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胸腺発生型の制御性T細胞分化を決定するTRAF6シグナル標的因子の同定

Publicly Offered Research

Project AreaImmunological Self Recognition and its Disorders
Project/Area Number 22021012
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

秋山 泰身  東京大学, 医科学研究所, 准教授 (50327665)

Project Period (FY) 2010 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥9,800,000 (Direct Cost: ¥9,800,000)
Fiscal Year 2011: ¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2010: ¥4,900,000 (Direct Cost: ¥4,900,000)
Keywords自己免疫 / 制御性T細胞 / シグナル伝達 / NF-kappaB / 胸腺 / 分化 / NF-κB
Research Abstract

胸腺発生型の制御性T細胞は自己免疫応答や過剰な免疫応答を抑制する。制御性T細胞の分化はT細胞抗原レセプター(TCR)とMHCクラスIIペプチド複合体の親和性が高い場合に亢進するとの仮説が有力であるが、TCRからのシグナルがどのような機構で制御性T細胞の分化を決定するのか、その分子基盤は曖昧である。他のグループによる遺伝子欠損マウスの解析から、NF-κBを活性化するシグナルとAkt活性化の抑制が制御性T細胞の分化決定に重要であることが判明している。しかしながら、これらのシグナルが未分化胸腺細胞でどのような現象を引き起こしているのか、ほとんど明らかでない。本年度は、特にTCR刺激に依存して活性化するNF-kB経路のどの段階にTRAF6が関与しているのか検討した。その結果、TRAF6はTCR刺激に依存して数分以内におきるNF-kappaB経路の活性化には必須であるが、その後に継続するNF-kappaB活性化には必要ないとの予想外の結果を得た。さらにTCRシグナルは制御性T細胞の分化に加え、T細胞の増殖にも必要であるが、TCR刺激に依存したT細胞の増殖にはTRAF6は必要でなかった。これらの結果は、TRAF6シグナルはTCR刺激に依存した制御性T細胞の分化におけるNF-kappaB活性化にだけ必要であり、増殖におけるNF-kappaB活性化には必要ないことを示唆している。次にTRAF6シグナルにより誘導され制御性T細胞の分化を決定する因子の同定を目指した。すなわちTCR刺激に依存して誘導される遺伝子の中で1時間以内に誘導され、かつTRAF6に依存して誘導される遺伝子を同定するため、マイクロアレイ解析を行った。マイクロアレイで同定された遺伝子についてqPCRで時簡特異およびTRAF6依存性を確認した。今後、これらの因子の解析を行うことで制御性T細胞の分化機構についての新奇知見が得られると期待できる。

Current Status of Research Progress
Current Status of Research Progress

3: Progress in research has been slightly delayed.

Reason

T細胞抗原レセプターシグナルによりTRAF6に依存して誘導される遺伝子群を同定できたが、その機能解析に予想外に時間を要したため。

Strategy for Future Research Activity

本研究課題でT細胞抗原受容体シグナルにより誘導される遺伝子の中でTRAF6に依存する遺伝子が複数個同定できており、これらの機能解析により制御性T細胞の分化を決定する因子の同定とその制御機構を明らかにできると期待できる。

Report

(2 results)
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • Research Products

    (29 results)

All 2011 2010

All Journal Article (14 results) (of which Peer Reviewed: 11 results) Presentation (15 results)

  • [Journal Article] Splenic extramedullary hemopoiesis caused by a dysfunctional mutation inthe2011

    • Author(s)
      Shinzawa M., Maruyama Y., Qin J., Akiyama N., Miyauchi M., Yanai H., Takami M., Inoue J., and Akiyama T*(corresponding author).
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 414 Issue: 4 Pages: 773-778

    • DOI

      10.1016/j.bbrc.2011.10.001

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RANK signaling induces interferon-stimulated genes inthe fetal thymic2011

    • Author(s)
      Ohshima D., Qin J., Konno H., Hirosawa A., Shiraishi T., Yanai H., Shimo Y., Shinzawa M., Akiyama N., Yamashita R., Nakai K., Akiyama T*(corresponding author), and
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 408 Issue: 4 Pages: 530-536

