Selective PRMT5 inhibition suppresses inflammatory T cell responses and autoimmunity.

Abstract

Abstract In the autoimmune disease Multiple Sclerosis (MS), pro-inflammatory, pathogenic T helper (Th) 1 and Th17 responses promote demyelination and disability. MS treatments that preferentially target inflammatory T cell responses may be beneficial to the field. Epigenetic modifications regulate cellular functions and phenotype and inhibition of all methylation reactions suppresses T cell proliferation and experimental autoimmune encephalomyelitis (EAE). However, the specific enzyme(s) responsible for these effects remain to be determined. Protein arginine methyltransferase 5 (PRMT5), the major Type II methyltransferase enzyme, mediates symmetric dimethylation of arginine residues of histones. Although PRMT5 is known to be up-regulated in many lymphoid malignancies, currently there is no known role for PRMT5 in T cells. In this study, we use memory Th cells and animal models to study the role of PRMT5 in T cell responses and autoimmunity. PRMT5 was up-regulated in memory Th cells upon activation in a process. We found that PRMT5 drove T cell proliferation, and pathogenic Th1 cells were more susceptible to PRMT5-selective inhibitor treatment than benign Th2 cells. PRMT5-selective inhibitors ameliorated disease severity in EAE, the mouse model of MS. This disease suppression correlated with suppression of myelin-specific T cell proliferation as well as IFNg and IL-17 cytokine production. Additionally, PRMT5 inhibitors suppressed pathogenic Th17 cell populations ex vivo. These results indicate that PRMT5 may be a promising therapeutic target in T cell-mediated autoimmune diseases such as Multiple Sclerosis.