Mechanisms of the development of colitis in T cell-specific Rap1-deficient mice

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07612
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: The University of Tokyo (2022); Kitasato University (2019-2021)
• Principal Investigator: Koko Katagiri 東京大学, 大学院総合文化研究科, 特任研究員 (00322157)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: colitis / Rap1 / TCR / regulatory T cells / microRNA / lymphopenia / proliferation

Outline of Final Research Achievements

T-cell-specific Rap1 deletion causes spontaneous colitis in mice. In the large intestinal lamina propria of these mice, RORgammat+Treg cells were scarcely induced by 4 weeks of age. The expression of CTLA-4 on Rap1-deficient Treg cells was impaired. Rap1-deficient T cells exhibited the defective nuclear translocation of NFAT and actin foci in response to TCR engagement, which is critical for Treg-mediated control of colitogenic Th17 responses. Integrin activation is associated with conformational regulation. We generated two kinds of mAbs that recognized Mn2+-dependent epitopes of β7. Using these mAbs, we found that the conversion of Rap1-GDP to GTP exerts two distinct effects stepwise on the conformation of α4β7. Colitogenic CD4+ T cells demonstrated the increased expression of miR-150. MiR-150 silencing completely inhibited the expansion of pathogenic Th17 cells and the development of colitis in Rap1KO mice. MiR-150 is a potential therapeutic target of IBD.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

Rap1シグナルがTCR distal signalに重要な役割を果たすこと及びRap1-GDPがインテグリンalpah4beta7の活性型構造を抑制していることを初めて明らかにした。また、miR-150の阻害は、リンパ節におけるLIP(lymphopenia-induced proliferation)を抑制し、大腸炎の発症を抑制することから、miR-150阻害剤はIBDなどの自己免疫疾患治療薬として有望であることを見出した。