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Elucidation of the T cell receptor signaling pathway that determines the functions of gdT cells

Research Project

Project/Area Number 16K19102
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Experimental pathology
Research InstitutionThe University of Tokyo

Principal Investigator

Muro Ryunosuke  東京大学, 大学院医学系研究科(医学部), 特任研究員 (80761262)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords胸腺 / T細胞受容体 / γδT細胞 / Syk / IL-17 / gdT細胞 / T細胞シグナル / ZAP70 / TCRシグナル / 炎症性サイトカイン
Outline of Final Research Achievements

IL-17 producing γδT (γδT17) cells play an important role in the early response to infection, whereas they are involved in the pathogenesis of inflammatory diseases and metastasis. Although the γδT17 cells are known to develop in the thymus, its precise molecular mechanism remained unclear. In this study, we aimed to clarify the molecular mechanism how T cell receptor (TCR) signal controls the development of γδT17 cells in the thymus. Studies with genetically modified mice revealed that Syk functions as a dominant tyrosine kinase in γδTCR signaling. We also found that Syk activates the PI3K/AKT pathway and LAT/ERK pathway, both of which are mandatory for the development of γδT17 cells.

Academic Significance and Societal Importance of the Research Achievements

本研究にて、研究代表者らはγδT細胞におけるSyk依存的なTCRシグナルを同定した。これまでγδT細胞のシグナル伝達機構は典型的αβT細胞と類似していると考えられてきたが、研究代表者らはγδT細胞に特有のTCRシグナル伝達がγδT細胞の機能決定に重要であることを明らかにし、世界に先駆けて発表した。免疫学領域における新たな知見を提供し、学術的意義の高い成果となった。本研究成果から、SykやPI3Kを標的とすることで、炎症性γδT細胞を人為的に制御できる可能性があり、炎症性疾患の治療法確立に繋がる可能性がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (23 results)

All 2019 2018 2017 2016

All Journal Article (6 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (17 results) (of which Int'l Joint Research: 6 results)

  • [Journal Article] T cell receptor signaling for γδT cell development2019

    • Author(s)
      Muro Ryunosuke、Takayanagi Hiroshi、Nitta Takeshi
    • Journal Title

      Inflammation and Regeneration

      Volume: 39 Issue: 1 Pages: 6-6

    • DOI

      10.1186/s41232-019-0095-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Arginine methylation controls the strength of γc-family cytokine signaling in T cell maintenance2018

    • Author(s)
      Inoue Maia、Okamoto Kazuo、Terashima Asuka、Nitta Takeshi、Muro Ryunosuke、Negishi-Koga Takako、Kitamura Toshio、Nakashima Tomoki、Takayanagi Hiroshi
    • Journal Title

      Nature Immunology

      Volume: 19 Issue: 11 Pages: 1265-1276

    • DOI

      10.1038/s41590-018-0222-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Rasal3-mediated T cell survival is essential for inflammatory responses2018

    • Author(s)
      Muro Ryunosuke、Nitta Takeshi、Kitajima Masayuki、Okada Toshiyuki、Suzuki Harumi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 496 Issue: 1 Pages: 25-30

    • DOI

      10.1016/j.bbrc.2017.12.159

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] γδTCR recruits the Syk/PI3K axis to drive proinflammatory differentiation program.2018

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Kenta Nakano, Tadashi Okamura, Hiroshi Takayanagi, Harumi Suzuki
    • Journal Title

      The Journal of Clinical Investigation

      Volume: 128 Issue: 1 Pages: 415-426

    • DOI

      10.1172/jci95837

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Human thymoproteasome variations influence CD8 T cell selection.2017

    • Author(s)
      Takeshi Nitta, Yuta Kochi, Ryunosuke Muro, Yoshihiko Tomofuji, Tadashi Okamura, Shigeo Murata, Harumi Suzuki, Takayuki Sumida, Kazuhiko Yamamoto, Hiroshi Takayanagi
    • Journal Title

      Science Immunology

      Volume: 2 Issue: 12 Pages: 5-165

    • DOI

      10.1126/sciimmunol.aan5165

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Histone Methyltransferase ESET Is Critical for T Cell Development2016

    • Author(s)
      Takikita, S. Muro, R. Takai, T. Otsubo, T. Kawamura, Y. I. Dohi, T. Oda, H. Kitajima, M. Oshima, K. Hattori, M. Endo, T. A. Toyoda, T. Weis, J. Shinkai, Y. Suzuki, H.
    • Journal Title

      J Immunol

      Volume: 197 Issue: 6 Pages: 2269-2279

    • DOI

      10.4049/jimmunol.1502486

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Proinflammatory γδT cell development by Syk/PI3K-mediated TCR signal transduction2018

