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In XLP<\/jats:styled-content>1 patients, upon ligand (CD<\/jats:styled-content>48) engagement, 2B<\/jats:styled-content>4 delivers inhibitory signals that impair the cytolytic activity of NK<\/jats:styled-content> (and T<\/jats:styled-content>) cells. This causes the selective inability to control EBV<\/jats:styled-content> infections and the occurrence of B<\/jats:styled-content>\u2010cell lymphomas. Here, we show that in the absence of SLAM<\/jats:styled-content>\u2010associated protein, co\u2010engagement of 2B<\/jats:styled-content>4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM<\/jats:styled-content>\u2010dependent signaling pathways including activating killer I<\/jats:styled-content>g\u2010like receptors. In XLP<\/jats:styled-content>1 NK<\/jats:styled-content> cells, 2B<\/jats:styled-content>4 affected both the cytolytic and IFN<\/jats:styled-content>\u2010\u03b3 production capabilities, functions that were restored upon disruption of the 2B<\/jats:styled-content>4\/CD<\/jats:styled-content>48 interactions. Notably, we provide evidence that 2B<\/jats:styled-content>4 dysfunction does not affect the activity of DNAM<\/jats:styled-content>\u20101 and NKG<\/jats:styled-content>2D<\/jats:styled-content> triggering receptors. Thus, while CD<\/jats:styled-content>48+<\/jats:sup> B<\/jats:styled-content>\u2010EBV<\/jats:styled-content> and lymphoma B<\/jats:styled-content> cells devoid of NKG<\/jats:styled-content>2D<\/jats:styled-content> and DNAM<\/jats:styled-content>\u20101 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP<\/jats:styled-content>1 NK<\/jats:styled-content> cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP<\/jats:styled-content>1 immunological defect and on the cross\u2010talk of inhibitory 2B<\/jats:styled-content>4 with triggering NK<\/jats:styled-content> (and T<\/jats:styled-content>) receptors.<\/jats:p>","DOI":"10.1002\/eji.201344312","type":"journal-article","created":{"date-parts":[[2014,2,4]],"date-time":"2014-02-04T20:28:02Z","timestamp":1391545682000},"page":"1526-1534","source":"Crossref","is-referenced-by-count":21,"title":["XLP<\/scp>1 inhibitory effect by 2B<\/scp>4 does not affect DNAM<\/scp>\u20101 and NKG<\/scp>2D<\/scp> activating pathways in NK<\/scp> cells"],"prefix":"10.1002","volume":"44","author":[{"given":"Raffaella","family":"Meazza","sequence":"first","affiliation":[{"name":"Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino\u2010Istituto Nazionale per la Ricerca sul Cancro Genoa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Tuberosa","sequence":"additional","affiliation":[{"name":"Dipartimento di Medicina Sperimentale Universit\u00e0 degli Studi di Genova Genoa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Cetica","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliero\u2010Universitaria Meyer Dipartimento di Oncoematologia Pediatrica Florence Italy"},{"name":"Istituto Toscano Tumori (I.T.T.) 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