biostudies-literatureSerr IKompetenznetz Diabetes mellitusGerman Center for Diabetes ResearchDeutsche ForschungsgemeinschaftJuvenile Diabetes Research FoundationNational Research Foundation of KoreaNational Institutes of HealthClinical Research Unit 257 CEDERGerman Federal Ministry of Education and Researcheaag1782https://www.ebi.ac.uk/biostudies/studies/S-EPMC5828501biostudies-literatureUnknown10(422)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 costimulatorScience translational medicineA miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.PMC5828501award309930JDRF 17-2012-16JDRF 2-SRA-2014-161-Q-Raward309935award309924award309936award309937UC4DK112217award309938award309931award309932award3099332015R1A3A2032927award309923award309934FKZ 01GI0805-07WE 4656/2award309929JDRF 6-2012-20FKZ 01GI0805CRC1054 B11CRC1811 B02Kuper CBecker MLoretz BWaisman AScherm MGFlynn VKSpornraft MHaase BGerlach KSegars JKalin SHippich MKaestner KHZiegler AGPalmisano RKim WUDaniel CKirchner BZahm AMLehr CMAchenbach PSchug JNikolaev ALiebsch NWillis RASerr IWeigmann BfalseA miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.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 costimulator2018-01-01T00:00:00Z2018 Jan2025-04-18T23:20:30.534Z2019-03-26T23:04:02ZS-EPMC58285012929886610.1126/scitranslmed.aag1782