Effector memory CD4+ T cells induce damaging innate inflammation and autoimmune pathology by engaging CD40 and TNFR on myeloid cells.

Cytokine storm and sterile inflammation are common features of T cell-mediated autoimmune diseases and T cell-targeted cancer immunotherapies. Although blocking individual cytokines can mitigate some pathology, the upstream mechanisms governing overabundant innate inflammatory cytokine production remain unknown. Here, we have identified a critical signaling node that is engaged by effector memory T cells (TEM) to mobilize a broad proinflammatory program in the innate immune system. Cognate interactions between TEM and myeloid cells led to induction of an inflammatory transcriptional profile that was reminiscent, yet entirely independent, of classical pattern recognition receptor (PRR) activation. This PRR-independent "de novo" inflammation was driven by preexisting TEM engagement of both CD40 and tumor necrosis factor receptor (TNFR) on myeloid cells. Cytokine toxicity and autoimmune pathology could be completely rescued by ablating these pathways genetically or pharmacologically in multiple models of T cell-driven inflammation, indicating that TEM instruction of the innate immune system is a primary driver of associated immunopathology. Thus, we have identified a previously unknown trigger of cytokine storm and autoimmune pathology that is amenable to therapeutic interventions.