Purinergic signaling in T cell physiology
T lymphocytes are white blood cells, which play a crucial role in coordinating the immune response against pathogens. T cells mature in the thymus and colonize peripheral lymphoid organs, such as lymph nodes, spleen and Peyer's patches in the gut, where immune responses originate. The T lymphocyte population is constituted by millions of cells expressing at the cell surface the T cell receptor (TCR), which is different from one cell to another. This heterogeneity allows the specific recognition by distinct T cells of the different antigens derived by microorganisms invading the body. The generation of the TCR repertoire diversity can lead to the recognition of normal components of the body. To avoid this, T cells expressing TCRs specific for self-antigens are inactivated, thus ensuring self-tolerance. However, recognition of self-antigens in pathological situations is responsible of autoimmune diseases. These diseases, which include type 1 diabetes, Crohn's disease, multiple sclerosis, rheumatoid arthritis and psoriasis depend on deregulated T cell activation against self, which ultimately results in inflammation and tissue destruction. Adenosine triphosphate (ATP), which is released by dieing cells, acts as a "danger signal" for the immune system. It activates various cells of the immune system through binding to specific receptors on the cell surface. In addition to this function, we have demonstrated that activated T cells release ATP; the secreted ATP interacts with receptors on the T cell surface and protracts T cell activation. The blockade of this interaction leads to abortive T cell activation upon antigen encounter and generation of a state of T cell "unresponsiveness", which ultimately results in reduced tissue destruction in mouse models of autoimmune diseases. This project is aimed at characterizing the molecular mechanisms underlying ATP contribution to T cell activation. Immune suppressive compounds are increasingly used for the treatment of autoimmune disorders or after organ transplants. The disadvantage of most drugs in use consists in their lack of specificity and the need for continuous life long treatment, which is often accompanied by unwanted side effects. The finding that in vitro and in vivo inhibition of ATP mediated signaling during T cell activation leads to T cell "unresponsiveness" opens the possibility for short time application of possible antagonists of ATP signalling as immunosuppressive pharmaceuticals.