Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis
Type
ArticleAuthors
Zeitelhofer, ManuelAdzemovic, 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
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Date
2017-02-14Online Publication Date
2017-02-14Print Publication Date
2017-02-28Permanent link to this record
http://hdl.handle.net/10754/623186
Metadata
Show full item recordAbstract
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.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.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/2017/02/13/1615783114ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1615783114