title: Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬.
abstract: Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS.
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.|Vascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Manuel
authors.initials: M
authors.lastname: Zeitelhofer
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Milena Z
authors.initials: MZ
authors.lastname: Adzemovic
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.|Science for Life Laboratory, 171 21 Solna, Sweden.|Mucosal and Salivary Biology Division, King's College London Dental Institute, London SE1 9RT, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Gomez-Cabrero
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Department of General Neurology, Medical University of Graz, 8036 Graz, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hochmeister
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: N'diaye
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Atul
authors.initials: A
authors.lastname: Paulson
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ruhrmann
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Almgren
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.|Science for Life Laboratory, 171 21 Solna, Sweden.|Biological and Environmental Sciences and Engineering Division, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology, 23955 Thuwal, Kingdom of Saudi Arabia.
authors.forename: Jesper N
authors.initials: JN
authors.lastname: Tegnér
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: Tomas J
authors.initials: TJ
authors.lastname: Ekström
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
authors.forename: André Ortlieb
authors.initials: AO
authors.lastname: Guerreiro-Cacais
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden; maja.jagodic@ki.se.
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D044127:Epigenesis, Genetic / Q000187:drug effects; D023281:Genomics / Q000379:methods; D008213:Lymphocyte Activation / Q000187:drug effects; D009103:Multiple Sclerosis / Q000188:drug therapy; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology*
chemical_list: D014807:Vitamin D
keywords: DNA methylation; epigenetics; experimental autoimmune encephalomyelitis; multiple sclerosis; vitamin D