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- Title
A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes.
- Authors
Serr, Isabelle; Scherm, Martin G.; Zahm, Adam M.; Schug, Jonathan; Flynn, Victoria K.; Hippich, Markus; Kälin, Stefanie; Becker, Maike; Achenbach, Peter; Nikolaev, Alexei; Gerlach, Katharina; Liebsch, Nicole; Loretz, Brigitta; Lehr, Claus-Michael; Kirchner, Benedikt; Spornraft, Melanie; Haase, Bettina; Segars, James; Küper, Christoph; Palmisano, Ralf
- Abstract
A miRNA181a/NFAT5 signaling axis promotes immune activation and interferes with the induction of regulatory T cells in islet autoimmunity. Meddling with microRNA to treat type 1 diabetes: Among other immune dysfunctions, patients with type 1 diabetes (T1D) have defective regulatory T cell responses. T cell differentiation is guided by many types of signals and could potentially be altered to treat autoimmunity. Serr and colleagues examined how the microRNA miRNA181a can push immune activation in the context of T1D. They combine results from patients and a mouse model to demonstrate that miRNA181a increases NFAT5 and dampens regulatory T cell induction. Inhibiting this microRNA or NFAT5 could potentially open up new avenues of restoring immune balance in T1D. 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.
- Subjects
T cells; TYPE 1 diabetes; TRANSCRIPTION factors; PROTEINS; T cell receptors
- Publication
Science Translational Medicine, 2018, Vol 10, Issue 422, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aag1782