Killer cell immunoglobulin-like receptor 3DL1 licenses CD16-mediated effector functions of natural killer cells.
Activating receptor-mediated recognition of stress-induced ligands or IgG antibody bridging of tumor or pathogen-associated antigens to the FcγRIII CD16 triggers NK cells to kill transformed and infected cells with reduced HLA-I expression. According to the licensing hypothesis, NK cells become competent for activating receptor-mediated triggering after a formative encounter between a NK inhibitory receptor and its ligand. This general hypothesis is supported by murine and human studies, but to date, evidence of a role for such licensing in human ADCC is ambiguous. Inhibitory receptor interactions with HLA-C promote NK cell ADCC licensing, but interactions between KIR3DL1 and its HLA-Bw4 ligand may be insufficient. We investigated the impact of KIR3DL1 and HLA-Bw4 coexpression on NK cell ADCC using a robust, genuine target system of antibody-bearing EBV-transformed B lymphocytes. Although numbers of KIR3DL1(+) NK cells were similar in HLA-Bw4(+) and HLA-Bw4(-) individuals, general levels of ADCC mediated against target cells were significantly higher in a group of HLA-Bw4(+)KIR3DL1(+) individuals than in a comparable HLA-Bw4(-) group. Flow cytometry demonstrated directly that a significantly higher fraction of KIR3DL1(+) NK cells derived from HLA-Bw4(+) compared with HLA-Bw4(-) individuals produced IFN-γ following stimulation with ADCC targets. Murine FcR-bearing P815 target cells also triggered higher levels of CD16-mediated cytotoxicity by NK cells from HLA-Bw4(+)KIR3DL1(+) individuals. These results indicate a prominent role for KIR3DL1/HLA-Bw4 interactions in licensing NK cells for CD16-mediated effector function.
Parsons
Matthew S
MS
Division of BioMedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Dr., St. John's, NL, Canada.
Zipperlen
Katrin
K
Gallant
Maureen
M
Grant
Michael
M
D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D007694:Killer Cells, Natural / Q000276:immunology*; D009154:Mutation; D009542:Niemann-Pick Diseases / Q000201:enzymology / Q000235:genetics; D010146:Pain / Q000276:immunology / Q000503:physiopathology; D017452:Receptors, IgG / Q000276:immunology*; D054341:Receptors, KIR3DL1 / Q000276:immunology*; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics
D017452:Receptors, IgG; D054341:Receptors, KIR3DL1; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase