1. 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
- Author
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Roberto Biassoni, Elena Landi, Michela Falco, Lorenzo Moretta, Simona Sivori, Silvia Parolini, Luigi D. Notarangelo, Emanuela Marcenaro, Raffaella Augugliaro, Cristina Bottino, and Alessandro Moretta
- Subjects
Cytotoxicity, Immunologic ,Male ,Herpesvirus 4, Human ,Immunology ,In Vitro Techniques ,Biology ,medicine.disease_cause ,src Homology Domains ,Mice ,chemistry.chemical_compound ,Interleukin 21 ,medicine ,Epstein-Barr virus ,Animals ,Humans ,Immunology and Allergy ,Receptors, Immunologic ,Receptor ,DNA Primers ,B-Lymphocytes ,natural killer cells ,Membrane Glycoproteins ,Lymphokine-activated killer cell ,Base Sequence ,Antibodies, Monoclonal ,Tyrosine phosphorylation ,Epstein–Barr virus ,Virology ,Lymphoproliferative Disorders ,Cell biology ,Killer Cells, Natural ,coreceptors function ,chemistry ,Mutation ,Interleukin 12 ,Immunoglobulin superfamily ,Original Article ,Src homology 2 domain–containing protein ,X-linked lymphoproliferative disease ,Proto-oncogene tyrosine-protein kinase Src - Abstract
In humans, natural killer (NK) cell function is regulated by a series of receptors 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 (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also 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 member of the immunoglobulin 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 tyrosine-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 cells derived from patients with X-linked lymphoproliferative disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-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 simultaneously 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.
- Published
- 2001