A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

Serr I, Scherm MG, Zahm AM, Schug J, Flynn VK, Hippich M, Kaelin S, Becker M, Achenbach P, Nikolaev A, Gerlach K, Liebsch N, Loretz B, Lehr CM, Kirchner B, Spornraft M, Haase B, Segars J, Kuper C, Palmisano R, Waisman A, Willis RA, Kim WU, Weigmann B, Kaestner KH, Ziegler AG, Daniel C (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Science Translational Medicine American Association for the Advancement of Science

Book Volume: 10

Journal Issue: 422

DOI: 10.1126/scitranslmed.aag1782

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, Treg 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 FoxP(3+) 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.

Authors with CRIS profile

Katharina Gerlach Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Ralf Palmisano Optical Imaging Center Erlangen (OICE) Benno Weigmann Medizinische Fakultät

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Helmholtz-Institut für Pharmazeutische Forschung Saarland (HIPS) DE Germany (DE) Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich DE Germany (DE) Deutsches Zentrum für Diabetesforschung e.V. (DZD) DE Germany (DE) US National Institutes of Health (NIH) US United States (USA) (US) University of Pennsylvania US United States (USA) (US) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) European Molecular Biology Laboratory (EMBL) DE Germany (DE) Catholic University of Korea KR Korea, Republic of (KR) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) Technische Universität München (TUM) DE Germany (DE) Johns Hopkins University (JHU) US United States (USA) (US)

How to cite

APA:

Serr, I., Scherm, M.G., Zahm, A.M., Schug, J., Flynn, V.K., Hippich, M.,... Daniel, C. (2018). A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Science Translational Medicine, 10(422). https://dx.doi.org/10.1126/scitranslmed.aag1782

MLA:

Serr, Isabelle, et al. "A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes." Science Translational Medicine 10.422 (2018).

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