title: Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells.
abstract: Natural killer (NK) cells are characterized by the ability to kill cells that lack HLA class I molecules while sparing autologous normal (HLA class I(+)) cells. However, patients with transporter-associated antigen processing (TAP) deficiency, though displaying strong reductions of HLA class I surface expression, in most instances do not experience NK-mediated autoimmune phenomena. A possible mechanism by which TAP(-/-) NK cells avoid autoreactivity against autologous HLA class I-deficient cells could be based on either quantitative or qualitative defects of surface receptors involved in NK cell triggering. In this study we show that NK cells derived from 2 patients with TAP2(-/-) express normal levels of all known triggering receptors. As revealed by the analysis of polyclonal and clonal NK cells, these receptors display normal functional capabilities and allow the killing of a panel of NK-susceptible targets, including autologous B-LCLs. On the other hand, TAP2(-/-) NK cells were unable to kill either allogeneic (HLA class I(+)) or autologous (HLA class I(-) ) phytohemagglutinin (PHA) blasts even in the presence of anti-HLA class I monoclonal antibody. These data suggest that TAP2(-/-) NK cells express still unknown inhibitory receptor(s) capable of down-regulating the NK cell cytotoxicity on binding to surface ligand(s) expressed by T cell blasts. Functional analyses, both at the polyclonal and at the clonal level, are consistent with the concept that the putative inhibitory receptor is expressed by virtually all TAP2(-/-) NK cells, whereas it is present only in rare NK cells from healthy persons. Another possibility would be that TAP2(-/-) NK cells are missing a still unidentified triggering receptor involved in NK cell-mediated killing of PHA blasts.
authors.affiliation: Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Vitale
authors.forename: Jacques
authors.initials: J
authors.lastname: Zimmer
authors.forename: Roberta
authors.initials: R
authors.lastname: Castriconi
authors.forename: Daniel
authors.initials: D
authors.lastname: Hanau
authors.forename: Lionel
authors.initials: L
authors.lastname: Donato
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Henri
authors.initials: H
authors.lastname: de la Salle
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
mesh_terms: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D002648:Child; D018389:Codon, Nonsense; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007109:Immunity / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D018389:Codon, Nonsense; D015395:Histocompatibility Antigens Class I; C112260:NCR1 protein, human; D055627:Natural Cytotoxicity Triggering Receptor 1; D011971:Receptors, Immunologic; C071692:TAP2 protein, human