Accumulating evidence indicates that cholesterol metabolism plays a major role during acquired immune response. Cholesterol metabolites oxysterols have recently been proposed to be involved in the pathogenesis of multiple sclerosis (MS), considered to be the first cause of neurologic disability among young adults in occidental countries. MS is characterized by demyelination throughout the central nervous system associated with inflammatory infiltrates of lymphocytic and mononuclear cell. The balance between pathogenicity of effector T cells and negative regulation imposed by regulatory T cells plays a major role in its development. Two important classes of regulatory T cells within the CD4+ subset are the Foxp3+ T-cells (Tregs) and IL-10-producing type 1 regulatory T cells (Tr1). Interest in Tr1 cells was revived with the discovery that they could be differentiated with the cytokine IL-27. This provided impetus to evaluate the potential of IL-27-induced Tr1 cells in autoimmune diseases. Here we propose to study the role oxysterol during Tr1 cell differentiation. We recently performed a screening for different oxysterols converting enzymes during T cell differentiation and found that IL-27 specifically induced the membrane-associated enzyme CH25H. Based on these results, we first propose to study how modulation of CH25H and its product, 25-hydroxycholesterol, influences Tr1 cell biology in vitro and in vivo using the murine model of MS, experimental autoimmune encephalomyelitis. We further aim to dissect the molecular pathways by which oxysterols modulates Tr1 cells in order to define new putative pharmaceutical targets to enhance Tr1 cell number and function. Indeed, this project will help unravel the role of cholesterol metabolites during CD4+ T cells differentiation and will assess their importance in the control of Tr1 cells during autoimmune diseases.