There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.

/pdf/a-novel-system-of-polymorphic-and-diverse-nk-cell-receptors-3szzdo95hv.pdf

A novel system of polymorphic and diverse NK cell receptors in primates.

Natural killer lymphocytes are essentially involved as the first line of defense against agents such as viruses and malignant cells. The activity of these cells is regulated via interaction of specific and diverse killer cell immunoglobulin-like receptors (KIR) with the highly polymorphic cognate MHC class I proteins on target cells. Genetic variability of both KIR and MHC-I ligands has been shown to be associated with resistance to many diseases, including infection with the immunodeficiency virus. Disease course and progression to AIDS after infection with human immunodeficiency virus-1 (HIV-1) is essentially influenced by the presence of the stimulatory KIR3DS1 receptor in combination with HLA-Bw4. Knowledge of such genetic interactions that contribute to not only disease resistance but also susceptibility are just as important. Such combined genetic factors were recently reported in the rhesus macaque AIDS model. Here, we review the rhesus macaque MHC class I and KIR gene systems and the role of their polymorphisms in the SIV infection model.

/pdf/mhc-and-kir-polymorphisms-in-rhesus-macaque-siv-infection-3s9hwlegs5.pdf

MHC and KIR Polymorphisms in Rhesus Macaque SIV Infection

The killer immunoglobulin-like receptors (KIR) as well as their MHC class I ligands display enormous genetic diversity and polymorphism in macaque species. Signals resulting from interaction between KIR or CD94/NKG2 receptors and their cognate MHC class I proteins essentially regulate the activity of natural killer (NK) cells. Macaque and human KIR share many features, such as clonal expression patterns, gene copy number variations, specificity for particular MHC class I allotypes, or epistasis between KIR and MHC class I genes that influence susceptibility and resistance to immunodeficiency virus infection. In this review article we also annotated publicly available rhesus macaque BAC clone sequences and provide the first description of the CD94-NKG2 genomic region. Besides the presence of genes that are orthologous to human NKG2A and NKG2F, this region contains three NKG2C paralogues. Hence, the genome of rhesus macaques contains moderately expanded and diversified NKG2 genes in addition to highly diversified KIR genes. The presence of two diversified NK cell receptor families in one species has not been described before and is expected to require a complex MHC-dependent regulation of NK cells.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.12666

Diversification of both KIR and NKG2 natural killer cell receptor genes in macaques - implications for highly complex MHC-dependent regulation of natural killer cells.

Despite extensive use of nonhuman primates as models for infectious diseases and reproductive biology, imprecise phenotypic and functional definitions exist for natural killer (NK) cells. This deficit is particularly significant in the burgeoning use of small, less expensive New World primate species. Using polychromatic flow cytometry, we identified peripheral blood NK cells as CD3-negative and expressing a cluster of cell surface molecules characteristic of NK cells (i.e., NKG2A, NKp46, NKp30) in three New World primate species – common marmosets, cotton-top tamarins, and squirrel monkeys. We then assessed subset distribution using the classical NK markers, CD56 and CD16. In all species, similar to Old World primates, only a minor subset of NK cells was CD56+, and the dominant subset was CD56–CD16+. Interestingly, CD56+ NK cells were primarily cytokine-secreting cells, whereas CD56–CD16+ NK cells expressed significantly greater levels of intracellular perforin, suggesting these cells might have greater potential for cytotoxicity. New World primate species, like Old World primates, also had a minor CD56–CD16– NK cell subset that has no obvious counterpart in humans. Herein we present phenotypic profiles of New World primate NK cell subpopulations that are generally analogous to those found in humans. This conservation among species should support the further use of these species for biomedical research.

/pdf/characterization-of-circulating-natural-killer-cells-in-v9t9fh3gil.pdf

Characterization of Circulating Natural Killer Cells in Neotropical Primates

Clusters of genes that evolved from single progenitors via repeated segmental duplications present significant challenges to the generation of a truly complete human genome sequence. Such clusters can confound both accurate sequence assembly and downstream computational analysis, yet they represent a hotbed of functional innovation, making them of extreme interest. We have developed an algorithm for reconstructing the evolutionary history of gene clusters using only human genomic sequence data. This method allows the tempo of large-scale evolutionary events in human gene clusters to be estimated, which in turn will facilitate primate comparative sequencing studies that will aim to reconstruct their evolutionary history more fully.

https://ocw.metu.edu.tr/pluginfile.php/1123/mod_resource/content/0/Schedule/reading5.pdf

Reconstructing the evolutionary history of complex human gene clusters

The common marmoset monkey (Callithrix jacchus) is a New World primate that is increasingly used in biomedical research as a model organism. Due to the occurrence of natural bone marrow chimerism, it represents a particularly useful primate model in immunological research. In this study, we describe the genomic organization of the CD94, NKG2, and LY49L genes in the NK complex (NKC) of the common marmoset based on complete sequencing of a bacterial artificial chromosome clonal contig. This region of the marmoset NKC is 1.5 times smaller than its human counterpart, but the genes are colinear and orthologous. One exception is the activating NKG2CE gene, which is probably an ancestral form of the NKG2C- and NKG2E-activating receptor genes of humans and great apes. The two completely sequenced marmoset bacterial artificial chromosome clones are derived from distinct haplotypes, which differ by 200 sites in the overlapping sequence. Analyses of NKC genes in nine additional marmoset individuals revealed a moderate degree of polymorphism of the CD94, NKG2A, NKG2CE, and NKG2D genes. Furthermore, expression analyses identified several alternatively spliced transcripts, particularly of the CD94 gene. Several products of alternative splicing of NKC genes are highly conserved among primates. Alternative transcriptional start sites were found, but these probably do not lead to a change of the translational start site or result in longer or shorter cytoplasmic regions of these type II membrane receptors.

Genomics and diversity of the common marmoset monkey NK complex.

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Genomics and diversity of the common marmoset monkey NK complex.