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dc.contributor.authorSerr, Isabelle
dc.contributor.authorScherm, Martin G
dc.contributor.authorZahm, Adam M
dc.contributor.authorSchug, Jonathan
dc.contributor.authorFlynn, Victoria K
dc.contributor.authorHippich, Markus
dc.contributor.authorKälin, Stefanie
dc.contributor.authorBecker, Maike
dc.contributor.authorAchenbach, Peter
dc.contributor.authorNikolaev, Alexei
dc.contributor.authorGerlach, Katharina
dc.contributor.authorLiebsch, Nicole
dc.contributor.authorLoretz, Brigitta
dc.contributor.authorLehr, Claus Michael
dc.contributor.authorKirchner, Benedikt
dc.contributor.authorSpornraft, Melanie
dc.contributor.authorHaase, Bettina
dc.contributor.authorSegars, James
dc.contributor.authorKüper, Christoph
dc.contributor.authorPalmisano, Ralf
dc.contributor.authorWaisman, Ari
dc.contributor.authorWillis, Richard A
dc.contributor.authorKim, Wan-Uk
dc.contributor.authorWeigmann, Benno
dc.contributor.authorKaestner, Klaus H
dc.contributor.authorZiegler, Anette-Gabriele
dc.contributor.authorDaniel, Carolin
dc.date.accessioned2018-03-22T10:07:29Z
dc.date.available2018-03-22T10:07:29Z
dc.date.issued2018-01-03
dc.identifier.citationA miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. 2018, 10 (422) Sci Transl Meden
dc.identifier.issn1946-6242
dc.identifier.pmid29298866
dc.identifier.doi10.1126/scitranslmed.aag1782
dc.identifier.urihttp://hdl.handle.net/10033/621330
dc.description.abstractMolecular 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.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleA miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.en
dc.typeArticleen
dc.contributor.departmentHIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalScience translational medicineen
refterms.dateFOA2018-06-12T17:22:37Z
html.description.abstractMolecular 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.


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