title: Protein kinase CK2 governs the molecular decision between encephalitogenic TH17 cell and Treg cell development.
abstract: T helper 17 (TH17) cells represent a discrete TH cell subset instrumental in the immune response to extracellular bacteria and fungi. However, TH17 cells are considered to be detrimentally involved in autoimmune diseases like multiple sclerosis (MS). In contrast to TH17 cells, regulatory T (Treg) cells were shown to be pivotal in the maintenance of peripheral tolerance. Thus, the balance between Treg cells and TH17 cells determines the severity of a TH17 cell-driven disease and therefore is a promising target for treating autoimmune diseases. However, the molecular mechanisms controlling this balance are still unclear. Here, we report that pharmacological inhibition as well as genetic ablation of the protein kinase CK2 (CK2) ameliorates experimental autoimmune encephalomyelitis (EAE) severity and relapse incidence. Furthermore, CK2 inhibition or genetic ablation prevents TH17 cell development and promotes the generation of Treg cells. Molecularly, inhibition of CK2 leads to reduced STAT3 phosphorylation and strongly attenuated expression of the IL-23 receptor, IL-17, and GM-CSF. Thus, these results identify CK2 as a nodal point in TH17 cell development and suggest this kinase as a potential therapeutic target to treat TH17 cell-driven autoimmune responses.
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Ulges
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Esther J
authors.initials: EJ
authors.lastname: Witsch
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Gautam
authors.initials: G
authors.lastname: Pramanik
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Klein
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Birkner
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bühler
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Beatrice
authors.initials: B
authors.lastname: Wasser
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Felix
authors.initials: F
authors.lastname: Luessi
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Natascha
authors.initials: N
authors.lastname: Stergiou
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Sarah
authors.initials: S
authors.lastname: Dietzen
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Till-Julius
authors.initials: TJ
authors.lastname: Brühl
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Toszka
authors.initials: T
authors.lastname: Bohn
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Georg
authors.initials: G
authors.lastname: Bündgen
authors.affiliation: Institute of Organic Chemistry, Johannes Gutenberg University of Mainz, 55128 Mainz, Germany;
authors.forename: Horst
authors.initials: H
authors.lastname: Kunz
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany.
authors.forename: Ari
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Department of Neurology, University Medical Center Mainz of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany;
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Institute for Immunology, University Medical Center of the Johannes Gutenberg University of Mainz, 55131 Mainz, Germany; boppt@uni-mainz.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D020381:Interleukin-17; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010766:Phosphorylation; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C515500:IL23R protein, human; D020381:Interleukin-17; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C528688:interleukin-23 receptor, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D047390:Casein Kinase II
keywords: FOXP3; MS therapy; TH17 cells; multiple sclerosis; regulatory T cells