Resurrecting KIR2DP1: A Key Intermediate in the Evolution of Human Inhibitory NK Cell Receptors That Recognize HLA-C

• Published in: The Journal of immunology (1950) Vol. 198; no. 5; pp. 1961 - 1973
• Main Authors: Hilton, Hugo G, Blokhuis, Jeroen H, Guethlein, Lisbeth A, Norman, Paul J, Parham, Peter
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01.03.2017
• Subjects: Alleles; Animals; Avidity; Biological Evolution; Chimpanzees; Clonal deletion; Dimorphism; Gene conversion; Gene deletion; Genes; Genomes; Haplotypes; Histocompatibility antigen HLA; HLA-C Antigens - genetics; HLA-C Antigens - immunology; HLA-C Antigens - physiology; Humans; Killer cell immunoglobulin-like receptors; Killer Cells, Natural - immunology; Linkage Disequilibrium; Lysine; Natural killer cells; Obsolescence; Pan troglodytes; Polymorphism, Genetic; Potassium channels (inwardly-rectifying); Preservation; Receptor mechanisms; Receptors, KIR - genetics; Receptors, KIR - immunology; Receptors, KIR2DL1 - chemistry; Receptors, KIR2DL1 - genetics; Receptors, KIR2DL1 - immunology; Receptors, KIR2DL2 - genetics; Receptors, KIR2DL2 - immunology; Receptors, KIR2DL3 - genetics; Receptors, KIR2DL3 - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1601835

is an inactive member of the human family, which includes all HLA-C-specific receptor genes. The lethal, and only, defect in is a nucleotide deletion in codon 88. Fixed in modern humans, the deletion is also in archaic human genomes. is polymorphic, with dimorphism at specificity-determining position 44. By repairing the deletion, we resurrected 11 alleles of , the functional antecedent of We demonstrate how K44-KIR2DP1 with lysine 44 recognized C1 HLA-C, whereas T44-KIR2DP1 recognized C2 HLA-C. Dimorphisms at 12 other KIR2DP1 residues modulate receptor avidity or signaling. KIR2DP1 and KIR2DL1 are neighbors in the centromeric region and are in tight linkage disequilibrium. Like , contributed to and haplotype differences. Encoded on , C1-specific K44-KIR2DP1 were stronger receptors than the attenuated C2-specific T44-KIR2DP1 encoded on The last common ancestor of humans and chimpanzees had diverse that passed on to chimpanzees but not to humans. Early humans inherited activating and an inhibitory , likely encoding a C1-specific receptor. The latter spawned the modern family of HLA-C receptors. KIR2DP1 has properties consistent with having been the founder gene. The first alleles encoded K44-C1 receptors; subsequently alleles encoding T44-C2 receptors evolved. The emergence of dedicated and genes encoding C1 and C2 receptors, respectively, could have led to obsolescence of Alternatively, pathogen subversion caused its demise. Preservation of functional polymorphism was a side effect of fixation of the deletion in by micro gene conversion.