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.
Madame Anne ASTIER (Institut National de la Santé et de la Recherche Médicale)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM Institut National de la Santé et de la Recherche Médicale
CNRS Centre National de la Recherche Scientifique
UB - TKI University of Bern / Theodor Kocher Institute
Help of the ANR 468,449 euros
Beginning and duration of the scientific project: December 2019 - 42 Months