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

Brain. 2016 Jun;139(Pt 6):1747-61. doi: 10.1093/brain/aww084. Epub 2016 Apr 28.

Abstract

Transforming growth factor beta (TGFβ) 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 naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ 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 TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ 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 TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis.

Keywords: TGFbeta; Tregs; microRNA; multiple sclerosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Gene Expression
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / metabolism*
  • Signal Transduction / genetics
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • MicroRNAs
  • Transforming Growth Factor beta