PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

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Date

2018-03-02

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Journal of Immunology

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Abstract

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), ex- pansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, in- cluding T cell–mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-kB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell–mediated inflammatory disease. The Journal of Immunology, 2017, 198: 000–000.

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Poster Division: Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)

Keywords

immunology, multiple sclerosis, autoimmunity, arginine methylation, T cell

Citation

Webb LM, Amici SA, Jablonski KA, Savardekar H, Panfil AR, Li L, Zhou W, Peine K, Karkhanis V, Bachelder E, Ainslie K, Green PL, Li C, Baiocchi RA, Guerau-de-Arellano M. (2017). "PRMT5-selective inhibitors suppress inflammatory T cell responses and Experimental Autoimmune Encephalomyelitis." J Immunol 198(4): 1439-1451. 2017. DOI: https://doi.org/10.4049/jimmunol.1601702