Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

Handle URI:
http://hdl.handle.net/10754/623186
Title:
Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬
Authors:
Zeitelhofer, Manuel; Adzemovic, Milena Z.; Gomez-Cabrero, David; Bergman, Petra; Hochmeister, Sonja; N'diaye, Marie; Paulson, Atul; Ruhrmann, Sabrina; Almgren, Malin; Tegner, Jesper; Ekström, Tomas J.; Guerreiro-Cacais, André Ortlieb; Jagodic, Maja
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.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Citation:
Zeitelhofer M, Adzemovic MZ, Gomez-Cabrero D, Bergman P, Hochmeister S, et al. (2017) Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬. Proceedings of the National Academy of Sciences 114: E1678–E1687. Available: http://dx.doi.org/10.1073/pnas.1615783114.
Publisher:
Proceedings of the National Academy of Sciences
Journal:
Proceedings of the National Academy of Sciences
Issue Date:
15-Feb-2017
DOI:
10.1073/pnas.1615783114
Type:
Article
ISSN:
0027-8424; 1091-6490
Sponsors:
This study was supported by the Swedish Research Council (M.J. and J.N.T.); the Swedish Association for Persons with Neurological Disabilities (M.J.); the Swedish Brain Foundation (M.J. and J.N.T.); the Swedish Medical Society (M.J.); the Petrus and Augusta Hedlunds Foundation (M.J.); Karolinska Institutet funds (to M.J. and S.R.); AFA Insurance (T.J.E. and J.N.T.); Wenner-Gren Foundations Grant (to M.Z.); and Biogen Idec Grant (to M.Z.A.).
Additional Links:
http://www.pnas.org/content/early/2017/02/13/1615783114
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorZeitelhofer, Manuelen
dc.contributor.authorAdzemovic, Milena Z.en
dc.contributor.authorGomez-Cabrero, Daviden
dc.contributor.authorBergman, Petraen
dc.contributor.authorHochmeister, Sonjaen
dc.contributor.authorN'diaye, Marieen
dc.contributor.authorPaulson, Atulen
dc.contributor.authorRuhrmann, Sabrinaen
dc.contributor.authorAlmgren, Malinen
dc.contributor.authorTegner, Jesperen
dc.contributor.authorEkström, Tomas J.en
dc.contributor.authorGuerreiro-Cacais, André Ortlieben
dc.contributor.authorJagodic, Majaen
dc.date.accessioned2017-04-13T11:51:00Z-
dc.date.available2017-04-13T11:51:00Z-
dc.date.issued2017-02-15en
dc.identifier.citationZeitelhofer M, Adzemovic MZ, Gomez-Cabrero D, Bergman P, Hochmeister S, et al. (2017) Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬. Proceedings of the National Academy of Sciences 114: E1678–E1687. Available: http://dx.doi.org/10.1073/pnas.1615783114.en
dc.identifier.issn0027-8424en
dc.identifier.issn1091-6490en
dc.identifier.doi10.1073/pnas.1615783114en
dc.identifier.urihttp://hdl.handle.net/10754/623186-
dc.description.abstractVitamin 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.en
dc.description.sponsorshipThis study was supported by the Swedish Research Council (M.J. and J.N.T.); the Swedish Association for Persons with Neurological Disabilities (M.J.); the Swedish Brain Foundation (M.J. and J.N.T.); the Swedish Medical Society (M.J.); the Petrus and Augusta Hedlunds Foundation (M.J.); Karolinska Institutet funds (to M.J. and S.R.); AFA Insurance (T.J.E. and J.N.T.); Wenner-Gren Foundations Grant (to M.Z.); and Biogen Idec Grant (to M.Z.A.).en
dc.publisherProceedings of the National Academy of Sciencesen
dc.relation.urlhttp://www.pnas.org/content/early/2017/02/13/1615783114en
dc.subjectVitamin Den
dc.subjectDNA methylationen
dc.subjectMultiple sclerosisen
dc.subjectEpigeneticsen
dc.subjectexperimental autoimmune encephalomyelitisen
dc.titleFunctional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬en
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.identifier.journalProceedings of the National Academy of Sciencesen
dc.contributor.institutionVascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.en
dc.contributor.institutionDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.en
dc.contributor.institutionDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Swedenen
dc.contributor.institutionMucosal and Salivary Biology Division, King's College London Dental Institute, London SE1 9RT, United Kingdom.en
dc.contributor.institutionDepartment of General Neurology, Medical University of Graz, 8036 Graz, Austria.en
dc.contributor.institutionmaja.jagodic@ki.se.en
kaust.authorTegner, Jesperen
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