Abstract
Abstract T cell mediated autoimmune diseases and associated tissue pathology is commonly attributed to inflammatory cytokines produced by the innate immune system. Similarly, CAR-T cell therapy and checkpoint blockades lead to innate cytokine storms and inflammation. While blocking individual cytokines can alleviate some of this pathology, the upstream mechanisms permitting self-reactive T cells to facilitate an innate inflammatory response remain unknown. We have discovered critical players that are engaged by effector memory CD4 (Tem) T cells to induce a broad transcriptional program in cells of the innate immune system. The pro-inflammatory response induced in innate immune cells is independent of pattern recognition receptors (PRRs), but mirrors genes induced by microbial recognition. We find that the innate inflammation is driven by combined engagement of TNFR and CD40 on myeloid cells presenting cognate antigen to Tem cells. Pro-inflammatory cytokine production and autoimmune pathology can be completely rescued by ablating the CD40 and TNFR pathways in several models of T cell driven inflammation. Thus, we have discovered a previously unknown trigger of innate inflammation and autoimmune pathology and propose that targeting this signaling node could be a more effective therapeutic approach than previously characterized cytokine-specific remedies. Supported by grant from NIH (R01 AI123176)
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