Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans

Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature Genetics (Impact Factor: 29.35). 09/2007; 39(9):1092-9. DOI: 10.1038/ng2111
Source: PubMed

ABSTRACT Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

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Available from: Robert William Vaughan, Jun 02, 2014
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    • "Thus, KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes and one lineage of conserved activating KIR3DS1. They also highlighted that random combination of polymorphic KIR3DL1 receptor and HLA-B ligands has vast potential for varying the NK cell response to infection [32]. Figure 1A shows that Bw4-80Thr alleles are significantly more common in CHIKV+ patients than in both DENV2+ and healthy individuals, individuals. "
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    ABSTRACT: Background Natural killer (NK) cells provide defense in the early stages of the immune response against viral infections. Killer cell immunoglobulin-like receptors (KIR) expressed on the surface of NK cells play an important role in regulating NK cell response through recognition of human leukocyte antigen (HLA) class I molecules on target cells. Previous studies have shown that specific KIR/ligand combinations are associated with the outcome of several viral infectious diseases. Methods We investigated the impact of inhibitory and activating KIR and their HLA-class I ligand genotype on the susceptibility to Chikungunya virus (CHIKV) and Dengue virus (DENV2) infections. From April to July 2010 in Gabon, a large outbreak of CHIKV and DENV2 concomitantly occurred in two provinces of Gabon (Ogooué-Lolo and Haut-Ogooué). We performed the genotypic analysis of KIR in the combination with their cognate HLA-class I ligands in 73 CHIKV and 55 DENV2 adult cases, compared with 54 healthy individuals. Results We found in CHIV-infected patients that KIR2DL1 and KIR2DS5 are significantly increased and decreased respectively, as compared to DENV2+ patients and healthy donors. The combination of KIR2DL1 and its cognate HLA-C2 ligand was significantly associated with the susceptibility to CHIKV infection. In contrast, no other inhibitory KIR-HLA pairs showed an association with the two mosquito-borne arboviruses. Conclusion These observations are strongly suggestive that the NK cell repertoire shaped by the KIR2DL1:HLA-C2 interaction facilitate specific infection by CHIKV.
    PLoS ONE 09/2014; 9(9):e108798. DOI:10.1371/journal.pone.0108798 · 3.23 Impact Factor
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    • "Comparable bimodal distributions are seen for the European, West-African, and Amerindian KIR haplotypes, with the exception of the telomeric region of the West- African KIR locus which has a paucity of telomeric B haplotype regions. This deficiency could have arisen from diseasespecific selection (Norman et al. 2007). Although having a striking bimodal distribution, the Amerindian KIR haplotypes have considerably less sequence diversity than the other populations , consistent with their overall low genetic diversity and the extended migration that was required for modern humans to reach the Americas. "
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    ABSTRACT: HLA class I molecules and killer cell immunoglobulin-like receptors (KIR) form a diverse system of ligands and receptors that individualize human immune systems in ways that improve the survival of individuals and populations. Human settlement of Oceania by island-hopping East and Southeast Asian migrants started ~3,500 years ago. Subsequently, New Zealand was reached ~750 years ago by ancestral Māori. To examine how this history impacted KIR and HLA diversity, and their functional interaction, we defined at high resolution the allelic and haplotype diversity of the 13 expressed KIR genes in 49 Māori and 34 Polynesians. Eighty KIR variants, including four 'new' alleles, were defined, as were 35 centromeric and 22 telomeric KIR region haplotypes, which combine to give >50 full-length KIR haplotypes. Two new and divergent variant KIR form part of a telomeric KIR haplotype, which appears derived from Papua New Guinea and was probably obtained by the Asian migrants en route to Polynesia. Māori and Polynesian KIR are very similar, but differ significantly from African, European, Japanese, and Amerindian KIR. Māori and Polynesians have high KIR haplotype diversity with corresponding allotype diversity being maintained throughout the KIR locus. Within the population, each individual has a unique combination of HLA class I and KIR. Characterizing Māori and Polynesians is a paucity of HLA-B allotypes recognized by KIR. Compensating for this deficiency are high frequencies (>50 %) of HLA-A allotypes recognized by KIR. These HLA-A allotypes are ones that modern humans likely acquired from archaic humans at a much earlier time.
    Immunogenetics 08/2014; 66(11). DOI:10.1007/s00251-014-0794-1 · 2.23 Impact Factor
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    • "Unexpectedly, the extensive polymorphisms found within individual KIR3D families are located predominantly at positions not implicated in HLA binding. This implies that most KIR3D polymorphisms, a number of which are subject to positive selection (49), are unlikely to impact affinity directly, but could potentially affect HLA binding indirectly by altering the clustering or expression levels of KIR3D receptors on the NK cell surface. In this way, evolutionary pressures may drive the diversification of KIR3D sequences at sites remote from the HLA-binding site. "
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    ABSTRACT: Natural killer (NK) cells are key components of innate immune responses to tumors and viral infections. NK cell function is regulated by NK cell receptors that recognize both cellular and viral ligands, including major histocompatibility complex (MHC), MHC-like, and non-MHC molecules. These receptors include Ly49s, killer immunoglobulin-like receptors, leukocyte immunoglobulin-like receptors, and NKG2A/CD94, which bind MHC class I (MHC-I) molecules, and NKG2D, which binds MHC-I paralogs such as the stress-induced proteins MICA and ULBP. In addition, certain viruses have evolved MHC-like immunoevasins, such as UL18 and m157 from cytomegalovirus, that act as decoy ligands for NK receptors. A growing number of NK receptor-ligand interaction pairs involving non-MHC molecules have also been identified, including NKp30-B7-H6, killer cell lectin-like receptor G1-cadherin, and NKp80-AICL. Here, we describe crystal structures determined to date of NK cell receptors bound to MHC, MHC-related, and non-MHC ligands. Collectively, these structures reveal the diverse solutions that NK receptors have developed to recognize these molecules, thereby enabling the regulation of NK cytolytic activity by both host and viral ligands.
    Frontiers in Immunology 03/2014; 5:123. DOI:10.3389/fimmu.2014.00123
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