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

Christina Lückel; Felix Picard; Hartmann Raifer; Lucia Campos Carrascosa; Anna Guralnik; Yajuan Zhang; Matthias Klein; Stefan Bittner; Falk Steffen; Sonja Moos; Federico Marini; Renee Gloury; Florian C. Kurschus; Ying Yin Chao; Wilhelm Bertrams; Veronika Sexl; Bernd Schmeck; Lynn Bonetti; Melanie Grusdat; Michael Lohoff; Christina E. Zielinski; Frauke Zipp; Axel Kallies; Dirk Brenner; Michael Berger; Tobias Bopp; Björn Tackenberg; Magdalena Huber

doi:10.1038/s41467-019-13731-z

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

Christina Lückel, Felix Picard, Hartmann Raifer, Lucia Campos Carrascosa, Anna Guralnik, Yajuan Zhang, Matthias Klein, Stefan Bittner, Falk Steffen, Sonja Moos, Federico Marini, Renee Gloury, Florian C. Kurschus, Ying Yin Chao, Wilhelm Bertrams, Veronika Sexl, Bernd Schmeck, Lynn Bonetti, Melanie Grusdat, Michael LohoffChristina E. Zielinski, Frauke Zipp, Axel Kallies, Dirk Brenner, Michael Berger, Tobias Bopp, Björn Tackenberg, Magdalena Huber^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

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

64 Scopus citations

Abstract

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.

Original language	English
Article number	5722
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13731-z
State	Published - 1 Dec 2019

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Publisher Copyright:
© 2019, The Author(s).

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Cite this

Lückel, C., Picard, F., Raifer, H., Campos Carrascosa, L., Guralnik, A., Zhang, Y., Klein, M., Bittner, S., Steffen, F., Moos, S., Marini, F., Gloury, R., Kurschus, F. C., Chao, Y. Y., Bertrams, W., Sexl, V., Schmeck, B., Bonetti, L., Grusdat, M., ... Huber, M. (2019). IL-17⁺ CD8⁺ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nature Communications, 10(1), Article 5722. https://doi.org/10.1038/s41467-019-13731-z

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title = "IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis",

abstract = "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.",

author = "Christina L{\"u}ckel and Felix Picard and Hartmann Raifer and {Campos Carrascosa}, Lucia and Anna Guralnik and Yajuan Zhang and Matthias Klein and Stefan Bittner and Falk Steffen and Sonja Moos and Federico Marini and Renee Gloury and Kurschus, {Florian C.} and Chao, {Ying Yin} and Wilhelm Bertrams and Veronika Sexl and Bernd Schmeck and Lynn Bonetti and Melanie Grusdat and Michael Lohoff and Zielinski, {Christina E.} and Frauke Zipp and Axel Kallies and Dirk Brenner and Michael Berger and Tobias Bopp and Bj{\"o}rn Tackenberg and Magdalena Huber",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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Lückel, C, Picard, F, Raifer, H, Campos Carrascosa, L, Guralnik, A, Zhang, Y, Klein, M, Bittner, S, Steffen, F, Moos, S, Marini, F, Gloury, R, Kurschus, FC, Chao, YY, Bertrams, W, Sexl, V, Schmeck, B, Bonetti, L, Grusdat, M, Lohoff, M, Zielinski, CE, Zipp, F, Kallies, A, Brenner, D, Berger, M, Bopp, T, Tackenberg, B & Huber, M 2019, 'IL-17⁺ CD8⁺ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis', Nature Communications, vol. 10, no. 1, 5722. https://doi.org/10.1038/s41467-019-13731-z

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T1 - IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis

AU - Lückel, Christina

AU - Picard, Felix

AU - Raifer, Hartmann

AU - Campos Carrascosa, Lucia

AU - Guralnik, Anna

AU - Zhang, Yajuan

AU - Klein, Matthias

AU - Bittner, Stefan

AU - Steffen, Falk

AU - Moos, Sonja

AU - Marini, Federico

AU - Gloury, Renee

AU - Kurschus, Florian C.

AU - Chao, Ying Yin

AU - Bertrams, Wilhelm

AU - Sexl, Veronika

AU - Schmeck, Bernd

AU - Bonetti, Lynn

AU - Grusdat, Melanie

AU - Lohoff, Michael

AU - Zielinski, Christina E.

AU - Zipp, Frauke

AU - Kallies, Axel

AU - Brenner, Dirk

AU - Berger, Michael

AU - Bopp, Tobias

AU - Tackenberg, Björn

AU - Huber, Magdalena

PY - 2019/12/1

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N2 - 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.

AB - 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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