STING is an intrinsic checkpoint inhibitor that restrains the TH17 cell pathogenic program.

External and intrinsic factors regulate the transcriptional profile of T helper 17 (T H 17) cells, thereby affecting their pathogenic potential and revealing their context-dependent plasticity. The stimulator of interferon genes (STING), a component of the intracellular DNA-sensing pathway, triggers immune responses but remains largely unexplored in T cells. Here, we describe an intrinsic role of STING in limiting the T H 17 cell pathogenic program. We demonstrate that non-pathogenic T H 17 cells express higher levels of STING than those activated under pathogenic conditions. Activation of STING induces interleukin-10 (IL-10) production in T H 17 cells, decreasing IL-17A and IL-23R expression in a type I interferon (IFN)-independent manner. Mechanistically, STING-induced IL-10 production partially requires aryl hydrocarbon receptor (AhR) signaling, while the decrease of IL-17A expression occurs due to a reduction of Rorγt transcriptional activity. Our findings reveal a regulatory function of STING in the T H 17 cell activation program, proposing it as a valuable target to limit T H 17-cell-mediated inflammation. [Display omitted] • The expression of STING is inversely associated with T H 17 cell pathogenic state • AhR signaling is involved in the STING-driven IL-10 expression in T H 17 cells • STING activation impairs Rorγt binding to Il17a CNS2 enhancer region T H 17 cells display a spectrum of pathogenic states depending on environmental and intrinsic cues. Damasceno et al. demonstrate that STING activation induces a non-pathogenic T H 17 profile. Mechanistically, STING impairs Rorγt-mediated Il17a transcription, thereby reducing IL-17A production. Besides that, STING activation promotes IL-10 expression through AhR signaling pathway. [ABSTRACT FROM AUTHOR]