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.