Mechanisms of adaptive immune regulation by regulatory T cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H04801
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 49:Pathology, infection/immunology, and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Hori Shohei 東京大学, 大学院薬学系研究科(薬学部), 教授 (50392113)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Keywords: 制御性T細胞 / 自己免疫疾患 / 免疫寛容

Outline of Final Research Achievements

In this study, we sought to elucidate the molecular basis of regulatory T (Treg) cell "adaptability", the ability to adapt and function in changing immune and tissue environments. Using knock-in mice harboring the Foxp3 A384T mutation, which impairs Treg cell accumulation in a tissue-restricted manner, we demonstrated that this mutation impairs the clonal expansion and tissue infiltration of effector Treg cells that receive strong TCR signals, thereby reducing the number of effector Treg cells in specific tissues. At the molecular level, this Foxp3 mutation impairs TCR-induced c-Myc upregulation in effector Treg cells and thereby their cell proliferation. In addition, our results suggest that Foxp3 promotes Treg activation and effector differentiation in cooperation with several transcription factors downstream of TCR signaling.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究により、Tregが免疫抑制機能を発現して自己免疫寛容を確立・維持するうえで、TregがTCRを介して組織抗原を認識することでエフェクター型Tregに分化し、クローン増殖して組織内に浸潤して組織環境に適応することが重要であることを明らかにした。そして、Tregの適応性を制御する分子機構の一端を解明した。これらの知見はTregによる免疫制御機構の新たな側面を解明したばかりでなく、組織選択的な自己免疫疾患の発症機序の理解や治療戦略の開発にもつながる可能性がある。