MicroRNA-29 controls Th1 bias of CD4+ T cells in multiple sclerosis (167.5)

Abstract

Abstract Multiple sclerosis (MS) is an inflammatory disease of the central nervous system initiated by autoreactive CD4+ T cells of a T-helper (Th)1 and Th17 phenotype. Identifying novel factors that control Th differentiation will lead to a better understanding of MS pathogenesis and the development of new therapeutic strategies. MicroRNAs (miRs) are small non-coding RNAs that negatively regulate post-transcriptional gene expression. Dicer-deficient CD4+ T cells that lack miRs produce more of the Th1-associated cytokine IFN-γ; however, the specific miR(s) responsible for controlling Th1 programming have not been defined. Using in silico target prediction algorithms, we identified miR-29 as a factor that could potentially regulate multiple genes in the Th1 pathway. We confirmed that miR-29 directly targets T-bet and IFN-γ, and gain- and loss-of-function experiments demonstrated the ability of miR-29 to modulate Th1 polarization. Importantly, we found that naïve CD4+ T cells from MS patients express lower basal levels of miR-29 than controls. We further established an inverse relationship between basal expression of miR-29 and expression of T-bet/IFN-γ following activation of MS patient T cells. These results identify miR-29 as a novel regulator of Th1 differentiation and function, and implicate low miR-29 as an MS susceptibility factor. Restoring miR-29 may therefore be a powerful therapeutic modality in MS and other Th1-driven autoimmune diseases.