Loss and Gain of Natural Killer Cell Receptor Function in an African Hunter-Gatherer Population

Hilton, Hugo G.; Norman, Paul J.; Nemat-Gorgani, Neda; Goyos, Ana; Hollenbach, Jill A.; Henn, Brenna M.; Gignoux, Christopher R.; Guethlein, Lisbeth A.; Parham, Peter

doi:10.1371/journal.pgen.1005439

Cited by 42 publications

(79 citation statements)

References 57 publications

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“…By comparison, the KhoeSan population from Southern Africa has one of the highest aggregate frequencies of HLA‐C allotypes expressing the C2 motif. Here, a KIR allotype that switched binding specificity entirely from C2 to C1 has evolved 34. Both of these binding changes are due to substitutions at residues subject to balancing selection (Fig.…”

Section: Kir Geneticsmentioning

confidence: 99%

“…3). Even a single nucleotide mutation can dramatically change receptor expression,25, 31, 32, 33 ligand specificity34, 35, 36 or signalling strength. KIR gene copy number variation influences NK cell education, shaping the NK cell repertoire 37.…”

Section: Kir Geneticsmentioning

confidence: 99%

“…Multiple novel KIR alleles may be discovered during population studies, and molecular analysis identifies the most functionally important. An example is KIR 2 DL 1*022 , which was discovered in the southern African KhoeSan population (a) and which differs from its parental allele KIR 2 DL 1*001 by a single nucleotide substitution in codon 44 (b) 34. Phylogenetic analyses that included the most closely related KIR from other hominoid species identified that residue 44 has been subject to balancing selection (c) 66.…”

Section: Kir Geneticsmentioning

confidence: 99%

“…For example, the cell surface expression of KIR3DL1 and the ability to recognize HLA‐Bw4 ligand vary according to allele, and hence KIR3DL1 alleles should be analysed accordingly in the disease context 25, 38, 58, 72. Similarly, polymorphism in the extracellular domain of KIR2DL1 influences the binding affinity to HLA‐C2 34, 40. Over 200 associations of KIR genes with disease resistance or susceptibility are published,56, 73 and the handful studied at high resolution are proving informative 58, 74, 75, 76.…”

Section: Kir Geneticsmentioning

confidence: 99%

“…Other residues are involved in the interaction however, and their polymorphism means that there is a range of binding characteristics determined by KIR allotype. The interactions of KIR2DL are further diversified by polymorphism within the subsets of C1‐bearing and C2‐bearing HLA allotypes 34, 103. The basis for these hierarchies may occur due to polymorphism at sites other than position 80, or the distinct repertoires of peptide presented by the different HLA‐C allotypes 106.…”

Section: Kir Ligand Bindingmentioning

confidence: 99%

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Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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SummaryKiller‐cell immunoglobulin‐like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

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Section: Kir Geneticsmentioning

confidence: 99%

Section: Kir Geneticsmentioning

confidence: 99%

Section: Kir Geneticsmentioning

confidence: 99%

Section: Kir Geneticsmentioning

confidence: 99%

Section: Kir Ligand Bindingmentioning

confidence: 99%

See 3 more Smart Citations

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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Missing or altered self: human NK cell receptors that recognize HLA-C

Hilton

Parham

2017

Immunogenetics

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Natural killer (NK) cells are fast-acting and versatile lymphocytes that are critical for innate immunity, adaptive immunity and placental development. Controlling NK cell function are interactions between killer-cell immunoglobulin-like receptors (KIRs) and their HLA-A, -B and -C ligands. Due to the extensive polymorphism of both KIR and HLA class I, these interactions are highly diversified and specific combinations correlate with protection or susceptibility to a range of infectious, autoimmune and reproductive disorders. Evolutionary, genetic and functional studies are consistent with the interactions between KIR and HLA-C being the dominant control mechanism of human NK cells. In addition to their recognition of the C1 and C2 epitopes, increasing evidence points to KIR having a previously unrecognized selectivity for the peptide presented by HLA-C. This selectivity appears to be a conserved feature of activating KIR and may partly explain the slow progress made in identifying their HLA class I ligands. The peptide selectivity of KIR allows NK cells to respond, not only to changes in the surface expression of HLA-C, but also to the more subtle changes in the HLA-C peptidome, such as occur during viral infection and malignant transformation. Here we review recent advances in understanding of human-specific KIR evolution and how the inhibitory and activating HLA-C receptors allow NK cells to respond to healthy cells, diseased cells and the semi-allogeneic cells of the fetus.

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A genomic perspective on HLA evolution

et al. 2017

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Several decades of research have convincingly shown that classical human leukocyte antigen (HLA) loci bear signatures of natural selection. Despite this conclusion, many questions remain regarding the type of selective regime acting on these loci, the time frame at which selection acts, and the functional connections between genetic variability and natural selection. In this review, we argue that genomic datasets, in particular those generated by next-generation sequencing (NGS) at the population scale, are transforming our understanding of HLA evolution. We show that genomewide data can be used to perform robust and powerful tests for selection, capable of identifying both positive and balancing selection at HLA genes. Importantly, these tests have shown that natural selection can be identified at both recent and ancient timescales. We discuss how findings from genomewide association studies impact the evolutionary study of HLA genes, and how genomic data can be used to survey adaptive change involving interaction at multiple loci. We discuss the methodological developments which are necessary to correctly interpret genomic analyses involving the HLA region. These developments include adapting the NGS analysis framework so as to deal with the highly polymorphic HLA data, as well as developing tools and theory to search for signatures of selection, quantify differentiation, and measure admixture within the HLA region. Finally, we show that high throughput analysis of molecular phenotypes for HLA genes—namely transcription levels—is now a feasible approach and can add another dimension to the study of genetic variation.

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Loss and Gain of Natural Killer Cell Receptor Function in an African Hunter-Gatherer Population

Cited by 42 publications

References 57 publications

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

Missing or altered self: human NK cell receptors that recognize HLA-C

A genomic perspective on HLA evolution

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