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.
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.
Vitale
Massimo
M
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Zimmer
Jacques
J
Castriconi
Roberta
R
Hanau
Daniel
D
Donato
Lionel
L
Bottino
Cristina
C
Moretta
Lorenzo
L
de la Salle
Henri
H
Moretta
Alessandro
A
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
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