Effector memory T cells induce innate inflammation by triggering DNA damage and a non-canonical STING pathway in dendritic cells.

Cognate interaction between CD4 effector memory T (T) cells and dendritic cells (DCs) induces innate inflammatory cytokine production, resulting in detrimental autoimmune pathology and cytokine storms. While T cells use tumor necrosis factor (TNF) superfamily ligands to activate DCs, whether T cells prompt other DC-intrinsic changes that influence the innate inflammatory response has never been investigated. We report the surprising discovery that T cells trigger double-strand DNA breaks via mitochondrial reactive oxygen species (ROS) production in interacting DCs. Initiation of the DNA damage response in DCs induces activation of a cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-independent, non-canonical stimulator of interferon genes (STING)-TNF receptor-associated factor 6 (TRAF6)-nuclear factor κB (NF-κB) signaling axis. Consequently, STING-deficient DCs display reduced NF-κB activation and subsequent defects in transcriptional induction and functional production of interleukin-1β (IL-1β) and IL-6 following their interaction with T cells. The discovery of T cell-induced innate inflammation through DNA damage and a non-canonical STING-NF-κB pathway presents this pathway as a potential target to alleviate T cell-driven inflammation in autoimmunity and cytokine storms.