X-linked lymphoproliferative (XLP) disease is a severe primary immunodeficiency. Immunodysregulatory phenomena are observed following EBV infection suggesting that defects exist in these effector populations. The gene defective in XLP is SAP (SLAM-associated protein), an intracellular adaptor protein that mediates signals through SLAM and other immunoglobulin superfamily receptors including 2B4. Cytotoxic T cells (CTLs) and natural killer (NK) cells play a major role in the normal immune response to Epstein-Barr virus (EBV) infection. EBV specific T cell lines (EBV-T cell lines) were generated from normal individuals and XLP patients and examined for CTL function in response to different stimuli. It has been shown that XLP patients can generate EBV-T cell lines that are phenotypically similar to those from unaffected individuals. XLP patient derived EBV-T cell lines showed a significant decrease in interferon-gamma (IFN-gamma) production in response to 2B4 and autologous EBV transformed lymphoblastoid cell line (LCL) stimulation but not in response to SLAM. Furthermore, XLP EBV-T cell lines demonstrated markedly decreased cytotoxic activity against autologous LCLs. By retroviral gene transfer of the SAP gene into XLP patient derived EBV-T cell lines, reconstitution of EFN-gamma production and cytotoxic activity has been shown, confirming the defects are SAP dependent. These studies demonstrate that in XLP the lack of SAP affects specific signalling pathways resulting in severe disruption of CTL function. In addition, SLAM and 2B4 expression on immune cell lineages has been investigated, the results suggest a wider range of 2B4 expression and deserve further investigation in relation to XLP molecular and cellular pathogenesis
