Abstract
Abstract Pro-inflammatory T cells mediate autoimmune demyelination in Multiple Sclerosis (MS). However, the factors driving their development and MS susceptibility are obscure. We investigated how miRNAs, newly described as post-transcriptional regulators of gene expression, contribute to pathogenic T cell differentiation in MS. We profiled miRNA expression in naïve CD4+ T cells of healthy (n=8) and untreated MS (n=22) donors. miR-128, miR-27a/b and miR-340 were increased in naïve CD4+ T cells from MS patients. miR-128, -27a/b and -340 directly suppressed the pro-Th2 factor Bmi1, resulting in decreased GATA-3 expression. miR-340 additionally suppressed the Th2 cytokine IL-4. Overall, these miRNAs suppressed Th2 and enhanced pro-inflammatory Th1 responses. In addition, transfection of myelin-specific T cells with these miRNAs worsened EAE while treatment of MS patient cells with miRNA inhibitors led to the restoration of Th2 responses. These findings link miR-128, -27ab and -340 overexpression in MS patients’ naïve CD4+ T cells to the pro-inflammatory T cell differentiation observed in MS and illustrate the biological significance and therapeutic potential of these miRNAs.
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