Epigenetic modulation of inflammatory T cell responses

Abstract

Abstract Pro-inflammatory T helper (Th) 1 and Th17 cell responses drive autoimmune attack of the central nervous system in Multiple Sclerosis (MS), resulting in disability. In contrast, regulatory Th2 and Treg responses are deficient. The reactivation and expansion of inflammatory T cells is linked to increased severity and active MS disease. Thus, therapeutic strategies that modulate this process would be beneficial. Epigenetic modifications such as histone methylation and acetylation provide control over cellular phenotype. The epigenetic modifying enzyme Protein arginine methyltransferase 5 (PRMT5) is the only known enzyme known to catalyze symmetric dimethylation (SDM) on arginine residues of histones. Although PRMT5 has been shown to be up-regulated in several cancers, there is currently no known role for PRMT5 in T cells. We have found that PRMT5 was up-regulated during re-activation of myelin-specific mouse memory T cells and Experimental Autoimmune Encephalomyelitis (EAE), suggesting that PRMT5 may control expansion of pathogenic autoimmune responses. To test this, we developed novel PRMT5-selective inhibitors in collaboration with the Drug Development Institute at OSU. These novel PRMT5 inhibitors preferentially suppressed Th1 over Th2 cell proliferation, an effect that was partially dependent on IL-2 suppression. In addition, we observed similar effects in human memory T cells, suggesting a conserved function of PRMT5 in both human and mouse. Genetic knockdown of PRMT5 with a short hairpin RNA similarly suppressed inflammatory Th1 cell proliferation. Overall, these data support a role for PRMT5 in memory T cell responses and as a promising therapeutic target in autoimmunity.