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Original Article |
b Istituto Nazionale per la Ricerca sul Cancro, 16132 Genova, Italy
c Dipartimento di Medicina Sperimentale, Università di Genova, 16132 Genova, Italy
d Istituto di Medicina Molecolare Angelo Nocivelli, Clinica Pediatrica, Università di Brescia, 25123 Brescia, Italy
e Department of Pediatrics, University of Washington, Seattle, Washington 98195-6320
f Department of Immunology, University of Vienna, A-1090 Vienna, Austria
g Centre d'Immunologie Pierre Fabre, F74164 St. Julien-en-Genevois, France
Dipartimento di Medicina Sperimentale, Sezione di Istologia, Via G.B. Marsano 10, 16132 Genova, Italy.39-10-51274739-10-3537868
alemoret{at}unige.it
2B4 is a surface molecule involved in activation of the natural killer (NK) cell–mediated cytotoxicity. It binds a protein termed Src homology 2 domain–containing protein (SH2D1A) or signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which in turn has been proposed to function as a regulator of the 2B4-associated signal transduction pathway. In this study, we analyzed patients with X-linked lymphoproliferative disease (XLP), a severe inherited immunodeficiency characterized by critical mutations in the SH2D1A gene and by the inability to control Epstein-Barr virus (EBV) infections. We show that, in these patients, 2B4 not only fails to transduce triggering signals, but also mediates a sharp inhibition of the NK-mediated cytolysis. Other receptors involved in NK cell triggering, including CD16, NKp46, NKp44, and NKp30, displayed a normal functional capability. However, their activating function was inhibited upon engagement of 2B4 molecules. CD48, the natural ligand of 2B4, is highly expressed on the surface of EBV+ B cell lines. Remarkably, NK cells from XLP patients could not kill EBV+ B cell lines. This failure was found to be the consequence of inhibitory signals generated by the interaction between 2B4 and CD48, as the antibody-mediated disruption of the 2B4–CD48 interaction restored lysis of EBV+ target cells lacking human histocompatibility leukocyte antigen (HLA) class I molecules. In the case of autologous or allogeneic (HLA class I+) EBV+ lymphoblastoid cell lines, restoration of lysis was achieved only by the simultaneous disruption of 2B4–CD48 and NK receptor–HLA class I interactions. Molecular analysis revealed that 2B4 molecules isolated from either XLP or normal NK cells were identical. As expected, in XLP-NK cells, 2B4 did not associate with SH2D1A, whereas similar to 2B4 molecules isolated from normal NK cells, it did associate with Src homology 2 domain–containing phosphatase 1.
Key Words: X-linked lymphoproliferative disease • Epstein-Barr virus infection • natural killer cell • natural cytotoxicity receptor • 2B4 molecule
S. Parolini and C. Bottino contributed equally to this work.
© 2000 The Rockefeller University Press
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