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

Area of Science:

• Neuroimmunology
• Endocrinology

Background:

• Multiple sclerosis (MS) is a CNS inflammatory disease driven by T-cell migration.
• Dysfunctional regulatory T cells (Tregs), including Foxp3+ Tregs and type I regulatory T cells (Tr1), are observed in MS patients.
• Vitamin D deficiency is linked to MS, suggesting a role for this nutrient.

Purpose of the Study:

• To investigate the effect of 1,25(OH)2D3 (active vitamin D) on CD4+ T cells in the context of MS.
• To explore the interaction between vitamin D and CD46 in promoting Tr1 cell differentiation and function.

Main Methods:

• CD4+ T cells from healthy donors and MS patients were co-activated using CD28 or CD46.
• The impact of 1,25(OH)2D3 on T cell activation, adhesion molecule expression, and Tr1 differentiation was assessed.
• Gene and microRNA expression (VDR, CYP24A1, miR-9) and CD46 expression were analyzed.
• t-Distributed Stochastic Neighbor Embedding (t-SNE) was used to visualize T cell phenotypes in a clinical cohort.

Main Results:

• 1,25(OH)2D3 differentially affected adhesion molecule expression on CD28- and CD46-costimulated T cells.
• Vitamin D enhanced Tr1 cell motility via a Vitamin D-CD46 crosstalk, indicated by increased VDR, CYP24A1, and miR-9.
• In MS patients supplemented with vitamin D, CD46 expression on T cells negatively correlated with vitamin D levels.
• t-SNE analysis revealed vitamin D-specific T cell clusters with altered adhesion phenotypes in vivo.

Conclusions:

• A significant crosstalk exists between vitamin D and CD46, preferentially impacting Tr1 cells.
• Vitamin D emerges as a crucial, modifiable environmental factor influencing MS pathogenesis.
• These findings offer novel insights into the therapeutic potential of vitamin D in managing MS.