S-Adenosylmethionine-dependent methylation modulates T cell immune response and lupus autoimmunity (116.13)

Abstract

Abstract Methylation modification is a key factor to maintain T and B cell immune responses and contributes to the development of autoimmune diseases. Failure to maintain the methylation status of CpG dinucleotide triggers T cell autoreactivity and results in the pathogenesis of systemic lupus erythematosus (SLE). However, methylated proteins have been considered as auto-antigens such as arginine-methylated myelin basic protein in multiple sclerosis (MS) and symmetrical dimethyl-arginines of SmD1 and SmD3 in SLE. Importantly, transmethylation reaction cannot achieve without the methyl donor supply. Herein, we demonstrate that the disruption of the metabolism of s-adenosylmethionine (SAM) cycle, the major methyl donor source for transmethylation, can modulate T cell functions. By giving excess methyl donor, SAM, or methylation inhibitor, methylthioadenosine (MTA), T cell immune responses were suppressed includes TCR signaling defect, impaired multiple Th1/Th2 cytokine productions, decreased T cell activation and proliferation. Moreover, intraperitoneal treatment of MTA markedly ameliorates splenomegaly, lymphadenopathy, peripheral autoantibodies production, renal IgG deposition and lymphocyte infiltration into the kidney in lupus-prone MRL/lpr mice. These studies demonstrate the central role of SAM-dependent methylation associated with T cell function and MRL lupus autoimmunity.