| Literature DB >> 29298866 |
Isabelle Serr1,2, Martin G Scherm1,2, Adam M Zahm3, Jonathan Schug3, Victoria K Flynn1,2, Markus Hippich2,4, Stefanie Kälin2,5, Maike Becker1,2, Peter Achenbach2,4, Alexei Nikolaev6, Katharina Gerlach7, Nicole Liebsch8, Brigitta Loretz8, Claus-Michael Lehr8,9, Benedikt Kirchner10, Melanie Spornraft10, Bettina Haase11, James Segars12, Christoph Küper13, Ralf Palmisano14, Ari Waisman6, Richard A Willis15, Wan-Uk Kim16,17, Benno Weigmann7, Klaus H Kaestner3, Anette-Gabriele Ziegler2,4, Carolin Daniel18,2.
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.Entities:
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Year: 2018 PMID： 29298866 PMCID： PMC5828501 DOI： 10.1126/scitranslmed.aag1782
Source DB: PubMed Journal: Sci Transl Med ISSN： 1946-6234 Impact factor: 17.956