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; Kuper, Christoph; Palmisano, Ralf; Waisman, Ari; Willis, Richard A.; Kim, Wan-Uk; Weigmann, Benno; Kästner, Klaus H.; Ziegler, Anette-Gabriele; Daniel, Carolin (2018): A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. In: Science Translational Medicine, Vol. 10, No. 422, 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.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
ISSN: | 1946-6234 |
Language: | English |
ID Code: | 63702 |
Deposited On: | 19. Jul 2019 12:13 |
Last Modified: | 04. Nov 2020 13:42 |
- BASE
- 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
- Kuper, Christoph
- Palmisano, Ralf
- Waisman, Ari
- Willis, Richard A.
- Kim, Wan-Uk
- Weigmann, Benno
- Kästner, Klaus H.
- Ziegler, Anette-Gabriele
- Daniel, Carolin
- Google Scholar
- 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
- Kuper, Christoph
- Palmisano, Ralf
- Waisman, Ari
- Willis, Richard A.
- Kim, Wan-Uk
- Weigmann, Benno
- Kästner, Klaus H.
- Ziegler, Anette-Gabriele
- Daniel, Carolin