title: NK cell killer Ig-like receptor repertoire acquisition and maturation are strongly modulated by HLA class I molecules.
abstract: The interaction between clonally distributed inhibitory receptors and their activating counterparts on NK cells and HLA class I molecules defines NK cell functions, but the role of HLA class I ligands in the acquisition of their receptors during NK development is still unclear. Although some studies demonstrated that HLA-C affects the expression of killer Ig-like receptors (KIR), other studies showed that NK cells acquire their KIR repertoire in a stochastic manner. Only when infected with human CMV is an expansion of self-specific KIR(+) NKG2C(+) NK cells detected. To gain more insight into this question, we compared the coexpression of different KIR molecules, NKG2A, CD8, and CD57, on NK cells in healthy donors and seven patients with deficient HLA class I expression due to mutations in one of the TAP genes. Our results show a correlation between the presence/absence of HLA class I molecules and the coexpression of their receptors. In an HLA class I low-expression context, an increase in KIR molecules' coexpression is detected on the NKG2A(+) CD8(+) subset. In functional assays, hyporesponsiveness was observed for TAP-deficient NK cells derived from four patients. In contrast, NK cells from patient five were functional, whereas CD107a(+) and IFN-γ(+) CD56(dim) NK cells presented a different pattern of HLA class I receptors compared with healthy donors. Taken together, our results provide strong evidence for the role of HLA class I molecules in NK cell maturation and KIR repertoire acquisition.
authors.affiliation: Laboratory of Immunogenetics and Allergology, Public Research Center for Health, L-1526 Luxembourg, Luxembourg;
authors.forename: Marwan
authors.initials: M
authors.lastname: Sleiman
authors.forename: Nicolaas H C
authors.initials: NH
authors.lastname: Brons
authors.forename: Tony
authors.initials: T
authors.lastname: Kaoma
authors.forename: Figen
authors.initials: F
authors.lastname: Dogu
authors.forename: Alexandra
authors.initials: A
authors.lastname: Villa-Forte
authors.forename: Patrick
authors.initials: P
authors.lastname: Lenoble
authors.forename: François
authors.initials: F
authors.lastname: Hentges
authors.forename: Katja
authors.initials: K
authors.lastname: Kotsch
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Gadola
authors.forename: Carlos
authors.initials: C
authors.lastname: Vilches
authors.forename: Jacques
authors.initials: J
authors.lastname: Zimmer
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000328:Adult; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D018959:CD57 Antigens / Q000276:immunology / Q000378:metabolism; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology / Q000378:metabolism; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D019002:CD56 Antigen; D018959:CD57 Antigens; D016827:CD8 Antigens; D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D052118:Lysosomal-Associated Membrane Protein 1; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054340:Receptors, KIR; C486171:Tap1 protein, mouse; D007371:Interferon-gamma