Cytoplasmic DNA sensing boosts CD4+ T cell metabolism for inflammatory induction

Abstract

Abstract DNA accumulation is associated with the development of autoimmune inflammatory diseases. However, the pathological role and underlying mechanism of cytoplasmic DNA accumulation in CD4+ T cells have not been well established. Here, we show that Trex1 deficiency-induced endogenous DNA accumulation in CD4+ T cells greatly promoted their induction of autoimmune inflammation in a lupus-like mouse model. Mechanistically, the accumulated DNA in CD4+ T cells was sensed by the KU complex, then triggered the activation of DNA-PKcs and ZAK and further facilitated the activation of AKT, which exacerbated glycolysis, thereby promoting the inflammatory responses. Accordingly, blocking the DNA sensing pathway in CD4+ T cells by genetic knockout of Zak or using our newly developed ZAK inhibitor iZAK2 attenuated all pathogenic characteristics in a lupus-like inflammation mouse model induced with Trex1-deficient CD4+ T cells. Overall, our study demonstrated a causal link between DNA-sensing and metabolic reprogramming in CD4+ T cells for inflammatory induction and suggested inhibition of the DNA sensing pathway may be a potential therapy for the treatment of inflammatory diseases.