Sap is necessary for mediating antigen-specific effector functions of CD4+ AND CD8+ T cells

X-linked lymphoproliferative disease (XLP) is a rare immunodeficiency caused by mutations in SH2D1A which encodes SAP (SLAM-associated protein). SAP functions as an adaptor protein downstream of the SLAM family of cell surface receptors, thereby contributing to lymphocyte activation. The major defects in patients with XLP are exquisite sensitivity to infection with Epstein–Barr virus (EBV) due to dysfunctional CD8+ T cells and NK cells, and impaired antibody responses due to an inability of CD4+ T cells to provide ‘help’ to B cells for their differentiation into antibody secreting plasma cells. We have been investigating the molecular basis underlying these defects in XLP using a combination of approaches: by studying the viral specificity of CD8+ T cells from XLP patients as well as female carriers of XLP, and by studying the breakdown in CD4+ T cell help to B cells in an animal model of XLP (i.e., sap-deficient mice). Results from these studies highlight a critical role for interactions between SAP-associating receptors on T cells and appropriate antigen-presenting cells for the generation of effector CD4+ and CD8+ T cells and that this process is severely compromised in the presence of loss-of-function mutations in SH2D1A.