    • Author(s)
      R. Muro, T. Nitta, H. Suzuki, H. Takayanagi
    • Organizer
      8th International γδ T cell conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 炎症性gdT細胞の分化を誘導するTCRシグナル伝達経路の同定2018

    • Author(s)
      室 龍之介、新田 剛、高柳 広
    • Organizer
      第5回 ベーシックリサーチカンファレンス
    • Related Report
      2018 Annual Research Report
  • [Presentation] gdT細胞におけるユニークなTCRシグナル伝達2018

    • Author(s)
      室龍之介、新田剛、鈴木春巳、高柳広
    • Organizer
      第28回 Kyoto T cell conference
    • Related Report
      2018 Annual Research Report
  • [Presentation] 非典型的TCRシグナルによる炎症性gdT細胞の制御2018

    • Author(s)
      室 龍之介, 新田 剛, 高柳 広
    • Organizer
      第33回 自己免疫研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 炎症性gdT細胞の分化制御機構2018

    • Author(s)
      室 龍之介、新田剛、高柳広
    • Organizer
      第39回日本炎症・再生医学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The tyrosine kinase Syk is required for development of proinflammatory gdT cells.2018

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Hiroshi Takayanagi
    • Organizer
      The 47th Annual Meeting of The Japanese Society for Immunology
    • Related Report
      2018 Annual Research Report
  • [Presentation] γδTCR recruits the Syk-PI3K axis to drive proinflammatory differentiation program2018

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Harumi Suzuki, Hiroshi Takayanagi
    • Organizer
      ThymOz International Conference on Thymus and T-cell Biology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 炎症性gdT細胞の分化を制御するSyk依存的TCRシグナル2018

    • Author(s)
      室 龍之介、 新田 剛、鈴木 春巳、高柳 広
    • Organizer
      第27回東京免疫フォーラム
    • Related Report
      2017 Research-status Report
  • [Presentation] Syk依存的TCRシグナルによる炎症性gdT細胞の分化制御2018

    • Author(s)
      室 龍之介、 新田 剛、高柳 広
    • Organizer
      第3回日本骨免疫学会 ウインターセミナー
    • Related Report
      2017 Research-status Report
  • [Presentation] Syk-mediated TCR signaling is required for γδT cell development and acquisition of proinflammatory potential2017

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Hiroshi Takayanagi, Harumi Suzuki
    • Organizer
      International Kyoto T Cell Conference 2017
    • Place of Presentation
      京都市
    • Year and Date
      2017-03-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Control of proinflammatory gdT cell development by linage-specific TCR signaling pathway2017

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Hiroshi Takayanagi, Harumi Suzuki
    • Organizer
      第46回 日本免疫学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Deciphering lineage-specific TCR signaling in IL-17-producing gdT cell development2017

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Harumi Suzuki, Hiroshi Takayanagi
    • Organizer
      The 5th Annual Meeting of the International Cytokine and Interferon Society
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] TCRシグナルによる炎症性gdT細胞の分化制御2017

    • Author(s)
      室 龍之介、 新田 剛、鈴木 春巳、高柳 広
    • Organizer
      第4回 ベーシックリサーチカンファレンス
    • Related Report
      2017 Research-status Report
  • [Presentation] The distinct roles of proximal TCR kinase regulate gdT cell development2016

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Hiroshi Takayanagi, Harumi Suzuki
    • Organizer
      第45回日本免疫学会学術集会
    • Place of Presentation
      那覇市
    • Year and Date
      2016-12-05
    • Related Report
      2016 Research-status Report
  • [Presentation] Syk依存的TCRシグナルによるIL-17産生型γδT細胞の分化制御2016

    • Author(s)
      室 龍之介、新田 剛、鈴木 春巳、高柳 広
    • Organizer
      日本リウマチ学会ベーシックリサーチカンファレンス
    • Place of Presentation
      東京都
    • Year and Date
      2016-10-14
    • Related Report
      2016 Research-status Report
  • [Presentation] The critical roles of RhoH for development of IL-17-producing γδT cell2016

    • Author(s)
      Muro Ryunosuke, Nitta Takeshi, Tamehiro Norimasa, Oda Hiroyo, Hiroshi Takayanagi, Suzuki Harumi
    • Organizer
      Gamma/Delta T Cell Conference
    • Place of Presentation
      London
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] DIFFERENTIAL REQUIREMENT OF ZAP/SYK KINASES FOR THE EARLY DEVELOPMENT OF γδT CELLS IN THE THYMUS2016

    • Author(s)
      Ryunosuke Muro, Takeshi Nitta, Norimasa Tamehiro, Hiroyo Oda, Masayuki Kitajima, Hiroshi Takayanagi, Harumi Suzuki
    • Organizer
      ThumUS 2016
    • Place of Presentation
      Hawaii
    • Year and Date
      2016-06-05
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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