MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis

Regulatory T cells (Tregs) are defective in multiple sclerosis. Severin et al. show that TGF beta signalling is reduced in T cells in multiple sclerosis owing to overexpression of miRNAs that negatively regulate the TGF beta pathway. This results in impaired Treg development, and implicates overexpression of specific miRNAs in multiple sclerosis susceptibility.Regulatory T cells (Tregs) are defective in multiple sclerosis. Severin et al. show that TGF beta signalling is reduced in T cells in multiple sclerosis owing to overexpression of miRNAs that negatively regulate the TGF beta pathway. This results in impaired Treg development, and implicates overexpression of specific miRNAs in multiple sclerosis susceptibility.Transforming growth factor beta (TGF beta) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naive CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGF beta signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGF beta signalling components in their naive CD4 T cells. The differentially expressed miRNAs negatively regulated the TGF beta pathway, resulting in a reduced capacity of naive CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGF beta-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGF beta signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGF beta-targeting miRNAs in naive CD4 T cells of patients with multiple sclerosis impairs TGF beta signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis.