Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis

T helper 17 (Th17) cells are a subset of CD4(+) T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m(5)C) methyltransferase Nsun2 in mouse CD4(+) T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m(5)C formation and consequently enhanced mRNA stability. Our study demonstrates a m(5)C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.