Elucidation of the molecular mechanism of T cell subcortical actin formation and its role in TCR signaling

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07287
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kyoto University
• Principal Investigator: Thumkeo Dean 京都大学, 医学研究科, 特定准教授 (40372594)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: T細胞 / アクチン / formin

Outline of Final Research Achievements

T cell-mediated immune responses are induced upon the recognition of non-self peptides presented by antigen-presenting cells through T cell receptors (TCR). It is known that T cells form a structure called immune synapse (IS) upon antigen stimulation. During this process, cytoskeleton actin undergoes large-scale reorganization. In this work, I have shown that the linear actin polymerizers, formin family proteins, promote TCR signaling through actin rearrangement in IS (Thumkeo et al., Science Advances, 2020). Moreover, in collaboration with the University of Colorado, we have further demonstrated that bioactive phospholipid LPA inhibited the localization and activation of the formin molecule mDia1 in antigen-stimulated T cells, resulting in abnormalities in the actin cytoskeleton structure. (Kremer, Buser, Thumkeo et al., PNAS 2022).Finally, we performed live imaging of F-actin using a super-resolution microscope and examined the effects of formins and Arp2/3 inhibitors.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

本研究はCD8 T細胞のTCRシグナル伝達にformin familyアクチン重合因子mDiaが重要であることを見出した。さらに、生理活性リン脂質LPAが抗原刺激依存的なmDiaの活性化と局在を阻害することを明らかにした。また、forminに加えて、Arp2/3 family重合因子も不可欠であるという所見を見出しており、これらの知見を統合させることにより、さらにTCRシグナル伝達の理解を深めることができると考えている。これまで、TCRシグナル伝達に関わる分子は免疫抑制剤など自己免疫疾患などの薬物の標的になっており、今後本研究で得られた知見の臨床応用が期待される。