Epstein-Barr virus (EBV) is a cause of serious disease in immunocompromised individuals, and is strongly associated with an expanding list of human cancers. The study of a rare congenital immunodeficiency, X-linked lymphoproliferative disease (XLP), defined by lack of natural killer T cells and exquisite sensitivity to EBV infection, could provide insight into immunity against EBV. XLP is caused by mutations in the SH2D1A gene that encodes an intracellular adaptor molecule, SLAM-associated protein (SAP) that has roles in signalling of SLAM family receptors. The unique B cell tropism of EBV led us to hypothesize that SAP and SLAM family receptors may be critical for optimal CD8 T cell immunity against antigen-expressing B cells and B lymphoma cells. Consistent with this hypothesis, Sh2d1a-/- CD8 T cells showed markedly diminished proliferation and effector functions relative to wild type CD8 T cells when cultured with antigen-coated B cells or B lymphoma cells. In contrast, wild type and Sh2d1a-/- CD8 T cells responded robustly when stimulated with either antigen-coated B cell-depleted splenocytes or antigen-presenting tumor cells lacking SLAM family receptor expression. To identify specific SLAM family receptors participating in the B cell-priming of CD8 T cells, we used a combination of SLAM receptor blocking antibodies and SLAM receptor-deficient CD8 T cells and B cells. These experiments implicated an interaction between CD48 on the B cell surface and 2B4 on the T cell surface as important for co-stimulation. Collectively, these observations indicate that the recognition of SLAM family receptors on the surface of antigen presenting-B cells and -B lymphoma cells may be essential for antigen priming and immunosurveillance by CD8 T cells.