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Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system mediated by pathological T cell responses directed against myelin proteins. T cell responses entail two main components: trafficking of the T cell to the target organ, and acquisition of an inflammatory phenotype. These processes are tightly regulated by complex biological networks to prevent excessive inflammatory responses and autoimmune disease.MicroRNAs (miRNAs) are short non-coding transcripts, 21-23 nucleotides long that negatively regulate posttranscriptional gene expression via antisense RNA-RNA interactions. miRNAs have recently emerged as critical regulators of immune function, and their dysregulation is associated with a variety of immune pathologies, including autoimmunity. In these studies, we establish a miRNA profile in the animal model for MS, experimental autoimmune encephalomyelitis (EAE). Further, we identify functional roles for two of the differentially expressed miRNAs, miR-155 and miR-29b, in the regulation of T cell trafficking and phenotype, respectively.T cell trafficking involves the coordinated expression of cell surface receptors, such as sphingosine-1 phosphate receptor 1 (S1PR1), that facilitate lymphocyte egress from peripheral lymphoid organs. Therapeutic agents that down-regulate S1PR1 prevent pathogenic T cells from migrating to the CNS and mediating pathology, thereby reducing relapse rates in MS patients. Expression of miR-155 inversely correlates with S1PR1 during T cell activation, and miR-155 directly hybridizes with the S1PR1 untranslated region (UTR), suggesting a miRNA:target relationship. Transgenic mice over-expressing miR-155 are protected from EAE, and this protection appears to be due to sequestration of autoreactive T cells in the periphery, implicating miR-155 as a novel regulator of T cell trafficking.miRNAs are important regulators of T-helper cell programming, as demonstrated by the preferential Th1 polarization of Dicer-deficient T cells that lack miRNAs. However, the specific miRNAs that regulate Th1 phenotype and their relationship to autoimmunity have not been delineated. Using genetic knockouts, we demonstrate that loss of endogenous miR-29, derived from the miR-29ab1 genomic cluster, results in unrestrained T-bet expression and IFN-γ production. miR-29b regulates T-bet and IFN-γ via a direct interaction with the 3’UTRs, and IFN-γ itself enhances miR-29b expression, establishing a novel regulatory feedback loop. miR-29b is increased in memory CD4+ T cells from MS patients, which may reflect chronic Th1 inflammation. In summary, we have implicated miRNAs in the pathogenesis of MS through regulation of T cell trafficking (miR-155) and T cell phenotype (miR-29b). More broadly, these studies add to the understanding of T cell-intrinsic regulatory mechanisms and highlight the emerging role of miRNAs in immunological networks that are induced in response to inflammation and autoimmune disease. |
