Vitamin D as a modulator of T cell activity in MS – VITADIMS

1- How does vitamin D act on an anti-inflammatory immune cell subtype?

In order to understand the role of VitD in this subtype of regulatory cells, we isolated immune cells from the blood of healthy individuals or those with MS and activated these cells in the presence or absence of VitD. We then compared the expression levels of molecules that are important to their function. We removed one of these proteins from the cells to demonstrate its importance in these cells.

2- How does it modulate the migration of immune cells to the brain?

We isolated the different subtypes of immune cells that were treated or not with VitD. The migration of these cells across blood/brain barrier models was then analyzed in a tube (in vitro). Finally, the migration of activated cells in the presence or absence of VitD was studied ‘in vivo’ in a mouse model of MS.

3- What is its effect on the immune system when MS patients are supplemented with VitD?

For this we compared the immune cells of the blood of MS patients who were recruited in a French clinical trial (D-lay MS) who received either a placebo or high-dose VitD. We studied the molecules expressed by the cells as well as the changes in their genes following VitD supplementation.

1- How does vitamin D act on an anti-inflammatory immune cell subtype?

We have shown that a protein is necessary in this subtype of immune cells because its deletion invalidates these cells. In addition, we have shown that the expression of a genetic variant (small modification in the gene) abrogated the beneficial effect of VitD in these cells.

2- How does it modulate the migration of immune cells to the brain?

We have shown that VitD blocks the migration of pathogenic immune cells to the brain, but that on the other hand, it allows the so-called regulatory cells with anti-inflammatory properties to pass through. This could explain the anti-inflammatory role of VitD in the context of MS

3- What is its effect on the immune system when MS patients are supplemented with VitD?

By comparing the expression profile of several molecules on the surface of cells before/after supplementation with VitD or a placebo, we showed that the cells of the immune system were indeed modified by VitD in humans. In addition, we showed that the expression of their genes was also modified. This shows an in vivo effect of VitD in humans.

Our data have identified several mechanisms by which VitD regulates the inflammatory response in MS. We first showed that it acts on a particular subtype of immune cells, but that this depends on the expression of a genetic variant in individuals. This therefore implies that VitD supplementation could be more or less effective depending on the expression of this genetic variant in individuals. This will have to be exploited on the response of other immune cells that are involved in MS, and also in other inflammatory diseases for which a role of VitD has been demonstrated.

We have also shown an effect on the migration of cells to the brain, which gives several leads to better understand how to control cell migration to the brain.

Finally, we observed changes in immune cells after supplementation in patients. As the clinical trial was positive, showing a reduction in the progression of the disease, we now want to exploit the changes that we observed within the immune cells in order to understand what is really happening in patients, which could provide new therapeutic avenues.

Multiple sclerosis (MS) is a complex chronic inflammatory disease of the central nervous system (CNS) that results from immune dysregulation, due to a complex interplay between environmental factors and genetic predisposition. There is a central role for lymphocytes, especially T cells, with a functional defect of regulatory T cells (Tregs) associated with an increased function of effector T cells recognizing auto-antigens. Migration of activated T cells into the CNS is also crucial for pathogenesis, and indeed, molecules controlling T-cell migration represent key targets for successful therapy.
Vitamin D deficiency is a public health problem and a recognized risk factor of MS. Vitamin D regulates inflammation by inducing both Foxp3+ Tregs and IL-10-secreting Type I regulatory T cells (Tr1), although the exact molecular mechanisms are skill unknow. The main aim of our proposal is to unravel novel mechanisms triggered by Vitamin D on T-cell functions. We will investigate the role of Vitamin D in T­cell signaling and in T-cell migration into the CNS both in vitro using a novel human blood-brain-barrier model and in vivo using animal models. We will analyze the in vivo impact of Vitamin D in patients with MS supplemented with high-dose Vitamin D as a monotherapy. We will assess T-cell functions before and after supplementation and identify novel pathways by analyzing by single-cell-RNAseq the global transcriptomic changes in these patients’ lymphocytes. These data will provide novel insights into the molecular mechanisms mediating the immuno­regulatory role of Vitamin D in MS and may provide new therapeutic targets to control pathogenic T­cell migration to the CNS and modulate regulatory T­cell function.