6533b7d2fe1ef96bd125edc8
RESEARCH PRODUCT
A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.
Ari WaismanMaike BeckerJames H. SegarsRichard A. WillisMarkus HippichAnette Gabriele ZieglerMartin G. SchermKatharina GerlachAdam M. ZahmBenedikt KirchnerStefanie KälinVictoria K. FlynnJonathan SchugBenno WeigmannChristoph KüperClaus-michael LehrNicole LiebschBettina HaaseKlaus H. KaestnerAlexei NikolaevIsabelle SerrRalf PalmisanoBrigitta LoretzPeter AchenbachWan-uk KimWan-uk KimCarolin DanielMelanie Spornraftsubject
CD4-Positive T-Lymphocytes0301 basic medicineRegulatory T cellBiologymedicine.disease_causeAutoimmunityMice03 medical and health sciencesNFAT5microRNAImmunogeneticsmedicineAnimalsHumansPI3K/AKT/mTOR pathwaygeographygeography.geographical_feature_categoryNFATC Transcription FactorsAntagomirsFOXP3Forkhead Transcription FactorsGeneral MedicineIsletMice Mutant StrainsMicroRNAsTolerance inductionDiabetes Mellitus Type 1030104 developmental biologymedicine.anatomical_structureCancer researchFemaledescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-03 |