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IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis

IL-17-producing CD8(+) (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cel...

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Autores principales: Lückel, Christina, Picard, Felix, Raifer, Hartmann, Campos Carrascosa, Lucia, Guralnik, Anna, Zhang, Yajuan, Klein, Matthias, Bittner, Stefan, Steffen, Falk, Moos, Sonja, Marini, Federico, Gloury, Renee, Kurschus, Florian C., Chao, Ying-Yin, Bertrams, Wilhelm, Sexl, Veronika, Schmeck, Bernd, Bonetti, Lynn, Grusdat, Melanie, Lohoff, Michael, Zielinski, Christina E., Zipp, Frauke, Kallies, Axel, Brenner, Dirk, Berger, Michael, Bopp, Tobias, Tackenberg, Björn, Huber, Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915776/
https://www.ncbi.nlm.nih.gov/pubmed/31844089
http://dx.doi.org/10.1038/s41467-019-13731-z
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author Lückel, Christina
Picard, Felix
Raifer, Hartmann
Campos Carrascosa, Lucia
Guralnik, Anna
Zhang, Yajuan
Klein, Matthias
Bittner, Stefan
Steffen, Falk
Moos, Sonja
Marini, Federico
Gloury, Renee
Kurschus, Florian C.
Chao, Ying-Yin
Bertrams, Wilhelm
Sexl, Veronika
Schmeck, Bernd
Bonetti, Lynn
Grusdat, Melanie
Lohoff, Michael
Zielinski, Christina E.
Zipp, Frauke
Kallies, Axel
Brenner, Dirk
Berger, Michael
Bopp, Tobias
Tackenberg, Björn
Huber, Magdalena
author_facet Lückel, Christina
Picard, Felix
Raifer, Hartmann
Campos Carrascosa, Lucia
Guralnik, Anna
Zhang, Yajuan
Klein, Matthias
Bittner, Stefan
Steffen, Falk
Moos, Sonja
Marini, Federico
Gloury, Renee
Kurschus, Florian C.
Chao, Ying-Yin
Bertrams, Wilhelm
Sexl, Veronika
Schmeck, Bernd
Bonetti, Lynn
Grusdat, Melanie
Lohoff, Michael
Zielinski, Christina E.
Zipp, Frauke
Kallies, Axel
Brenner, Dirk
Berger, Michael
Bopp, Tobias
Tackenberg, Björn
Huber, Magdalena
author_sort Lückel, Christina
collection PubMed
description IL-17-producing CD8(+) (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8(+) T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond.
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spelling pubmed-69157762019-12-18 IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis Lückel, Christina Picard, Felix Raifer, Hartmann Campos Carrascosa, Lucia Guralnik, Anna Zhang, Yajuan Klein, Matthias Bittner, Stefan Steffen, Falk Moos, Sonja Marini, Federico Gloury, Renee Kurschus, Florian C. Chao, Ying-Yin Bertrams, Wilhelm Sexl, Veronika Schmeck, Bernd Bonetti, Lynn Grusdat, Melanie Lohoff, Michael Zielinski, Christina E. Zipp, Frauke Kallies, Axel Brenner, Dirk Berger, Michael Bopp, Tobias Tackenberg, Björn Huber, Magdalena Nat Commun Article IL-17-producing CD8(+) (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC-to-TBX21, along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8(+) T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond. Nature Publishing Group UK 2019-12-16 /pmc/articles/PMC6915776/ /pubmed/31844089 http://dx.doi.org/10.1038/s41467-019-13731-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lückel, Christina
Picard, Felix
Raifer, Hartmann
Campos Carrascosa, Lucia
Guralnik, Anna
Zhang, Yajuan
Klein, Matthias
Bittner, Stefan
Steffen, Falk
Moos, Sonja
Marini, Federico
Gloury, Renee
Kurschus, Florian C.
Chao, Ying-Yin
Bertrams, Wilhelm
Sexl, Veronika
Schmeck, Bernd
Bonetti, Lynn
Grusdat, Melanie
Lohoff, Michael
Zielinski, Christina E.
Zipp, Frauke
Kallies, Axel
Brenner, Dirk
Berger, Michael
Bopp, Tobias
Tackenberg, Björn
Huber, Magdalena
IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
title IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
title_full IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
title_fullStr IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
title_full_unstemmed IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
title_short IL-17(+) CD8(+) T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
title_sort il-17(+) cd8(+) t cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915776/
https://www.ncbi.nlm.nih.gov/pubmed/31844089
http://dx.doi.org/10.1038/s41467-019-13731-z
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