GNTB-A, a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr-virus-infected B cells in X-linked lymphoproliferative disease

In humans, natural killer (NK) cell function is regulated by a series of re ceptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (ni-Ab)-mediated c ross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activati on, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that al so NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel m ember of the inmunoglobulin superfamily belonging to the CD2 subfamily. NTB -A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyro sine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain-containing protein (SH2D1A) as well as with SH2 domain-containing phosphatases (SHPs). Importantly, analysis of NK cell s derived from patients with X-linked lymphoproliferative disease (XLP) sho wed that the lack of SH2D1A protein profoundly affects the function not onl y of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitor y rather than activating signals. These inhibitory signals are induced by t he interaction of NTB-A with still undefined ligands expressed on Epstein-B arr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NT B-A can partially revert this inhibitory effect,while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneous ly masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.