SLAM family receptors 2B4 and CD48 are key drivers of CD8 T cell priming by B cells

Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we utilized SAP-deficient ( Sh2d1a −/− ) mice to investigate the hypothesis that SAP is critical for CD8 T cell immune surveillance of antigen-expressing B cells or B lymphoma cells. Sh2d1a −/− CD8 T cells exhibited greatly diminished proliferation relative to wild type when antigen-presenting-B cells or -B lymphoma cells served as the primary APC. By contrast, Sh2d1a −/− CD8 T cells responded equivalently to wild type CD8 T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed antigen presentation. Through application of SLAM family receptor blocking antibodies or SLAM family receptor-deficient CD8 T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the antigen-driven CD8 T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8 T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.