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

Isabelle Serr; Martin G. Scherm; Adam M. Zahm; Jonathan Schug; Victoria K. Flynn; Markus Hippich; Stefanie Kälin; Maike Becker; Peter Achenbach; Alexei Nikolaev; Katharina Gerlach; Nicole Liebsch; Brigitta Loretz; Claus Michael Lehr; Benedikt Kirchner; Melanie Spornraft; Bettina Haase; James Segars; Christoph Küper; Ralf Palmisano; Ari Waisman; Richard A. Willis; Wan Uk Kim; Benno Weigmann; Klaus H. Kaestner; Anette Gabriele Ziegler; Carolin Daniel

doi:10.1126/scitranslmed.aag1782

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

Isabelle Serr, Martin G. Scherm, Adam M. Zahm, Jonathan Schug, Victoria K. Flynn, Markus Hippich, Stefanie Kälin, Maike Becker, Peter Achenbach, Alexei Nikolaev, Katharina Gerlach, Nicole Liebsch, Brigitta Loretz, Claus Michael Lehr, Benedikt Kirchner, Melanie Spornraft, Bettina Haase, James Segars, Christoph Küper, Ralf PalmisanoAri Waisman, Richard A. Willis, Wan Uk Kim, Benno Weigmann, Klaus H. Kaestner, Anette Gabriele Ziegler, Carolin Daniel

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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 (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.

Original language	English (US)
Article number	eaag1782
Journal	Science translational medicine
Volume	10
Issue number	422
DOIs	https://doi.org/10.1126/scitranslmed.aag1782
State	Published - Jan 3 2018
Externally published	Yes

ASJC Scopus subject areas

General Medicine

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Serr, I., Scherm, M. G., Zahm, A. M., Schug, J., Flynn, V. K., Hippich, M., Kälin, S., Becker, M., Achenbach, P., Nikolaev, A., Gerlach, K., Liebsch, N., Loretz, B., Lehr, C. M., Kirchner, B., Spornraft, M., Haase, B., Segars, J., Küper, C., ... Daniel, C. (2018). A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Science translational medicine, 10(422), Article eaag1782. https://doi.org/10.1126/scitranslmed.aag1782

Serr, I, Scherm, MG, Zahm, AM, Schug, J, Flynn, VK, Hippich, M, Kälin, S, Becker, M, Achenbach, P, Nikolaev, A, Gerlach, K, Liebsch, N, Loretz, B, Lehr, CM, Kirchner, B, Spornraft, M, Haase, B, Segars, J, Küper, C, Palmisano, R, Waisman, A, Willis, RA, Kim, WU, Weigmann, B, Kaestner, KH, Ziegler, AG & Daniel, C 2018, 'A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes', Science translational medicine, vol. 10, no. 422, eaag1782. https://doi.org/10.1126/scitranslmed.aag1782

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

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 (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.",

author = "Isabelle Serr and Scherm, {Martin G.} and Zahm, {Adam M.} and Jonathan Schug and Flynn, {Victoria K.} and Markus Hippich and Stefanie K{\"a}lin and Maike Becker and Peter Achenbach and Alexei Nikolaev and Katharina Gerlach and Nicole Liebsch and Brigitta Loretz and Lehr, {Claus Michael} and Benedikt Kirchner and Melanie Spornraft and Bettina Haase and James Segars and Christoph K{\"u}per and Ralf Palmisano and Ari Waisman and Willis, {Richard A.} and Kim, {Wan Uk} and Benno Weigmann and Kaestner, {Klaus H.} and Ziegler, {Anette Gabriele} and Carolin Daniel",

note = "Publisher Copyright: Copyright {\textcopyright} 2018 The Authors, some rights reserved.",

year = "2018",

month = jan,

day = "3",

doi = "10.1126/scitranslmed.aag1782",

language = "English (US)",

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T1 - A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes

AU - Serr, Isabelle

AU - Scherm, Martin G.

AU - Zahm, Adam M.

AU - Schug, Jonathan

AU - Flynn, Victoria K.

AU - Hippich, Markus

AU - Kälin, Stefanie

AU - Becker, Maike

AU - Achenbach, Peter

AU - Nikolaev, Alexei

AU - Gerlach, Katharina

AU - Liebsch, Nicole

AU - Loretz, Brigitta

AU - Lehr, Claus Michael

AU - Kirchner, Benedikt

AU - Spornraft, Melanie

AU - Haase, Bettina

AU - Segars, James

AU - Küper, Christoph

AU - Palmisano, Ralf

AU - Waisman, Ari

AU - Willis, Richard A.

AU - Kim, Wan Uk

AU - Weigmann, Benno

AU - Kaestner, Klaus H.

AU - Ziegler, Anette Gabriele

AU - Daniel, Carolin

PY - 2018/1/3

Y1 - 2018/1/3

N2 - 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.

AB - 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.

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JF - Science translational medicine

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M1 - eaag1782

ER -

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

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