SAP-mediated DGKa inhibition triggers a novel cell fate switch in antigen-activated T cells: implications for XLP1 therapy

X-linked lymphoproliferative disease (XLP1) is a rare inherited syndrome (rate: 1/1.000.000) caused by mutations of SH2D1A gene, contained in the X chromosome, which impair the production or the function of SAP protein. SAP is essential for the immune response and in particular for the elimination of exceeding antigen-activated lymphocytes, the so called Ristimulation-Induced Cell Death (RICD). Thus, upon activation by persistent viral infection, SAP-defective T cells of patients with XLP1, accumulate in several tissues giving rise to the diverse expression of the disease. With the support of two previous Telethon grants, we showed that upon T cell activation, SAP inhibits the activity of diacylglycerol kinase alpha (DGKa), an enzyme which consumes diacylglycerol, a lipid molecule acting as intracellular messenger. Thus, in absence of SAP, DGKa is always active, i.e. consumes less diacylglycerol, thus impairing its function. Indeed, we recently demonstrated that DGKa inhibition in vitro rescues defective RICD of T cells from patients with XLP1, and in vivo reduces the immune-pathology in a murine model of XLP1. In this project, we intend: i) to develop novel and more specific DGKa inhibitors, whose efficacy will be assayed both in vitro and in the murine model of XLP1 pathology; ii) to elucidate the molecular mechanisms by which SAP regulates DGKa, and in turn, by which diacylglycerol regulates the cell fate of activated T cells, i.e. their RICD. The identification of such mechanisms may reveal also other inherited syndromes, where DGKa deregulation may contribute to the development of the pathology and that may be counteracted by novel DGKa inhibitors.