    • DOI

      10.1016/j.bbrc.2011.04.049

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Okumura K., Kamradt T., Saito H., Nakae S. Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage2011

    • Author(s)
      Ohno T., Oboki K., Kajiwara N., Tanaka S., Ikeda M., Iikura M., Akiyama T., Inoue J., Matsumoto K., Sudo K., Azuma M.,
    • Journal Title

      Plos One

      Volume: 6 Issue: 4 Pages: 18404-18404

    • DOI

      10.1371/journal.pone.0018404

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma2011

    • Author(s)
      Mouri Y
    • Journal Title

      Journal of Immunology

      Volume: 186 Issue: 9 Pages: 5047-5057

    • DOI

      10.4049/jimmunol.1003533

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TRAF6 directs commitment to regulatory T cells in thymocytes2011

    • 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

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RANK and CD40 signaling induce expression of AIRE in medullary thymic epithelial cells2011

    • Author(s)
      秋山伸子, ら
    • Journal Title

      Clinical Immunology and Allergology

      Volume: 56 Pages: 238-246

    • NAID

      40019017857

    • Related Report
      2011 Annual Research Report
  • [Journal Article] Regulation of central tolerance by RANKL signaling2011

    • Author(s)
      新澤美穂, ら
    • Journal Title

      Clin Calcium

      Volume: 21 Pages: 1193-1199

    • Related Report
      2011 Annual Research Report
  • [Journal Article] Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation2011

    • Author(s)
      Ohno, et al.
    • Journal Title

      Plos One

      Volume: (in press 掲載確定)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lymphotoxin Signal Promotes Thymic Organogenesis by Eliciting RANK Expression in tl2011

    • Author(s)
      Mouri, et al.
    • Journal Title

      J.Immunol.

      Volume: (in press 掲載確定)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TRAF6 directs commitment to regulatory T cells in thymocytes2011

    • Author(s)
      Shimo, et al.
    • Journal Title

      Genes Cell

      Volume: 16 Pages: 437-447

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TRAF6 negatively regulates the Jak1-Erk pathway in interleukin-2 signaling2011

    • Author(s)
      Motegi, et al.
    • Journal Title

      Genes Cell

      Volume: 16 Pages: 179-189

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic Potential of Anti-Interleukin-17A Aptamer : Suppression of Interleukin-17A signaling and Attenuation of autoimmunity in mouse models.2011

    • Author(s)
      Ishiguro, et al.
    • Journal Title

      Arth.Rheu

      Volume: 63 Pages: 455-466

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Requiem protein links RelB/p52 and the Brm-type SWI/SNF complex in a non-canonical NF-κB pathway.2011

    • Author(s)
      Tando, et al.
    • Journal Title

      J.Biol.Chem.

      Volume: 2856 Pages: 21915-21960

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 自己免疫寛容を誘導する胸腺内シグナル制御機構2011

    • Author(s)
      秋山泰身、新澤美穂
    • Journal Title

      化学と生物

      Volume: 49 Pages: 2-4

    • Related Report
      2010 Annual Research Report
  • [Presentation] Oscillation of non-canonical NF-kB activation pathway2011

    • Author(s)
      関崇生
    • Organizer
      第34回日本分子生物学会年会
    • Place of Presentation
      横浜、パシフィコ横浜
    • Year and Date
      2011-12-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] Molecular mechanisms to establish the thymic microenvironment essential for central tolerance2011

    • Author(s)
      Taishin Akiyama
    • Organizer
      6th Chiba University G-COE Symposium
    • Place of Presentation
      千葉、ホテルニューオータニ幕張(招待講演)
    • Year and Date
      2011-11-30
    • Related Report
      2011 Annual Research Report
  • [Presentation] Roles of TNF family signals in establishing thymic microenvironment2011

    • Author(s)
      秋山伸子
    • Organizer
      第40回日本免疫学会学術集会
    • Place of Presentation
      千葉幕張メッセ
    • Year and Date
      2011-11-29
    • Related Report
      2011 Annual Research Report
  • [Presentation] A novel regulatory mechanism of NF-kB inducing kinase (NIK) activation in the immune system2011

