1. A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes
- Author
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Ari Waisman, Maike Becker, James H. Segars, Richard A. Willis, Markus Hippich, Anette Gabriele Ziegler, Martin G. Scherm, Katharina Gerlach, Adam M. Zahm, Benedikt Kirchner, Stefanie Kälin, Victoria K. Flynn, Jonathan Schug, Benno Weigmann, Christoph Küper, Claus-Michael Lehr, Nicole Liebsch, Bettina Haase, Klaus H. Kaestner, Alexei Nikolaev, Isabelle Serr, Ralf Palmisano, Brigitta Loretz, Peter Achenbach, Wan-Uk Kim, Carolin Daniel, Melanie Spornraft, and HIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Regulatory T cell ,Biology ,medicine.disease_cause ,Autoimmunity ,Mice ,03 medical and health sciences ,NFAT5 ,microRNA ,Immunogenetics ,medicine ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,geography ,geography.geographical_feature_category ,NFATC Transcription Factors ,Antagomirs ,FOXP3 ,Forkhead Transcription Factors ,General Medicine ,Islet ,Mice, Mutant Strains ,MicroRNAs ,Tolerance induction ,Diabetes Mellitus, Type 1 ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Female - Abstract
Molecular checkpoints that trigger the onset of islet autoimmunity or progression to human type 1 diabetes (T1D) are incompletely understood. Using T cells from children at an early stage of islet autoimmunity without clinical T1D, we find that a microRNA181a (miRNA181a)-mediated increase in signal strength of stimulation and costimulation links nuclear factor of activated T cells 5 (NFAT5) with impaired tolerance induction and autoimmune activation. We show that enhancing miRNA181a activity increases NFAT5 expression while inhibiting FOXP3+ regulatory T cell (Treg) induction in vitro. Accordingly, Treg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)-mediated NFAT5, which interferes with FoxP3+ Treg induction. Blocking miRNA181a or NFAT5 increases Treg induction in murine and humanized models and reduces murine islet autoimmunity in vivo. These findings suggest targeting miRNA181a and/or NFAT5 signaling for the development of innovative personalized medicines to limit islet autoimmunity.
- Published
- 2018