1,25-Dihydroxyvitamin D3 increases the methionine cycle, CD4+ T cell DNA methylation and Helios+Foxp3+ T regulatory cells to reverse autoimmune neurodegenerative disease

• Published in: Journal of neuroimmunology Vol. 324; pp. 100 - 114
• Main Authors: Moore, Jerott R., Hubler, Shane L., Nelson, Corwin D., Nashold, Faye E., Spanier, Justin A., Hayes, Colleen E.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.11.2018
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2018.09.008

We investigated how one calcitriol dose plus vitamin D3 reverses experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol rapidly increased CD4+ T cell Ikzf2 transcripts, Helios protein, and CD4+Helios+FoxP3+ T regulatory cells. It also rapidly increased CD4+ T cell Bhmt1 transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme activity, and global DNA methylation. BHMT1 transmethylates homocysteine to replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmt1 gene expression, reduced DNA methylation, and elevated systemic homocysteine in mice with EAE. We hypothesize that calcitriol drives a transition from encephalitogenic CD4+ T cell to Treg cell dominance by upregulating Ikzf2 and Bhmt1, recycling homocysteine to methionine, reducing homocysteine toxicity, maintaining DNA methylation, and stabilizing CD4+Helios+FoxP3+Tregulatory cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmt1 and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, and betaine's protective effects in MTHFR-deficiency suggest similar regulatory mechanisms exist in humans. [Display omitted] •The vitamin D receptor is required in T cells for vitamin D3-mediated EAE remission.•1,25-(OH)2D3 induces Bhmt1 and Ikzf2 transcription in CD4+ T cells in vivo.•1,25-(OH)2D3 increases Helios+Foxp3+regulatory T cells.•1,25-(OH)2D3 controls methionine metabolism to maintain global DNA methylation in CD4+ T cells.