Evolution of Killer Cell Ig-Like Receptor (<i>KIR</i>) Genes: Definition of an Orangutan <i>KIR</i> Haplotype Reveals Expansion of Lineage III KIR Associated with the Emergence of MHC-C

Guethlein, Lisbeth A.; Aguilar, Anastazia M. Older; Abi-Rached, Laurent; Parham, Peter

doi:10.4049/jimmunol.179.1.491

Cited by 84 publications

(152 citation statements)

References 66 publications

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“…In some, like the seals, it is a single conserved and nonpolymorphic gene, and in others, such as the dog, it appears to have been deleted (Hammond et al 2009). In contrast, in the higher primates, the KIR locus has evolved to become a diverse multigene family encoding MHC Class I receptors (Khakoo et al 2000;Rajalingam et al 2004;Sambrook et al 2005;Guethlein et al 2007). On the basis of current information, KIR diversity appears greatest in the human species, where the combined effects of genecontent diversity and allelic polymorphism are such that unrelated individuals have distinct KIR genotypes (Shilling et al 2002).…”

Section: Discussionmentioning

confidence: 99%

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Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes

Norman¹,

Abi-Rached²,

et al. 2009

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Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric ''half'' was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family.

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Section: Discussionmentioning

confidence: 99%

“…Thus, the variants of 3DL1/2v have the potential for functional difference. That all hominoid KIR haplotypes have a lineage II gene with an exon 9 orthologous to that of 3DL2, despite much recombination, points to the importance of the signaling domain it encodes Sambrook et al 2005;Guethlein et al 2007). …”

Section: Discussionmentioning

confidence: 99%

Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes

Norman¹,

Abi-Rached²,

et al. 2009

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“…mutually support a model in which arginine 16 and cysteine 148 give KIR2DL2 additional hinge flexibility that permits effective binding to both C2 and C1. Furthermore, independent evidence for the functional importance of variation at positions 16 and 148 is analysis showing that it was produced by natural selection during evolution of the hominoids (Ͼ0.95 by Bayesian posterior probability, L. Abi-Rached, personal communications), the only species that have MHC-C and cognate KIR (40).…”

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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“…A variable family of KIR3DL genes is specific to the simian primates. Shown is a schematic of the KIR locus in a variety of primate and non-primate species [19][20][21][22][23][24][25]. A single representative KIR haplotype is shown for each species.…”

Section: Killer Cell Immunoglobulin-like Receptors Recognize Four Mutmentioning

confidence: 99%

Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules

Parham

Norman

Abi-Rached

et al. 2012

Phil. Trans. R. Soc. B

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163

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In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity-combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands-drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species.

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Evolution of Killer Cell Ig-Like Receptor (KIR) Genes: Definition of an Orangutan KIR Haplotype Reveals Expansion of Lineage III KIR Associated with the Emergence of MHC-C

Cited by 84 publications

References 66 publications

Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes

Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes

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

Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules

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