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

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.