title: Resurrecting KIR2DP1: A Key Intermediate in the Evolution of Human Inhibitory NK Cell Receptors That Recognize HLA-C.
abstract: KIR2DP1is an inactive member of the humanlineage III KIRfamily, which includes all HLA-C-specific receptor genes. The lethal, and only, defect inKIR2DP1is a nucleotide deletion in codon 88. Fixed in modern humans, the deletion is also in archaic human genomes.KIR2DP1is polymorphic, with dimorphism at specificity-determining position 44. By repairing the deletion, we resurrected 11 alleles ofKIR2DP1F, the functional antecedent ofKIR2DP1We demonstrate how K44-KIR2DP1Fwith lysine 44 recognized C1+HLA-C, whereas T44-KIR2DP1Frecognized C2+HLA-C. Dimorphisms at 12 other KIR2DP1Fresidues modulate receptor avidity or signaling. KIR2DP1 and KIR2DL1 are neighbors in the centromericKIRregion and are in tight linkage disequilibrium. LikeKIR2DL1,KIR2DP1contributed toCenAandCenB KIRhaplotype differences. Encoded onCenA, C1-specific K44-KIR2DP1Fwere stronger receptors than the attenuated C2-specific T44-KIR2DP1Fencoded onCenBThe last common ancestor of humans and chimpanzees had diverselineage III KIRthat passed on to chimpanzees but not to humans. Early humans inherited activatingKIR2DS4and an inhibitorylineage III KIR, likely encoding a C1-specific receptor. The latter spawned the modern family of HLA-C receptors. KIR2DP1Fhas properties consistent withKIR2DP1Fhaving been the founder gene. The firstKIR2DP1Falleles encoded K44-C1 receptors; subsequentlyKIR2DP1Falleles encoding T44-C2 receptors evolved. The emergence of dedicatedKIR2DL2/3andKIR2DL1genes encoding C1 and C2 receptors, respectively, could have led to obsolescence ofKIR2DP1FAlternatively, pathogen subversion caused its demise. Preservation ofKIR2DP1Ffunctional polymorphism was a side effect of fixation of the deletion inKIR2DP1Fby micro gene conversion.
authors.affiliation: Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305; and hhilton@stanford.edu peropa@stanford.edu.|Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305 hhilton@stanford.edu peropa@stanford.edu.
authors.forename: Hugo G
authors.identifier: 0000-0003-1488-7194
authors.initials: HG
authors.lastname: Hilton
authors.affiliation: Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305; and.|Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Jeroen H
authors.identifier: 0000-0002-1478-581X
authors.initials: JH
authors.lastname: Blokhuis
authors.affiliation: Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305; and.|Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.affiliation: Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305; and.|Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.affiliation: Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305; and hhilton@stanford.edu peropa@stanford.edu.|Department of Microbiology and Immunology, School of Medicine, Stanford University, Stanford, CA 94305 hhilton@stanford.edu peropa@stanford.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D000483:Alleles; D000818:Animals; D005075:Biological Evolution; D015236:HLA-C Antigens / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D006239:Haplotypes; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D015810:Linkage Disequilibrium; D002679:Pan troglodytes; D011110:Polymorphism, Genetic; D054340:Receptors, KIR / Q000235:genetics* / Q000276:immunology*; D054342:Receptors, KIR2DL1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D054343:Receptors, KIR2DL2 / Q000235:genetics / Q000276:immunology; D054344:Receptors, KIR2DL3 / Q000235:genetics / Q000276:immunology
chemical_list: D015236:HLA-C Antigens; D054340:Receptors, KIR; D054342:Receptors, KIR2DL1; D054343:Receptors, KIR2DL2; D054344:Receptors, KIR2DL3