Purinergic control of adaptive immunity by P2X7 receptor
The present project aims at investigating the role played by extracellular adenosine 5’-triphosphate (ATP) in regulating the function of a subset of white blood cells, namely T lymphocytes. ATP is usually confined inside the cell where it constitutes the source of chemical energy for the majority of cellular functions. However, ATP has also a less widely appreciated function as signaling molecule in the extracellular space. In fact, ATP can be released by mammalian cells and activate so called purinergic receptors in the plasma membrane, known as P2. Two classes of P2 receptors exist in eukaryotic cells. The first is constituted by P2Y receptors, which are metabotropic, i.e. coupled to heterotrimeric guanine nucleotide-binding protein (G-protein) and modulate mainly intracellular calcium as well as cyclic AMP levels; the second is composed by P2X receptors, which are ionotropic, i.e. ligand-gated cation-permeable channels that open when bound to ATP. A wealth of functions is regulated by P2 receptors, including secretion, tissue blood flow, cell volume and inflammation. In fact, ATP is massively released upon cell death and acts as a “danger associated molecular pattern” (DAMP) for cells of the innate immune system. P2X7 is the principal P2X subtype expressed in T lymphocytes. We have recently demonstrated that ATP inhibits the development and function of immunosuppressive regulatory T cells (Tregs) through P2X7 receptor stimulation. This T cell subset is of fundamental importance in maintaining the integrity of our organism since its defect results in severe autoimmune manifestations with tissue destruction in multiple organs. The present project is aimed at characterizing signal transduction events elicited by P2X7 stimulation in T cells, identifying critical molecules in this signalling cascade and defining the role of P2X7 in small intestine mucosa, a site where ATP is found in the extracellular space and bacteria constitute a continuous challenge for cells of the immune system associated with mucosa. In this respect we will investigate possible differences in gut microflora in mice in which T cells are devoid of P2X7 receptor because of a deletion in the gene coding for P2X7. The experiments proposed in this project will provide insights into the role of P2X7-mediated regulation of T cell function and adaptive immune response. Given that basic science is a fundamental step towards translational research, understanding the molecular mechanisms that govern T cell responsiveness will improve our knowledge of the pathogenesis of autoimmune diseases. The project is expected to delineate novel targets amenable to pharmacological intervention in autoimmune disorders. Epidemiological relevance of autoimmune diseases in modern societies is such that the discovery of therapeutic targets is a major priority in the setting of health research policies.