Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13587-3
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Funding
- IZKF [J-50]
- Deutsche Forschungsgemeinschaft (DFG) [KFO-257, WE 4656/2, DFG-CRC1811]
- Research Group at Helmholtz Zentrum Munchen
- German Center for Diabetes Research (DZD)
- Deutsche Forschungsgemeinschaft [CRC1054]
- National Institute of Health Grant [UC4DK112217]
- Hans Fischer Senior Fellowship from the Technische Universitat Munchen
- Juvenile Diabetes Research Foundation [JDRF 2-SRA-2014-161-Q-R, JDRF 17-2012-16, JDRF 6-2012-20]
- Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus) - Federal Ministry of Education and Research [FKZ 01GI0805-07, FKZ 01GI0805]
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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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