miRNAs targeting TGF?-signaling disrupt Treg development and function in CNS autoimmunity.

Abstract Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system. Regulatory T cells (Tregs) exhibit impaired function in MS, and microRNAs (miRNAs) are known to regulate the development and activity of these cells. Our group recently performed a large miRNA profiling study on naïve CD4 T cells in untreated MS patients. These data revealed that large number of TGFβ-signaling pathway targeting miRNAs are upregulated in MS patients compared to healthy controls. This dysregulation limits the in vitrogeneration of human regulatory T cells (Tregs). Administration of TGFβ-associated miRNAs in utero or after birth resulted in reduced Treg frequencies compared to controls. miRNA-treated mice of various strains were more susceptible to CNS autoimmunity modelled by induction of experimental autoimmune encephalomyelitis (EAE) at 8–10 weeks of age. Tregs isolated from miRNA-treated mice also showed a loss of T cell receptor (TCR) repertoire diversity after induction of EAE as TCR Vβ deep sequencing revealed. Our findings indicate that increased levels of TGFβ-associated miRNAs lead to impaired Treg development and function contributing to an increased susceptibility to CNS autoimmunity. This may provide further understanding of Treg dysfunction in MS patients.