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Person in charge of the Unit : Oui
In microenvironments such as the gastrointestinal tract, in which immune reactivity against intestinal flora or dietary antigen poses a significant risk to the host, immunosuppressive, regulatory elements predominate to suppress local inflammation. Nevertheless, even in highly regulated sites, immune responses need to occur to allow proper control of microbial expansion. How mucosal immune responses inside this tolerance-prone environment are regulated remains largely elusive.ATP is one of the universal cell energy metabolite and functions also as extracellular signaling molecules. In the immune system, extracellular ATP works as a 'danger' signal. The ATP sources are multiple: in particular, cell damage leads to a marked increase in the ATP concentration in the immediate extracellular milieu and intestinal bacteria are able to generate and secrete large amounts of ATP. These observations suggest that, inside the intestine, where T cells are chronically activated and in close contact with intestinal flora, the extracellular ATP generation needs to be tightly regulated to avoid excessive immune activation leading eventually to immunopathology.There is evidence that intestinal T cells are able to mediate extracellular ATP catabolism via the expression of two ectonucleotidase: CD39 and CD73. This capacity to remove ATP from the extracellular space and to generate adenosine seems to negatively regulate the intestinal immune response.Ourfirst objective is therefore to study the role of adenosine in the regulation of mucosal immune responses, including the differentiation and effector function of helper T cells and regulatory T cells.Secondly, inflamed tissue can become hypoxic. T cells are able to sense hypoxia by the Hypoxia inducible transcription factor (HIF-1), a heterodimeric protein composed of two subunits: HIF-1α and HIF-1β.Our second objective is to test whether specialized T helper subsets are differentially adapted to hypoxia and how these inflammatory effector cells can operate in a hypoxic tissue. Understanding the immunomodulatory role of adenosine and the mechanisms underlying immune cell adaptation to hypoxia would help to identify the cellular and molecular pathways involved in immunoregulation in normal, inflamed or cancerous tissues.