NK Cell Receptors of the Orangutan (<i>Pongo pygmaeus</i>): A Pivotal Species for Tracking the Coevolution of Killer Cell Ig-Like Receptors with MHC-C

Guethlein, Lisbeth A.; Flodin, Laura R.; Adams, Erin J.; Parham, Peter

doi:10.4049/jimmunol.169.1.220

Cited by 95 publications

(126 citation statements)

References 52 publications

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“…Phylogenetic comparisons have favored an evolutionary model in which MHC-C allotypes carrying C1 and their cognate inhibitory KIR evolved before C2-bearing allotypes and their cognate KIR (41). Knowing now that KIR2DL2/3 has a weak, broad affinity for C2 and that KIR2DL1 has no affinity for C1, we can explain how the C2 epitope and its cognate KIR evolved under natural selection after the C1 epitope and C1-specific KIR were already in place.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Polymorphism at Two Positions Distal to the Ligand-Binding Site Makes KIR2DL2 a Stronger Receptor for HLA-C Than KIR2DL3

Moesta

Norman²,

Yawata³

et al. 2008

The Journal of Immunology

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Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes. The allotypically related KIR2DL2*001 and KIR2DL3*001 interacted with all C1, but they violated the simple rule through interactions with several C2 allotypes, notably Cw*0501 and Cw*0202, and two HLA-B allotypes (B*4601 and B*7301) that share polymorphisms with HLA-C. Although the specificities of the “cross-reactions” were similar for KIR2DL2*001 and KIR2DL3*001, they were stronger for KIR2DL2*001, as were the reactions with C1. Mutagenesis explored the avidity difference between KIR2DL2*001 and KIR2DL3*001. Recombinant mutants mapped the difference to the Ig-like domains, where site-directed mutagenesis showed that the combination, but not the individual substitutions, of arginine for proline 16 in D1 and cysteine for arginine 148 in D2 made KIR2DL2*001 a stronger receptor than KIR2DL3*001. Neither residue 16 or 148 is part of, or near to, the ligand-binding site. Instead, their juxtaposition near the flexible hinge between D1 and D2 suggests that their polymorphisms affect the ligand-binding site by changing the hinge angle and the relative orientation of the two domains. This study demonstrates how allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2/3 has diversified this receptor’s interactions with HLA-C.

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Section: Discussionmentioning

confidence: 99%

Synergistic Polymorphism at Two Positions Distal to the Ligand-Binding Site Makes KIR2DL2 a Stronger Receptor for HLA-C Than KIR2DL3

Moesta

Norman²,

Yawata³

et al. 2008

The Journal of Immunology

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348

468

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“…The KIR family is important in humans and other primates, having undergone extensive diversification under positive selection. In contrast, the CD94-NKG2A system has remained relatively well conserved across the species with orthologous genes in primates and a closely related functional homolog in rodents (3,4). Consistent with the coevolution of these families and their MHC class I ligands, KIR bind polymorphic MHC class I, HLA-A, -B, and -C molecules, whereas CD94-NKG2A binds the conserved oligomorphic HLA-E molecule or the rodent homolog Qa-1 (5,6).…”

mentioning

confidence: 96%

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

Cheent

Jamil

Cassidy

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide selectivity is a feature of inhibitory receptors for MHC class I expressed by natural killer (NK) cells. CD94-NKG2A operates in tandem with the polymorphic killer cell Ig-like receptors (KIR) and Ly49 systems to inhibit NK cells. However, the benefits of having two distinct inhibitory receptor-ligand systems are not clear. We show that noninhibitory peptides presented by HLA-E can augment the inhibition of NKG2A + NK cells mediated by MHC class I signal peptides through the engagement of CD94 without a signaling partner. Thus, CD94 is a peptide-selective NK cell receptor, and NK cells can be regulated by nonsignaling interactions. We also show that KIR + and NKG2A + NK cells respond with differing stoichiometries to MHC class I down-regulation. MHC-I-bound peptide functions as a molecular rheostat controlling NK cell function. Selected peptides which in isolation do not inhibit NK cells can have different effects on KIR and NKG2A receptors. Thus, these two inhibitory systems may complement each other by having distinct responses to bound peptide and surface levels of MHC class I.innate immunity | MHC-I peptides

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“…The similarities of the promoters and their regulation may ensure that the control of any novel KIR combination is readily facilitated. Significantly, the KIR2DL4 gene is well conserved in primates (61,63,64) and has qualitatively different regulation from the other KIR. The large differences demonstrated between the promoter of KIR2DL4 and those of variegated KIR may provide an explanation for the distinct phenotypes of these genes.…”

Section: Figure 3 (Continues)mentioning

confidence: 99%

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

Stewart

Bergen

Trowsdale

2003

The Journal of Immunology

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The killer Ig-like receptors (KIR) are a family of highly related MHC class I receptors that show extreme genetic polymorphism both within the human population and between closely related primate species, suggestive of rapid evolutionary diversification. Most KIR are expressed in a variegated fashion by the NK population, giving rise to an NK repertoire of specificities for MHC class I. We compared the promoter for KIR3DL1, which exhibits variegated gene expression, with that for KIR2DL4, which is expressed by all NK cell clones. Maximum transcriptional activity of each was encoded within ∼270 bp upstream of the translation initiation codon. The KIR2DL4 promoter drove reporter gene expression only in NK cells, while the KIR3DL1 promoter was active in a range of cell types, suggesting that the latter requires other regulatory elements for physiological expression. In NK cells, reporter gene expression driven by the KIR2DL4 promoter was greater than that driven by the KIR3DL1 promoter. DNase I footprinting revealed that transcription factor binding sites differ between the two promoters. The data indicate that while the promoters of these two KIR genes share 67% nucleotide identity, they have evolved distinct properties consistent with different roles in regulating the generation of NK repertoire.

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NK Cell Receptors of the Orangutan (Pongo pygmaeus): A Pivotal Species for Tracking the Coevolution of Killer Cell Ig-Like Receptors with MHC-C

Cited by 95 publications

References 52 publications

Synergistic Polymorphism at Two Positions Distal to the Ligand-Binding Site Makes KIR2DL2 a Stronger Receptor for HLA-C Than KIR2DL3

Synergistic Polymorphism at Two Positions Distal to the Ligand-Binding Site Makes KIR2DL2 a Stronger Receptor for HLA-C Than KIR2DL3

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

Different and Divergent Regulation of the KIR2DL4 and KIR3DL1 Promoters

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