Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

Stimulatorof 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 STINGligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1activation and sustained activation of IRF3are required for cGAMP-induced IFN-I production, and the mTORC1activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1inhibition in response to costimulation depends on IRF3and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STINGstimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STINGand TCR signaling pathways are mutually regulated through mTORC1to modulate T-cell functions.