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

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.

Tet2 at the interface between cancer and immunity

“…Vitamin C interacts with the core catalytic domain of Tet2, directly boosting its catalytic activities 4 . Additionally, Tet2 expression can be directly altered at the post-transcriptional level 41 , 45 . Numerous microRNAs (miRs) post-transcriptionally inhibit Tet expression and certain miRs work together to control the expression of Tet genes.…”

Advances in Human Immune System Mouse Models for Personalized Treg-Based Immunotherapies

“…Treg stability is mainly mediated by epigenetic mechanisms, most importantly the demethylation of the conserved non-coding sequence 2 (CNS2) in the Foxp3 locus ( 71 ). We were able to show that microRNA (miRNA) 142-3p contributes to Treg instability during progression of Type 1 Diabetes (T1D) by targeting TET2, a molecule that can actively demethylate DNA ( 37 , 72 , 73 ). MiRNAs are small non-coding RNAs that can sequence-specifically inhibit their target mRNAs, thereby regulating complex cellular states, such as T cell activation, which makes them important targets for immunotherapy ( 74 ).…”

“…Accordingly, a miR122 inhibitor is currently being tested in clinical trials for hepatitis C virus (HCV) infections, highlighting the feasibility of targeting miRNAs for immune modulation in human diseases ( 75 ). Regarding miRNA modulation for Treg targeting, we used NSG mice reconstituted with PBMCs and were able to demonstrate that the blockade of miRNAs that impact Treg induction or stability in vivo enhances human Treg frequencies both in the periphery and in the pancreas ( 36 , 37 , 76 ). Lessons learned from the autoimmune setting could be used for cancer immunotherapy.…”

Mechanisms of skin autoimmunity: Cellular and soluble immune components of the skin

“…90 Besides epigenetic modifications, noncoding RNAs such as micro RNA or long noncoding RNA modify immune homeostasis in autoimmune diseases. 91 In psoriasis, micro RNA interfering with T H 17 immunity might be a genetic risk factor. 92 4) Sex bias: Sex is an independent variable of immunity.…”