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

2.50
Hdl Handle:
http://hdl.handle.net/10033/621330
Title:
A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.
Authors:
Serr, Isabelle; Scherm, 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 ( 0000-0002-5864-8462 ) ; 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
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, 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.
Affiliation:
HIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
Citation:
A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. 2018, 10 (422) Sci Transl Med
Journal:
Science translational medicine
Issue Date:
3-Jan-2018
URI:
http://hdl.handle.net/10033/621330
DOI:
10.1126/scitranslmed.aag1782
PubMed ID:
29298866
Type:
Article
Language:
en
ISSN:
1946-6242
Appears in Collections:
publications of the department drug delivery ([TC] DDEL)

Full metadata record

DC FieldValue Language
dc.contributor.authorSerr, Isabelleen
dc.contributor.authorScherm, Martin Gen
dc.contributor.authorZahm, Adam Men
dc.contributor.authorSchug, Jonathanen
dc.contributor.authorFlynn, Victoria Ken
dc.contributor.authorHippich, Markusen
dc.contributor.authorKälin, Stefanieen
dc.contributor.authorBecker, Maikeen
dc.contributor.authorAchenbach, Peteren
dc.contributor.authorNikolaev, Alexeien
dc.contributor.authorGerlach, Katharinaen
dc.contributor.authorLiebsch, Nicoleen
dc.contributor.authorLoretz, Brigittaen
dc.contributor.authorLehr, Claus Michaelen
dc.contributor.authorKirchner, Benedikten
dc.contributor.authorSpornraft, Melanieen
dc.contributor.authorHaase, Bettinaen
dc.contributor.authorSegars, Jamesen
dc.contributor.authorKüper, Christophen
dc.contributor.authorPalmisano, Ralfen
dc.contributor.authorWaisman, Arien
dc.contributor.authorWillis, Richard Aen
dc.contributor.authorKim, Wan-Uken
dc.contributor.authorWeigmann, Bennoen
dc.contributor.authorKaestner, Klaus Hen
dc.contributor.authorZiegler, Anette-Gabrieleen
dc.contributor.authorDaniel, Carolinen
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.en
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

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