A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.
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Authors
Serr, IsabelleScherm, Martin G
Zahm, Adam M
Schug, Jonathan
Flynn, Victoria K
Hippich, Markus
Kälin, Stefanie
Becker, Maike
Achenbach, Peter
Nikolaev, Alexei
Gerlach, Katharina
Liebsch, Nicole
Loretz, Brigitta
Lehr, Claus Michael

Kirchner, Benedikt
Spornraft, Melanie
Haase, Bettina
Segars, James
Küper, Christoph
Palmisano, Ralf
Waisman, Ari
Willis, Richard A
Kim, Wan-Uk
Weigmann, Benno
Kaestner, Klaus H
Ziegler, Anette-Gabriele
Daniel, Carolin
Issue Date
2018-01-03
Metadata
Show full item recordAbstract
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, Treginduction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect Treginduction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)-mediated NFAT5, which interferes with FoxP3+Treginduction. Blocking miRNA181a or NFAT5 increases Treginduction 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.Citation
A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. 2018, 10 (422) Sci Transl MedAffiliation
HIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.Journal
Science translational medicinePubMed ID
29298866Type
ArticleLanguage
enISSN
1946-6242ae974a485f413a2113503eed53cd6c53
10.1126/scitranslmed.aag1782
Scopus Count
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
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