Endogenous retrovirus promotes the aberrant T cell differentiation in systemic lupus erythematosus via RIG-I pathway

The dysregulated differentiation of T lymphocyte play an important role in systemic lupus erythematosus (SLE). However, the underlying mechanism remains unclear. Here, we showed that many transcripts derived from human endogenous retroviruses (HERVs) were highly expressed in CD4 + T cells from SLE patients due to DNA hypomethylation, some of which were characterized by double strand RNAs (dsRNAs). Excessive dsRNAs promoted Th1/Th17 differentiation and inhibited Treg cell differentiation via the activation of dsRNA sensor retinoic acid-inducible gene I (RIG-I). And T cell-specific ablation of RIG-I alleviated disease progression in experimental autoimmune encephalomyelitis (EAE) mice model and lupus-like mice model. Importantly, we demonstrated that dsRNA-activated RIG-I protein bind lactate dehydrogenase A (LDHA) and regulate histone lysine 18 lactylation (H3K18Lac) and acetylation (H3K18Ac) modifications in T cell differentiation via changing lactate level. Collectively, our findings uncover a novel role and mechanism of HERVs and RIG-I in regulating the aberrant differentiation of T cells in SLE patients.