miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes

Nat Commun. 2019 Dec 13;10(1):5697. doi: 10.1038/s41467-019-13587-3.

Abstract

In type 1 diabetes, the appearance of islet autoantibodies indicates the onset of islet autoimmunity, often many years before clinical symptoms arise. While T cells play a major role in the destruction of pancreatic beta cells, molecular underpinnings promoting aberrant T cell activation remain poorly understood. Here, we show that during islet autoimmunity an miR142-3p/Tet2/Foxp3 axis interferes with the efficient induction of regulatory T (Treg) cells, resulting in impaired Treg stability in mouse and human. Specifically, we demonstrate that miR142-3p is induced in islet autoimmunity and that its inhibition enhances Treg induction and stability, leading to reduced islet autoimmunity in non-obese diabetic mice. Using various cellular and molecular approaches we identify Tet2 as a direct target of miR142-3p, thereby linking high miR142-3p levels to epigenetic remodeling in Tregs. These findings offer a mechanistic model where during islet autoimmunity miR142-3p/Tet2-mediated Treg instability contributes to autoimmune activation and progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / genetics*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Child
  • DNA-Binding Proteins / genetics*
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Dioxygenases
  • Epigenesis, Genetic / immunology
  • Gene Expression Regulation / immunology
  • Gene Knockdown Techniques
  • Humans
  • Islets of Langerhans / immunology
  • Male
  • Mice, Knockout
  • MicroRNAs / agonists
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Primary Cell Culture
  • Proto-Oncogene Proteins / genetics*
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • DNA-Binding Proteins
  • MIRN142 microRNA, human
  • MicroRNAs
  • Mirn142 microRNA, mouse
  • Proto-Oncogene Proteins
  • Dioxygenases
  • TET2 protein, human
  • Tet2 protein, mouse