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

Martin G. Scherm, Isabelle Serr, Adam M. Zahm, Jonathan Schug, Saverio Bellusci, Rossella Manfredini, Victoria K. Salb, Katharina Gerlach, Benno Weigmann, Anette-Gabriele Ziegler, Klaus H. Kaestner and Carolin Daniel ()
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Martin G. Scherm: Helmholtz Diabetes Center at Helmholtz Zentrum München
Isabelle Serr: Helmholtz Diabetes Center at Helmholtz Zentrum München
Adam M. Zahm: University of Pennsylvania
Jonathan Schug: University of Pennsylvania
Saverio Bellusci: Universities of Giessen and Marburg Lung Center
Rossella Manfredini: University of Modena and Reggio Emilia
Victoria K. Salb: Helmholtz Diabetes Center at Helmholtz Zentrum München
Katharina Gerlach: University of Erlangen-Nuremberg
Benno Weigmann: University of Erlangen-Nuremberg
Anette-Gabriele Ziegler: Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health
Klaus H. Kaestner: University of Pennsylvania
Carolin Daniel: Helmholtz Diabetes Center at Helmholtz Zentrum München

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13587-3

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