Effector Memory T cells induce DC-intrinsic DNA damage and a non-canonical STING pathway during innate inflammation [ATAC]
A breach in tolerance to self-antigens induces expansion of autoreactive T cells, ultimately leading to autoimmune inflammation. While autoreactive T cells are principal drivers of autoimmunity, tissue pathology is alternatively driven by innate cytokines, indicating that autoreactive T cells can induce innate inflammation. This study has led to the discovery that effector memory T (Tem) cells trigger double stranded breaks via mitochondrial ROS production in interacting DCs. Consequently, initiation of the DNA damage response leads to activation of a cGAS-independent, STING-TRAF6-NFkB signaling axis. STING deficient DCs display significant defects in transcriptional induction and functional production of IL-1b and IL-6 following their interaction with Tem cells, both in vitro and in vivo. The discovery of Tem induced innate inflammation through DNA damage and a non-canonical STING-mediated NFkB activation presents this pathway as a potential target to alleviate T cell driven autoimmune inflammation. Overall design: WT or STING golden ticket BMDCs were co-cultured with in vitro generated effector memory T (Tem) cells + anti-CD3 for 1 hour. BMDCs were then sorted away from Tem cells and submitted for sequencing. Control samples include WT and STING golden ticket sorted BMDCs previously cultured with Tem cells - anti-CD3 (unstimulated).