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Original Article

^a Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy
^b Dipartimento di Medicina Sperimentale, Università di Genova, 16132 Italy
^c Dipartimento di Scienze Biomediche e Biotecnologie, Clinica Pediatrica, Università di Brescia, Brescia 25123 Italy
^d Istituto di Medicina Molecolare Angelo Nocivelli, Clinica Pediatrica, Università di Brescia, Brescia 25123 Italy
^e Istituto Giannina Gaslini, 16148 Genova, Italy
Dipartimento di Medicina Sperimentale, Sezione di Istologia, Via G.B. Marsano 10, 16132 Genova, Italy.39-010-51-27-4739-010-35-37-868

alemoret{at}unige.it

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.

Key Words: X-linked lymphoproliferative disease • coreceptors function • natural killer cells • Epstein-Barr virus • Src homology 2 domain–containing protein

C. Bottino, M. Falco, and S. Parolini contributed equally to this work.

© 2001 The Rockefeller University Press

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