A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

Isabelle Serr, Martin G. Scherm, Adam M. Zahm, Jonathan Schug, Victoria K. Flynn, Markus Hippich, Stefanie Kälin, Maike Becker, Peter Achenbach, Alexei Nikolaev, Katharina Gerlach, Nicole Liebsch, Brigitta Loretz, Claus Michael Lehr, Benedikt Kirchner, Melanie Spornraft, Bettina Haase, James Segars, Christoph Küper, Ralf PalmisanoAri Waisman, Richard A. Willis, Wan Uk Kim, Benno Weigmann, Klaus H. Kaestner, Anette Gabriele Ziegler, Carolin Daniel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbereaag1782
JournalScience Translational Medicine
Volume10
Issue number422
DOIs
StatePublished - Jan 3 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Serr, I., Scherm, M. G., Zahm, A. M., Schug, J., Flynn, V. K., Hippich, M., Kälin, S., Becker, M., Achenbach, P., Nikolaev, A., Gerlach, K., Liebsch, N., Loretz, B., Lehr, C. M., Kirchner, B., Spornraft, M., Haase, B., Segars, J., Küper, C., ... Daniel, C. (2018). A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Science Translational Medicine, 10(422), [eaag1782]. https://doi.org/10.1126/scitranslmed.aag1782