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Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis .
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Feb 28; Vol. 114 (9), pp. E1678-E1687. Date of Electronic Publication: 2017 Feb 14. - Publication Year :
- 2017
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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.
- Subjects :
- Animals
Cell Differentiation drug effects
Cell Proliferation drug effects
Down-Regulation drug effects
Epigenesis, Genetic drug effects
Genomics methods
Lymphocyte Activation drug effects
Multiple Sclerosis drug therapy
Rats
Signal Transduction genetics
Signal Transduction immunology
Th1 Cells drug effects
Th17 Cells drug effects
Up-Regulation drug effects
CD4-Positive T-Lymphocytes drug effects
Encephalomyelitis, Autoimmune, Experimental drug therapy
Vitamin D pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 114
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 28196884
- Full Text :
- https://doi.org/10.1073/pnas.1615783114