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Scherm, Martin G.; Serr, Isabelle; Zahm, Adam M.; Schug, Jonathan; Bellusci, Saverio; Manfredini, Rossella; Salb, Victoria K.; Gerlach, Katharina; Weigmann, Benno; Ziegler, Anette-Gabriele; Kaestner, Klaus H. and Daniel, Carolin (2019): miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes. In: Nature Communications, Vol. 10, 5697 [PDF, 2MB]


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.

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