PRMT5-mediated arginine methylation controls the strength of signaling via γc-family cytokines required for T cell maintenance

Abstract

Abstract Protein arginine methylation is a post-translational modification which is involved in a wide range of biological processes such as transcriptional control and pre-mRNA splicing. Various cytokines, including IL-2 and IL-7, play crucial roles in T cell development and activation. These cytokines utilize the common cytokine receptor γ-chain (γc, encoded by Il2rg) and its associated kinase JAK3 for signal transduction, but the regulatory mechanism underlying γc and JAK3 expression remains to be elucidated. Here we show that protein arginine methyltransferase 5 (PRMT5) has a pivotal role in the maintenance of invariant NKT (iNKT), CD4+T and CD8+T cells. T-cell specific deletion of the Prmt5 gene resulted in a severe loss of iNKT cells as well as a decreased number of CD4+T and CD8+T cells. PRMT5-mediated arginine methylation is essential for the expression of γc and JAK3 required for iNKT cell development and the proliferation and survival of peripheral T cells. PRMT5 stimulates the symmetric dimethylation of the Sm proteins that facilitates the splicing of the Il2rg and Jak3 premRNA in T cells. Taken together, our findings show that PRMT5-mediated arginine methylation is a crucial determinant of the strength of signaling via γc-family cytokines and T cell maintenance.