The role of Arf pathway in onset of Th17-mediated autoimmune disease.

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16701
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kansai Medical University
• Principal Investigator: SUMIYOSHI Mami 関西医科大学, 医学部, 助教 (50779402)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: T細胞 / 自己免疫疾患 / 炎症性腸疾患 / 多発性硬化症 / 免疫応答 / 小胞輸送 / ADP ribosylation factor

Outline of Final Research Achievements

Recently, we have revealed that the naive CD4+ T cells lacking both Arf1 and Arf6 failed to induce colitis in naive CD4+ T cell-induced colitis model, one of the widely used mouse models of inflammatory bowel disease. Considering that Th17 cells play a pivotal role in the pathogenesis of naive CD4+ T cell-induced colitis, one can argue that suppression of colitis could reflect the impaired ability of Arf1/6-deficient naive CD4+ T cells to differentiate or the defect in survival of Th17 cells. However, Arf1/6-deficient CD4+ T cells normally differentiated to pathogenic Th17 cells in vitro and pathogenic Th17 cells generated from Arf1/6-deficient CD4+ T cells survived to a level comparable to control in vivo. On the other hand, the lack of both Arf1 and Arf6 rendered naive T cells susceptible to apoptosis upon TCR stimulation. We also found that Arf1/6-deficient mice were completely resistant to induction of EAE, another type of Th17-mediated inflammatory disease of the CNS.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

これまでの研究からは、Arf1とArf6は細胞内で異なる輸送経路を制御していると信じられてきたが、本研究により、Arf1とArf6が「TCR刺激におけるナイーブT細胞の生存維持」という特定の条件下では相補的に働くことが世界で初めて明らかとなった点に高い学術的意義がある。さらに、本研究を発展させることによりこれまで報告のなかったArfファミリーを介した小胞輸送制御とアポトーシス制御の関連を紐解くことに繋がる。加えて、Arf欠損に伴う自己免疫病態抑制の分子基盤が解明されるなら、自己免疫病態に対する新たな治療法開発に繋がるものと期待される。