title: Polymorphic HLA-C Receptors Balance the Functional Characteristics of KIR Haplotypes.
abstract: The human killer cell Ig-like receptor (KIR) locus comprises two groups of KIR haplotypes, termed A and B. These are present in all human populations but with different relative frequencies, suggesting they have different functional properties that underlie their balancing selection. We studied the genomic organization and functional properties of the alleles of the inhibitory and activating HLA-C receptors encoded by KIR haplotypes. Because every HLA-C allotype functions as a ligand for KIR, the interactions between KIR and HLA-C dominate the HLA class I-mediated regulation of human NK cells. The C2 epitope is recognized by inhibitory KIR2DL1 and activating KIR2DS1, whereas the C1 epitope is recognized by inhibitory KIR2DL2 and KIR2DL3. This study shows that the KIR2DL1, KIR2DS1, and KIR2DL2/3 alleles form distinctive phylogenetic clades that associate with specific KIR haplotypes. KIR A haplotypes are characterized by KIR2DL1 alleles that encode strong inhibitory C2 receptors and KIR2DL3 alleles encoding weak inhibitory C1 receptors. In striking contrast, KIR B haplotypes are characterized by KIR2DL1 alleles that encode weak inhibitory C2 receptors and KIR2DL2 alleles encoding strong inhibitory C1 receptors. The wide-ranging properties of KIR allotypes arise from substitutions throughout the KIR molecule. Such substitutions can influence cell surface expression, as well as the avidity and specificity for HLA-C ligands. Consistent with the crucial role of inhibitory HLA-C receptors in self-recognition, as well as NK cell education and response, most KIR haplotypes have both a functional C1 and C2 receptor, despite the considerable variation that occurs in ligand recognition and surface expression.
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors: Hugo G
authors: HG
authors: Hilton
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors: Lisbeth A
authors: LA
authors: Guethlein
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors: Ana
authors: http://orcid.org/0000-0002-6962-727X
authors: A
authors: Goyos
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors: Neda
authors: N
authors: Nemat-Gorgani
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and.
authors: David A
authors: DA
authors: Bushnell
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
authors: Paul J
authors: PJ
authors: Norman
authors: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305 peropa@stanford.edu.
authors: Peter
authors: P
authors: Parham
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D000939:Epitopes / Q000276:immunology; D005787:Gene Frequency; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D006239:Haplotypes / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology*; D054342:Receptors, KIR2DL1 / Q000235:genetics / Q000276:immunology*; D054343:Receptors, KIR2DL2 / Q000235:genetics / Q000276:immunology*; D054344:Receptors, KIR2DL3 / Q000235:genetics / Q000276:immunology*
chemical_list: D000939:Epitopes; D015236:HLA-C Antigens; C093100:KIR2DL1 protein, human; C515077:KIR2DL2 protein, human; C515078:KIR2DL3 protein, human; C496212:KIR2DS1 protein, human; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3