title: HLA alleles determine differences in human natural killer cell responsiveness and potency.
abstract: Epidemiological studies have associated certain human disease outcomes with particular killer cell Ig-like receptor (KIR) and HLA genotypes. However, the functional explanation for these associations is poorly understood, because the KIRs were initially described as natural killer (NK) cell inhibitory receptors with specificity for HLA molecules on their cellular targets. Yet resolution of infections is often associated with genotypic pairing of inhibitory KIRs with their cognate HLA ligands. Recent studies in mice indicate a second role for MHC-specific inhibitory receptors, i.e., self-MHC recognition confers functional competence on the NK cell to be triggered through their activation receptors, a process termed licensing. As a result, licensed NK cells with self-MHC-specific receptors are more readily activated as compared with unlicensed NK cells without self-MHC-specific receptors. Such results predict that human NK cells may undergo a similar process. Here, we examined the human NK cell subset expressing KIR3DL1, the only known KIR specific for HLA-Bw4 alleles. The KIR3DL1(+) subset in normal donors with two HLA-B-Bw4 genes displayed increased responsiveness to tumor stimulation compared with the KIR3DL1(+) subset from individuals with only one or no Bw4 genes. By contrast, NK cells lacking KIR3DL1 showed no differences. Therefore, these data indicate that particular KIR and HLA alleles are associated with more responsive NK cells, strongly suggesting that human NK cells are also subjected to NK cell licensing, and providing a potential functional explanation for the influence of KIR and HLA genes in disease as well as interindividual differences in NK cell potency.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.forename: John B
authors.initials: JB
authors.lastname: Sunwoo
authors.forename: Liping
authors.initials: L
authors.lastname: Yang
authors.forename: Taewoong
authors.initials: T
authors.lastname: Choi
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Song
authors.forename: Anthony R
authors.initials: AR
authors.lastname: French
authors.forename: Anna
authors.initials: A
authors.lastname: Vlahiotis
authors.forename: Jay F
authors.initials: JF
authors.lastname: Piccirillo
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Thalachallour
authors.initials: T
authors.lastname: Mohanakumar
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
authors.forename: Bo
authors.initials: B
authors.lastname: Dupont
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Yokoyama
mesh_terms: D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D003601:Cytotoxicity Tests, Immunologic; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D011110:Polymorphism, Genetic; D054341:Receptors, KIR3DL1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018709:Statistics, Nonparametric
chemical_list: D016207:Cytokines; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1