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

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16011
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kansai 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
• Keywords: Rap-GAP / T cell trafficking / integrin / lung / Rap1 / LFA1 / T-cell recirculation / egress

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.

Free Research Field

消化器内科

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。