Cutting edge: Defective NK cell activation in X-linked lymphoproliferativedisease

X-linked lymphoproliferative disease (XLP) is characterized by a selective immune deficiency to EBV, The molecular basis of XLP has been attributed to mutations of signaling lymphocytic activation molecule-associated protein, an intracellular molecule known to associate with the lymphocyte-activatin g surface receptors SLAM and 2B4. We have identified a single nucleotide mu tation in SLAM-associated protein that affects the NK cell function of male s carrying the mutated gene. In contrast to normal controls, both NK and ly mphokine-activated killer cell cytotoxicity was significantly reduced in tw o XLP patients. In addition to decreased baseline cytotoxicity, ligation of 2B4 significantly augmented Ng lytic function in normal controls but faile d to enhance the cytotoxicity of NK cells from XLP patients. These findings suggest that association of SAP with 2B4 is necessary for optimal NK/lymph okine-activated killer cytotoxicity and imply that alterations in SAP/2B4 s ignaling contribute to the immune dysfunction observed in XLP.