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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.* ; Palmisano, R.* ; Waisman, A.* ; Willis, R.A.* ; Kim, W.U.* ; Weigmann, B.* ; Kaestner, K.H.* ; Ziegler, A.G.* ; Daniel, C.

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

Sci. Transl. Med. 10:eaag1782 (2018)
Verlagsversion Postprint DOI PMC
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Transcription Factor; Nod Mice; Foxp3 Locus; In-vivo; Insulin; Activation; Translation; Expression; Antigen; Nfat5
Sprache englisch
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Zeitschrift Science Translational Medicine
Quellenangaben Band: 10, Heft: 422, Seiten: , Artikelnummer: eaag1782 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Type 1 Diabetes Immunology (TDI)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502191-001
DOI 10.1126/scitranslmed.aag1782
WOS ID WOS:000419215400001
Scopus ID 85040128609
PubMed ID 29298866
Erfassungsdatum 2018-01-14
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