title: Allelic variation in KIR2DL3 generates a KIR2DL2-like receptor with increased binding to its HLA-C ligand.
abstract: Although extensive homology exists between their extracellular domains, NK cell inhibitory receptors killer Ig-like receptor (KIR) 2DL2*001 and KIR2DL3*001 have previously been shown to differ substantially in their HLA-C binding avidity. To explore the largely uncharacterized impact of allelic diversity, the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated for surface expression and binding affinity to their HLA-C group 1 and 2 ligands. Although no significant differences in the degree of cell membrane localization were detected in a transfected human NKL cell line by flow cytometry, surface plasmon resonance and KIR binding to a panel of HLA allotypes demonstrated that KIR2DL3*005 differed significantly from other KIR2DL3 allelic products in its ability to bind HLA-C. The increased affinity and avidity of KIR2DL3*005 for its ligand was also demonstrated to have a larger impact on the inhibition of IFN-γ production by the human KHYG-1 NK cell line compared with KIR2DL3*001, a low-affinity allelic product. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 in KIR2DL3*005 were critical to the observed phenotype. Although these residues are distal to the KIR/HLA-C interface, molecular modeling suggests that alteration in the interdomain hinge angle of KIR2DL3*005 toward that found in KIR2DL2*001, another strong receptor of the KIR2DL2/3 family, may be the cause of this increased affinity. The regain of inhibitory capacity by KIR2DL3*005 suggests that the rapidly evolving KIR locus may be responding to relatively recent selective pressures placed upon certain human populations.
authors.affiliation: Department of Oncology, C.W. Bill Young Marrow Donor Recruitment and Research Program, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Frazier
authors.forename: Noriko
authors.initials: N
authors.lastname: Steiner
authors.forename: Lihua
authors.initials: L
authors.lastname: Hou
authors.forename: Sivanesan
authors.initials: S
authors.lastname: Dakshanamurthy
authors.forename: Carolyn Katovich
authors.initials: CK
authors.lastname: Hurley
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D000595:Amino Acid Sequence; D016000:Cluster Analysis; D005434:Flow Cytometry; D014644:Genetic Variation; D015236:HLA-C Antigens / Q000378:metabolism*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000235:genetics; D054343:Receptors, KIR2DL2 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054344:Receptors, KIR2DL3 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D015236:HLA-C Antigens; C515078:KIR2DL3 protein, human; D008024:Ligands; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3