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

Jerott R. Moore, Shane L. Hubler, Corwin D. Nelson, Faye E. Nashold, Justin A. Spanier, Colleen E. Hayes

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)100-114
Number of pages15
JournalJournal of Neuroimmunology
Volume324
DOIs
StatePublished - Nov 15 2018

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