title: Humans differ from other hominids in lacking an activating NK cell receptor that recognizes the C1 epitope of MHC class I.
abstract: Modulation of human NK cell function by killer cell Ig-like receptors (KIR) and MHC class I is dominated by the bipartite interactions of inhibitory lineage III KIR with the C1 and C2 epitopes of HLA-C. In comparison, the ligand specificities and functional contributions of the activating lineage III KIR remain poorly understood. Using a robust, sensitive assay of KIR binding and a representative panel of 95 HLA class I targets, we show that KIR2DS1 binds C2 with ~50% the avidity of KIR2DL1, whereas KIR2DS2, KIR2DS3, and KIR2DS5 have no detectable avidity for C1, C2, or any other HLA class I epitope. In contrast, the chimpanzee has activating C1- and C2-specific lineage III KIR with strong avidity, comparable to those of their paired inhibitory receptors. One variant of chimpanzee Pt-KIR3DS2, the activating C2-specific receptor, has the same avidity for C2 as does inhibitory Pt-KIR3DL4, and a second variant has ~73% the avidity. Chimpanzee Pt-KIR3DS6, the activating C1-specific receptor, has avidity for C1 that is ~70% that of inhibitory Pt-KIR2DL6. In both humans and chimpanzees we observe an evolutionary trend toward reducing the avidity of the activating C1- and C2-specific receptors through selective acquisition of attenuating substitutions. However, the extent of attenuation has been extreme in humans, as exemplified by KIR2DS2, an activating C1-specific receptor that has lost all detectable avidity for HLA class I. Supporting such elimination of activating C1-specific receptors as a uniquely human phenomenon is the presence of a high-avidity activating C1-specific receptor (Gg-KIR2DSa) in gorilla.
authors.affiliation: Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Achim K
authors.initials: AK
authors.lastname: Moesta
authors.forename: Thorsten
authors.initials: T
authors.lastname: Graef
authors.forename: Laurent
authors.initials: L
authors.lastname: Abi-Rached
authors.forename: Anastazia M
authors.initials: AM
authors.lastname: Older Aguilar
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D000818:Animals; D005075:Biological Evolution; D000939:Epitopes / Q000276:immunology; D006071:Gorilla gorilla; D015236:HLA-C Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D002679:Pan troglodytes; D054340:Receptors, KIR / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000939:Epitopes; D015236:HLA-C Antigens; C433932:KIR2DS2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D054340:Receptors, KIR
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