop
  • Place of Presentation: La Jolla, CA, USA(招待講演)
  • Year and Date: 2012-02-07
• [Presentation] Resolving the controversy over regulatory T cell plasticity (2012)
  • Author(s): Hori, S.
  • Organizer: The 14^<th> International Conference on Lymphocyte Activation and Immune Regulation : T cell Differentiation and Plasticity
  • Place of Presentation: Newport Beach, CA, USA(招待講演)
  • Year and Date: 2012-02-04
• [Presentation] Plasticity of Foxp3+ T cells : its implications in Treg cell lineage commitment (2012)
  • Author(s): Hori S
  • Organizer: The 4th International Symposium on "Immunological Sefl"
  • Place of Presentation: 京都
  • Year and Date: 2012-01-27
• [Presentation] Plasticity of Foxp3+ T cells : its implications in Treg cell lineage commitment (2012)
  • Author(s): Hori, S.
  • Organizer: The 4^<th> International Symposium on "Immunological Self"
  • Place of Presentation: 京都大学芝蘭会館、京都(招待講演)
  • Year and Date: 2012-01-27
• [Presentation] Genetic and environmental control of regulatory T cell fitness in tissues (2012)
  • Author(s): Hori S
  • Organizer: The 41st Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 神戸
• [Presentation] Resolving the controversy over regulatory T cell plasticity (2012)
  • Author(s): Hori S
  • Organizer: The 3rd International Conference on Regulatory T cells and Helper T cell subsets and Clinical Application in Human Diseases
  • Place of Presentation: Shanghai, China
• [Presentation] Resolving the controversy over regulatory T cell plasticity (2012)
  • Author(s): Hori S
  • Organizer: The 14th International Conference on Lymphocyte Activation and Immune Regulation : T cell Differentiation and Plasticity
  • Place of Presentation: Newport Beach, CA, USA
• [Presentation] Genetic and environmental control of regulatory T cell fitness in tissues. (2012)
  • Author(s): Hori, S.
  • Organizer: The 41st Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 神戸
  • Invited
• [Presentation] Resolving the controversy over regulatory T cell plasticity. (2012)
  • Author(s): Hori, S.
  • Organizer: The 3rd International Conference on Regulatory T cells and Helper T cell subsets and Clinical Application in Human Diseases
  • Place of Presentation: Shanghai, China
  • Invited
• [Presentation] Analysis of IPEX mutations reveals a critical role of the KLEG1+ subset of regulatory T cells in the regulation of autoimmunity (2011)
  • Author(s): Hori, S.
  • Organizer: The 40^<th> Annual Meeting of the Japanese Society for Immunology
  • Place of Presentation: 幕張メッセ、千葉(招待講演)
  • Year and Date: 2011-11-29
• [Presentation] マウスCD4+T細胞におけるIkarosファミリー転写因子Heliosの発現誘導シグナルの解析 (2011)
  • Author(s): 早津徳人
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-29
• [Presentation] High-throughput sequencing provides quantitative evidence for distinct TCR repertoires of Tregs and conventional T cells (2011)
  • Author(s): Mariotti-Ferrandiz, M.E., et al
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ、千葉
  • Year and Date: 2011-11-28
• [Presentation] 制御性T細胞による自己免疫制御 (2011)
  • Author(s): 堀昌平
  • Organizer: 第35回阿蘇シンポジウム
  • Place of Presentation: 阿蘇リゾートグランヴィリオホテル、熊本(招待講演)
  • Year and Date: 2011-07-29
• [Presentation] Genetic control of regulatory T cell fitness in tissues
  • Author(s): Hori, S.
  • Organizer: The 7th International Leukocyte Signal Transduction Conference
  • Place of Presentation: ギリシャ、コス島
  • Invited
• [Presentation] Genetic control of regulatory T cell homeostasis in non-lymphoid tissues
  • Author(s): Hori, S.
  • Organizer: The 3rd Bizan Immunology Symposium at the University of Tokushima, “Immune System Development, Deviation, and Regulation”
  • Place of Presentation: 徳島市
  • Invited
• [Presentation] 制御性T細胞による自己免疫制御
  • Author(s): 堀昌平
  • Organizer: 第6回Symphony研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 制御性T細胞による自己免疫制御
  • Author(s): 堀昌平
  • Organizer: 第8回自己免疫疾患研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] 制御性T細胞による自己免疫制御
  • Author(s): 堀昌平
  • Organizer: 第1回Legendセミナー
  • Place of Presentation: 東京
  • Invited
• [Presentation] Genome-wide analysis of Foxp3-dependent transcriptional program in Treg cells using hypomorphic Foxp3 mutant mice
  • Author(s): Hayatsu, N., et al.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張
• [Presentation] Genome-wide analysis of Foxp3-dependent transcriptional program in Treg cells using hypomorphic Foxp3 mutant mice
  • Author(s): Hayatsu, N., et al.
  • Organizer: KTCC (Kyoto T Cell Conference) 2013
  • Place of Presentation: 京都
• [Presentation] Genetic control of Foxp3+ regulatory T cell fitness in peripheral tissues
  • Author(s): Murakami, R. et al.
  • Organizer: KTCC (Kyoto T Cell Conference) 2013
  • Place of Presentation: 京都
• [Remarks]
  • URL: http://www.riken.jp/research/labs/ims/immun_homeost/
• [Remarks] 理化学研究所統合生命医科学研究センター免疫恒常性研究チームの研究紹介
  • URL: http://www.riken.jp/research/labs/ims/immun_homeost/
• [Remarks]
  • URL: http://www.riken.jp/r-world/research/lab/rcai/home/index.html