Objective 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. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencescell biologymedical and health sciencesbasic medicineneurologymultiple sclerosismedical and health sciencesbasic medicineimmunologyautoimmune diseasesnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-2011-CIG - Marie-Curie Action: "Career Integration Grants" Call for proposal FP7-PEOPLE-2011-CIG See other projects for this call Funding Scheme MC-CIG - Support for training and career development of researcher (CIG) Coordinator UNIVERSITE DE GENEVE EU contribution € 75 000,00 Address RUE DU GENERAL DUFOUR 24 1211 Geneve Switzerland See on map Region Schweiz/Suisse/Svizzera Région lémanique Genève Activity type Higher or Secondary Education Establishments Administrative Contact Patrice Lalive (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