    • Author(s)
      新澤美穂
    • Organizer
      第40回日本免疫学会学術集会
    • Place of Presentation
      千葉幕張メッセ
    • Year and Date
      2011-11-29
    • Related Report
      2011 Annual Research Report
  • [Presentation] 胸腺髄質上皮細胞の遺伝子発現制御機構2011

    • Author(s)
      秋山泰身
    • Organizer
      京都T cell conference
    • Place of Presentation
      京都芝蘭会館
    • Year and Date
      2011-06-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] Regulation of gene expressions in the development of medullary thymic epithelial cells2011

    • Author(s)
      Taishin Akiyama
    • Organizer
      EUThyme-Rolduc Meeting
    • Place of Presentation
      オランダLeeuvenhorst
    • Year and Date
      2011-05-21
    • Related Report
      2011 Annual Research Report
  • [Presentation] RANK signaling induces interferon-stimulated genes in the fetal thymic stroma2011

    • Author(s)
      Taishin Akiyama
    • Organizer
      TNF conference 2011
    • Place of Presentation
      淡路島、夢舞台国際会議場
    • Year and Date
      2011-05-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] Roles of TNF receptor family members on development of thymic microenvironment required for immunological self-tolerance2011

    • Author(s)
      Taishin Akiyama
    • Organizer
      TNF conference 2011
    • Place of Presentation
      淡路島、夢舞台国際会議場
    • Year and Date
      2011-05-16
    • Related Report
      2011 Annual Research Report
  • [Presentation] REGULATION OF GENE EXPRESSIONS IN MEDULLARY THYMIC EPITHELIAL CELLS2010

    • Author(s)
      秋山泰身, ら
    • Organizer
      The Second Workshop of Synthetic Immunology
    • Place of Presentation
      京都、京都大学芝蘭会館
    • Year and Date
      2010-12-16
    • Related Report
      2010 Annual Research Report
  • [Presentation] Molecular mechanisms underlying the development of thymic environment essential for immunological self-tolerance2010

    • Author(s)
      秋山泰身
    • Organizer
      第33回日本分子生物学会・第83回生化学会大会
    • Place of Presentation
      神戸、神戸ポートアイランド
    • Year and Date
      2010-12-06
    • Related Report
      2010 Annual Research Report
  • [Presentation] TRAF6 controls commitment to regulatory T-cell lineage and T-cell receptor signals in thymocytes2010

    • Author(s)
      Yusuke Shimo, ら
    • Organizer
      14th International congress in Immunology
    • Place of Presentation
      神戸、神戸ポートピアホテル 神戸国際展示場
    • Year and Date
      2010-08-24
    • Related Report
      2010 Annual Research Report
  • [Presentation] A negative feedback regulation of medullary thymic epithelial cell development by RANK signal-dependent expression of osteoprotegerin2010

    • Author(s)
      Taishin Akiyama, ら
    • Organizer
      14th International congress in Immunology
    • Place of Presentation
      神戸、神戸ポートピアホテル 神戸国際展示場
    • Year and Date
      2010-08-23
    • Related Report
      2010 Annual Research Report
  • [Presentation] RANKL-RANK-OPG system in establishment of immunological tolerance2010

    • Author(s)
      Taishin Akiyama
    • Organizer
      3rd International Conference on Osteoimmunology : Interactions of the Immune and Skeletal Systems
    • Place of Presentation
      ギリシャ、サントリーニ
    • Year and Date
      2010-06-24
    • Related Report
      2010 Annual Research Report
  • [Presentation] 胸腺発生型の制御性T細胞分化を制御するTRAF6シグナルの解析2010

    • Author(s)
      下茂佑輔, ら
    • Organizer
      京都T cell conference
    • Place of Presentation
      京都、京大芝蘭会館
    • Year and Date
      2010-06-04
    • Related Report
      2010 Annual Research Report
  • [Presentation] Development of thymic niches essential for preventing autoimmunity2010

    • Author(s)
      Taishin Akiyama
    • Organizer
      The 1st International Conference on Frontiers of Regenerative Medicine & Biomedical Science
    • Place of Presentation
      中国、広州
    • Year and Date
      2010-05-14
    • Related Report
      2010 Annual Research Report

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Published: 2010-08-23   Modified: 2018-03-28  

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