PRMT1 Plays a Critical Role in Th17 Differentiation by Regulating Reciprocal Recruitment of STAT3 and STAT5

Abstract

Th17 cells are a class of Th cells that secrete IL-17 and mediate pathogenic immunity responsible for autoimmunity including experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis. Retinoic acid-related orphan receptor γ t (RORγt) is the critical transcription factor that controls the differentiation of Th17 cells. However, little is known about the transcriptional cofactors for RORγt in the regulation of Th17 differentiation. In this study, we demonstrate that protein arginine N-methyltransferase 1 (PRMT1) associates with RORγt and regulates mouse Th17 differentiation. Overexpression of PRMT1 promoted Th17 differentiation, whereas inactivation or knockdown of PRMT1 decreased Th17 differentiation while expanding Foxp3⁺ regulatory T cells. Consistently, pharmacological inhibition of PRMT1 impaired the generation of Th17 cells and prevented induction of experimental autoimmune encephalomyelitis in mice. Mechanistically, PRMT1-dependent modification of asymmetric histone 4 arginine 3 dimethylation 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.