In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 10, No. 422 ( 2018-01-03)
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 (T reg ) induction in vitro. Accordingly, T reg induction is improved using T cells from NFAT5 knockout (NFAT5ko) animals, whereas altering miRNA181a activity does not affect T reg induction in NFAT5ko T cells. Moreover, high costimulatory signals result in phosphoinositide 3-kinase (PI3K)–mediated NFAT5, which interferes with FoxP3 + T reg induction. Blocking miRNA181a or NFAT5 increases T reg 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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aag1782
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2018
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