Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis

Front Immunol. 2020 Nov 24:11:598727. doi: 10.3389/fimmu.2020.598727. eCollection 2020.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease. Herein, we examined the impact of 1,25(OH)2D3 on CD4+ T cells coactivated by either CD28 to induce polyclonal activation or by the complement regulator CD46 to promote Tr1 differentiation. Addition of 1,25(OH)2D3 led to a differential expression of adhesion molecules on CD28- and CD46-costimulated T cells isolated from both healthy donors or from patients with MS. 1,25(OH)2D3 favored Tr1 motility though a Vitamin D-CD46 crosstalk highlighted by increased VDR expression as well as increased CYP24A1 and miR-9 in CD46-costimulated T cells. Furthermore, analysis of CD46 expression on T cells from a cohort of patients with MS supplemented by vitamin D showed a negative correlation with the levels of circulating vitamin D. Moreover, t-Distributed Stochastic Neighbor Embedding (t-SNE) analysis allowed the visualization and identification of clusters increased by vitamin D supplementation, but not by placebo, that exhibited similar adhesion phenotype to what was observed in vitro. Overall, our data show a crosstalk between vitamin D and CD46 that allows a preferential effect of Vitamin D on Tr1 cells, providing novel key insights into the role of an important modifiable environmental factor in MS.

Keywords: CD46; adhesion; multiple sclerosis; type I regulatory T cells; vitamin D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers
  • Chemotaxis / drug effects
  • Chemotaxis / immunology
  • Dietary Supplements
  • Female
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Membrane Cofactor Protein / metabolism*
  • Middle Aged
  • Models, Biological
  • Multiple Sclerosis / etiology*
  • Multiple Sclerosis / metabolism*
  • Multiple Sclerosis / pathology
  • Signal Transduction* / drug effects
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Vitamin D / metabolism*
  • Vitamin D / pharmacology

Substances

  • Biomarkers
  • CD46 protein, human
  • Membrane Cofactor Protein
  • Vitamin D