Critical role of PRMT1 in Th17 differentiation by regulating the reciprocal recruitments of STAT3 and STAT5

摘要

Th17 cells are a class of T helpers that secrete IL-17 and mediate pathogenic immunity responsible for autoimmunity including experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. RORγt is the critical transcription factor that controls the differentiation of Th17 cells. However, little is known about the transcriptional co-factors for RORVγt in the regulation of Th17 differentiation. Here, we demonstrate that protein arginine N-methyltransferase 1 (PRMT1) associates with RORγt expanding Foxp3⁺ regulatory T cells. Consistently, pharmacological inhibition of PRMT1 impaired the generation of Th17 cells and prevented induction of EAE in mouse. Mechanistically, PRMT1-dependent modification of asymmetric histone 4 arginine 3 dimethylation (H4R3me2a), is required to stabilize the stimulatory STAT3 to displace the inhibitory STAT5 at IL-17 locus, resulting in the activation of IL-17 gene. Furthermore, PRMT1-facilitated recruitment of STAT3 overcame the inhibition of Th17 differentiation exerted by IL-2-induced STAT5 activation. PRMT1 thus regulates Th17 differentiation by controlling the reciprocal recruitment of STAT3 and STAT5. Our study thus reveals PRMT1 as a novel target for alleviating Th17-mediated autoimmunity by decreasing RORγt-dependent generation of pathogenic Th17 cells.