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Regulation of regulatory T cell dynamics by Rap1 inactivation regulators and its effect on the pathogenesis of colitis

Research Project

Project/Area Number 21K16011
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKansai Medical University

Principal Investigator

Horitani Shunsuke  関西医科大学, 医学部, 助教 (90701649)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsRap-GAP / T cell trafficking / integrin / lung / Rap1 / LFA1 / T-cell recirculation / egress / インテグリン / Rasa3 / Sipa1 / RapGap / 炎症性腸疾患 / 制御性T細胞 / Rap1シグナル
Outline of Research at the Start

炎症性腸疾患では、制御性T細胞による過剰な免疫反応の抑制機構が破綻し、組織破壊を伴うTh1、Th17反応の亢進が認められる。制御性T細胞はTh細胞の産生・活性化を抑制し、通常のリンパ球とは異なる高い移動性を示しながら抗原提示細胞等と相互作用する。この過程で接着分子インテグリンが重要な役割を担っている。低分子量G蛋白質Rap1はインテグリン接着能を調節するマスターレギュレーターである。本研究ではRap1活性化制御による制御性T細胞の特徴的な接着動態を生み出す機構およびその破綻による抑制機能、炎症性腸疾患発症への影響を明らかにする。

Outline of Final Research Achievements

Rap1-GTPase is essential for integrin activation and lymphocyte trafficking. We showed that Rasa3 and Sipa1 are crucial lymphocyte trafficking regulators that inactivate Rap1 by using T-cell-specific Rasa3 and Sipa1 double knockout mice (DKO). DKO T cells induced spontaneous Rap1 activation and adhesion. Due to firm adhesion to capillary beds, DKO T cells were consequently trapped in the lung, however lung sequestration was rescued by inhibition of LFA1 with neutralizing antibodies or loss of talin1 or Rap1. DKO T cells exhibited normal extravasation into lymph nodes, rapid interstitial migration, increased chemotactic responses to CCL21 and sphingosine-1-phosphate, and entry into lymphatic sinuses. However, DKO T cells severely delayed exit. DKO T cells retained high motility in lymphatic sinuses and frequently returned to the lymph node parenchyma, resulting in defective egress. These results reveal the critical trafficking processes that require Rap1 inactivation.

Academic Significance and Societal Importance of the Research Achievements

本研究成果により、円滑なT細胞の再循環にはRap1を抑制して不必要なインテグリンの活性化を防ぐ必要があることが明らかとなった。
Rasa3とSipa1によるRap1の不活性化制御が生体内でのT細胞の接着・移出過程を調節し、T細胞の再循環に重要な役割を果たしていることを明らかとなり、これらの分子を標的とした免疫調節薬の開発に寄与することが期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (3 results)

All 2024 2023 2022

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] The critical role of Rap1-GAPs Rasa3 and Sipa1 in T cells for pulmonary transit and egress from the lymph nodes2023

    • Author(s)
      Horitani Shunsuke、Ueda Yoshihiro、Kamioka Yuji、Kondo Naoyuki、Ikeda Yoshiki、Naganuma Makoto、Kinashi Tatsuo
    • Journal Title

      Frontiers in Immunology

      Volume: 14 Pages: 1234747-1234747

    • DOI

      10.3389/fimmu.2023.1234747

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Rap1-GAPs Rasa3 and Sipa1 are required for pulmonary transit and egress from the lymph nodes in T cells.2024

    • Author(s)
      堀谷俊介
    • Organizer
      日本免疫学会学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] The critical role of RapGAPs in T cell recirculation and egress from lymph node.2022

    • Author(s)
      堀谷俊介
    • Organizer
      日本免疫学会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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