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制御性T細胞の不可逆的運命決定機構の解明

Publicly Offered Research

Project AreaMolecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
Project/Area Number 25118733
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe Institute of Physical and Chemical Research

Principal Investigator

堀 昌平  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) 2013-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000)
Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Keywords細胞運命 / 制御性T細胞 / 転写制御 / エピジェネティック制御 / シグナル伝達
Outline of Annual Research Achievements

本研究は、Foxp3+ T細胞が可塑性を失ってTregへ不可逆的に分化するメカニズムを解明することを目指し、今年度以下の課題について研究を進めた。
1.胸腺内TregコミットメントにおけるIL-2シグナルの役割:胸腺内Treg分化を追跡する分子タイマーを利用し、Foxp3を発現し始めた細胞がCD25陽性及び陰性2つの集団からなり、CD25+細胞においてのみFoxp3遺伝子座のDNA脱メチル化が経時的に進行することが分かった。一方、CD25-細胞をIL-2存在下で培養するとCD25発現とFoxp3遺伝子の脱メチル化が進行したことから、Foxp3遺伝子の脱メチル化におけるIL-2シグナルの役割が示唆された。
2. TCRシグナル伝達経路の役割:これまでに試験管内Treg分化系を用いた解析から、持続的なTCRシグナルによってFoxp3遺伝子座の脱メチル化を伴った安定なFoxp3発現が誘導されることがわかった。そして、経時的transcriptome解析から、安定なFoxp3発現誘導と相関して活性化される幾つかのシグナル伝達分子、転写因子、クロマチン修飾因子が推定された。本年度、幾つかの候補分子について阻害剤を用いた解析、ノックダウン解析を行ったが、Foxp3発現の安定性に有意な影響を与える分子は同定できなかった。
3. Foxp3発現の自己制御機構:これまでにレトロウィルスを用いてナイーブCD4 T細胞にFoxp3を強制発現させ、これをマウスに移入することで内在性のFoxp3発現が誘導されることを見いだした。このFoxp3発現の自己制御は生体内に存在する何らかの環境因子に依存することが想定され、本年度その同定を試みた。そして、試験管内でもTGF-β及びレチノイン酸両者が存在するときに自己制御が働くことを見いだした。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (20 results)

All 2015 2014 2013 Other

All Journal Article (6 results) (of which Peer Reviewed: 6 results,  Open Access: 3 results,  Acknowledgement Compliant: 2 results) Presentation (13 results) (of which Invited: 7 results) Remarks (1 results)

  • [Journal Article] Helios enhances regulatory T cell function in cooperation with Foxp32015

    • Author(s)
      Takatori H, Kawashima H, Matsuki A, Meguro K, Tanaka S, Iwamoto T, Sanayama Y, Nishikawa N, Tamachi T, Ikeda K, Suto A, Suzuki K, Kagami S, Hirose K, Kubo M, Hori S, Nakajima H
    • Journal Title

      Arthritis Rheumatol

      Volume: 67 Issue: 6 Pages: 1491-502

    • DOI

      10.1002/art.39091

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Sphingosine-1-phosphate receptor 2 is critical for follicular helper T cell retention in germinal centers.2014

    • Author(s)
      Moriyama S, Takahashi N, Green JA, Hori S, Kubo M, Cyster JG, Okada T
    • Journal Title

      Journal of Experimental Medicine

      Volume: 211 Issue: 7 Pages: 1297-1305

    • DOI

      10.1084/jem.20131666

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The epigenetic regulator Uhrf1 facilitates proliferation and maturation of colonic regulatory T cells2014

    • Author(s)
      Yuuki Obata*, Yukihiro Furusawa*, Takaho A. Endo, Jafar Sharif, Daisuke Takahashi, Koji Atarashi, Manabu Nakayama, Satoshi Onawa, Yumiko Fujimura, Masumi Takahashi, Tomokatsu Ikawa, Takeshi Otsubo, Yuki I. Kawamura, Taeko Dohi, Shoji Tajima, Osamu Ohara, Kenya Honda, Shohei Hori, Hiroshi Ohno, Haruhiko Koseki and Koji Hase. 【* : 筆頭筆者】
    • Journal Title

      Nature Immunology

      Volume: 15 Issue: 6 Pages: 571-579

    • DOI

      10.1038/ni.2886

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells2014

    • Author(s)
      Hori, S.
    • Journal Title

      Immunological Reviews

      Volume: 259 Issue: 1 Pages: 159-172

    • DOI

      10.1111/imr.12175

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expansion of Foxp3(+) T-cell populations by Candida albicans enhances both Th17-cell responses and fungal dissemination after intravenous challenge2014

    • Author(s)
      Whibley, N., et al.
    • Journal Title

      European Journal of Immunology

      Volume: 44 Issue: 4 Pages: 1069-1083

    • DOI

      10.1002/eji.201343604

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Commensal microbe-derived butyrate induces colonic regulatory T cells2013

    • 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

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] Foxp3-dependent control of regulatory T cell function and homeostasis.2015

    • Author(s)
      Hori, S.
    • Organizer
      Academy of Immunology and Microbiology seminar series
    • Place of Presentation
      Pohang, Republic of Korea
    • Year and Date
      2015-03-18
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Foxp3 and BATF cooperatively controls regulatory T cell homeostasis in non-lymphoid tissues.2014

    • Author(s)
      Murakami R, Hayatsu N, Miyao T, Kimura A, Hori S
    • Organizer
      第43回日本免疫学会学術集会
    • Place of Presentation
      京都、国立京都国際会館
    • Year and Date
      2014-12-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] A role of restricted DNA binding specificity and affinity of Foxp3 uncovered by analysis of a disease-causing missense mutation.2014

    • Author(s)
      Hayatsu N, Miyao T, Murakami R, Endo T, Ohara S, Hori S
    • Organizer
      第43回日本免疫学会学術集会
    • Place of Presentation
      京都、国立京都国際会館
    • Year and Date
      2014-12-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Understanding genotype-phenotype relationships: lessons learned from disease-causing Foxp3 mutations.2014

    • Author(s)
      Hori, S.
    • Organizer
      Monash Univ. & RIKEN IMS Workshop
    • Place of Presentation
      横浜、理化学研究所
    • Year and Date
      2014-08-05
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Foxp3遺伝子変異マウスを用いた免疫恒常性破綻メカニズムの研究2014

    • Author(s)
      早津徳人、宮尾貴久、村上龍一、木村翔彦、堀昌平
    • Organizer
      第24回 Kyoto T Cell Conference
    • Place of Presentation
      京都、京都平安ホテル
    • Year and Date
      2014-05-17
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
    • 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
    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
  • [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
    • Related Report
      2013 Annual Research Report
  • [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

    • URL

      http://www.riken.jp/research/labs/ims/immun_homeost/

    • Related Report
      2014 Annual Research Report

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Published: 2013-05-15   Modified: 2019-07-29  

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