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.

miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes / Scherm, M. G.; Serr, I.; Zahm, A. M.; Schug, J.; Bellusci, S.; Manfredini, R.; Salb, V. K.; Gerlach, K.; Weigmann, B.; Ziegler, A. -G.; Kaestner, K. H.; Daniel, C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), pp. 1-15. [10.1038/s41467-019-13587-3]

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

Manfredini R.;
2019

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.
2019
10
1
1
15
miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes / Scherm, M. G.; Serr, I.; Zahm, A. M.; Schug, J.; Bellusci, S.; Manfredini, R.; Salb, V. K.; Gerlach, K.; Weigmann, B.; Ziegler, A. -G.; Kaestner, K. H.; Daniel, C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), pp. 1-15. [10.1038/s41467-019-13587-3]
Scherm, M. G.; Serr, I.; Zahm, A. M.; Schug, J.; Bellusci, S.; Manfredini, R.; Salb, V. K.; Gerlach, K.; Weigmann, B.; Ziegler, A. -G.; Kaestner, K. H.; Daniel, C.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1221487
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