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

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.