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

Department of Structural Biology, Stanford University, Stanford, CA 94305, USA.
Philosophical Transactions of The Royal Society B Biological Sciences (Impact Factor: 7.06). 03/2012; 367(1590):800-11. DOI: 10.1098/rstb.2011.0266
Source: PubMed


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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    • "Only some of the 13 human KIRs have been demonstrated to recognize HLA class I. In contrast, no ligand has yet been identified for KIR2DS2, 2DS3, 2DS5, 2DL5, 3DS1, and 3DL3 (87)(Table 1C). "
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    ABSTRACT: By means of a complex receptor array, Natural killer (NK) cells can recognize variable patterns of ligands and regulate or amplify accordingly their effector functions. Such NK receptors include old, rather conserved, molecules, such as toll-like receptors (TLRs), which enable NK cells to respond both to viral and bacterial products, and newer and evolving molecules, such as killer Ig-like receptors and natural cytotoxicity receptors, which control NK cytotoxicity and are responsible for the elimination of virus-infected or tumor cells without damaging self-unaltered cells. In addition, to rapidly gain new functions NK cells also can acquire new receptors by trogocytosis. Thus, NK cells may have adapted their receptors to different functional needs making them able to play a key role in the modulation of critical events occurring in several compartments of human body (primarily in SLCs but also in decidua during pregnancy). In this review, we will discuss on how the various types of receptors can be used to address specific functions in different immunological contexts.
    Frontiers in Immunology 03/2014; 5:105. DOI:10.3389/fimmu.2014.00105
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    • "Another major limitation to translation of findings obtained in mice to humans has been represented for a long time by the absence of markers conserved between mice and humans. Indeed, human NK cells express an array of either inhibitory or activating receptors undergoing high rate of evolution, even when compared to high-related chimpanzees (Parham et al., 2012), and that is quite different from that expressed by mouse NK cells (Vivier et al., 2008). The Natural Cytotoxicity Receptor (NCR) encompass three molecules initially described in human NK cells: NKp30, NKp44, and NKp46. "
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    ABSTRACT: Understanding Natural Killer (NK) cell anatomical distribution is key to dissect the role of these unconventional lymphocytes in physiological and disease conditions. In mouse, NK cells have been detected in various lymphoid and non-lymphoid organs, while in humans the current knowledge of NK cell distribution at steady state is mainly restricted to lymphoid tissues. The translation to humans of findings obtained in mice is facilitated by the identification of NK cell markers conserved between these two species. The Natural Cytotoxicity Receptor (NCR) NKp46 is a marker of the NK cell lineage evolutionary conserved in mammals. In mice, NKp46 is also present on rare T cell subsets and on a subset of gut Innate Lymphoid Cells (ILCs) expressing the retinoic acid receptor-related orphan receptor γt (RORγt) transcription factor. Here, we documented the distribution and the phenotype of human NKp46(+) cells in lymphoid and non-lymphoid tissues isolated from healthy donors. Human NKp46(+) cells were found in splenic red pulp, in lymph nodes, in lungs, and gut lamina propria, thus mirroring mouse NKp46(+) cell distribution. We also identified a novel cell subset of CD56(dim)NKp46(low) cells that includes RORγt(+) ILCs with a lineage(-)CD94(-)CD117(bright)CD127(bright) phenotype. The use of NKp46 thus contributes to establish the basis for analyzing quantitative and qualitative changes of NK cell and ILC subsets in human diseases.
    Frontiers in Immunology 11/2012; 3:344. DOI:10.3389/fimmu.2012.00344
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    • "The expanded KIR gene cluster is unique to primates, and typically there are only a few KIR genes in other vertebrate species (Parham et al. 2012). In humans, the KIRs are highly variable and in a state of evolutionary flux, and, curiously, humans are the only species that have distinctive A and B haplotypes (Parham et al. 2012). The reasons for these phenomena have not been established, but they are indicative of balancing selection, potentially driven by immunity and reproduction. "
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    ABSTRACT: The KIR complex appears to be evolving rapidly in humans, and more than 50 different haplotypes have been described, ranging from four to 14 KIR loci. Previously it has been suggested that most KIR haplotypes consist of framework genes, present in all individuals, which bracket a variable number of other genes. We used a new technique to type 793 families from the United Kingdom and United States for both the presence/absence of all individual KIR genes as well as copy number and found that KIR haplotypes are even more complex. It is striking that all KIR loci are subject to copy number variation (CNV), including the so-called framework genes, but CNV is much more frequent in KIR B haplotypes than KIR A haplotypes. These two basic KIR haplotype groups, A and B, appear to be following different evolutionary trajectories. Despite the great diversity, there are 11 common haplotypes, derived by reciprocal recombination near KIR2DL4, which collectively account for 94% of KIR haplotypes determined in Caucasian samples. These haplotypes could be derived from combinations of just three centromeic and two telomeric motifs, simplifying disease analysis for these haplotypes. The remaining 6% of haplotypes displayed novel examples of expansion and contraction of numbers of loci. Conventional KIR typing misses much of this additional complexity, with important implications for studying the genetics of disease association with KIR that can now be explored by CNV analysis.
    Genome Research 09/2012; 22(10):1845-54. DOI:10.1101/gr.137976.112 · 14.63 Impact Factor
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