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Sci Transl Med ; 10(422)2018 01 03.
Article in English | MEDLINE | ID: mdl-29298866

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, 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.


Subject(s)
Diabetes Mellitus, Type 1/metabolism , MicroRNAs/metabolism , NFATC Transcription Factors/metabolism , Animals , Antagomirs , CD4-Positive T-Lymphocytes/metabolism , Diabetes Mellitus, Type 1/genetics , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Humans , Immunogenetics , Mice , Mice, Mutant Strains , MicroRNAs/genetics , NFATC Transcription Factors/genetics
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