biostudies-literatureImanishi TNCI NIH HHSGrant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science KAKENHIe201800282https://www.ebi.ac.uk/biostudies/studies/S-EPMC6348487biostudies-literatureUnknown2(1)Stimulator of interferon genes (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 costimulation of T cells with the STING ligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1 activation and sustained activation of IRF3 are required for cGAMP-induced IFN-I production, and the mTORC1 activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1 inhibition in response to costimulation depends on IRF3 and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STING stimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T-cell functions.Life science allianceReciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function.PMC634848716K08852R01 CA194404Hoshii THirao ASaito TMatsuda SMiyake KArita MAkira SUnno MIkeda KBarber GNIshii KJImanishi TYoneda NKobayashi WfalseReciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function.Stimulator of interferon genes (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 costimulation of T cells with the STING ligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1 activation and sustained activation of IRF3 are required for cGAMP-induced IFN-I production, and the mTORC1 activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1 inhibition in response to costimulation depends on IRF3 and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STING stimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T-cell functions.2019-01-01T00:00:00Z2019 Feb2026-05-01T01:14:39.646Z2025-05-29T14:37:32.995ZS-EPMC63484873068368810.26508/lsa.201800282