Study of the regulation of T cell activation by cytosolic DNA sensor in T cells

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08852
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Immunology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Imanishi Takayuki 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (10513442)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: STING / mTOR / TCR / I型インターフェロン

Outline of Final Research Achievements

STING plays a key role in detecting cytosolic DNA and induces type I interferon (IFN-I) responses for host defense against pathogens. Although T cells highly express STING, its physiological role remains unknown. Here we show that a STING ligand cGAMP strongly inhibits T cell growth by inhibiting mTORC1 functions through IRF3 and IRF7. Although cGAMP alone failed to induce IFN-I production, co-stimulation of T cells via TCR and STING induced sustained activation of IRF3, leading to IFN-I production. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. IFN-I production also depends on TCR-induced mTORC1 activation. Finally, we demonstrated that STING stimulation in T cells is effective in inducing anti-tumor responses in vivo. Our studies demonstrate that outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T cell functions.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、T細胞のSTINGは自然免疫細胞のSTINGと異なり、cGAMPによるIFN-I応答の誘導にはTCR/CD28の共刺激が必要である一方で、T細胞の増殖も抑制することが明らかになった。このようにT細胞のSTINGは自然免疫系とは異なる機能があるため、STINGが関与する様々な病態を理解する上で重要な知見を提供したと言える。また、T細胞のSTINGがcGAMPを介した抗腫瘍免疫にも重要であることを示したため、T細胞のSTINGを標的とした新たながん免疫療法の開発に繋がる可能性が示唆された。