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

Serr, Isabelle
; 
Scherm, Martin G
; 
Zahm, Adam M
; 
Schug, Jonathan
; 
Flynn, Victoria K
; 
Hippich, Markus
; 
Kälin, Stefanie
; 
Becker, Maike
; 
Achenbach, Peter
; 
Nikolaev, Alexei
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2018-01-03
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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.
Citation
A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. 2018, 10 (422) Sci Transl Med
Affiliation
HIPS, Helmholtz-Institute für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
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Science translational medicine
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http://hdl.handle.net/10033/621330
DOI
10.1126/scitranslmed.aag1782
PubMed ID
29298866
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en
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1946-6242
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publications of the research group drug delivery ([HIPS] DDEL)