To further refine and improve biomedical research in rhesus macaques, it is necessary to increase our knowledge concerning both the degree of allelic variation (polymorphism) and diversity (gene copy number variation) in the killer cell immunoglobulin-like receptor (KIR) gene cluster. Pedigreed animals in particular should be studied, as segregation data will provide clues to the linkage of particular KIR genes/alleles segregating on a haplotype and to its gene content as well. A dual strategy allowed us to screen the presence and absence of genes and the corresponding transcripts, as well as to track differences in transcription levels. On the basis of this approach, 14 diverse KIR haplotypes have been described. These haplotypes consist of multiple inhibitory and activating Mamu-KIR genes, and any gene present on one haplotype may be absent on another. This suggests that the cost of accelerated evolution by recombination may be the loss of certain framework genes on a haplotype.

NK cells are essential in shaping immune responses and play an important role during pregnancy and in controlling infections. Killer cell immunoglobulin-like receptors (KIRs) educate the NK cell and determine its state of activation. Our goal was to determine how the KIR repertoire of the rhesus macaque (Macaca mulatta) has been shaped during evolution. The presence or absence of 22 KIR gene groups was determined in 378 animals. Some unexpected observations were made in an outbred colony comprising animals of different origins. For instance, the KIR region appears to be highly plastic, and an unprecedented number of genotypes and haplotypes was observed. In contrast to humans, there is no distinction between group A and B haplotypes in the rhesus macaque, suggesting that different selective forces may be operative. Moreover, specific genes appear to be either present or absent in animals of different geographic origins. This extreme plasticity may have been propelled by co-evolution with the rhesus macaque MHC class I region, which shows signatures of expansion. The mosaic-like complexity of KIR genotypes as observed at the population level may represent an effective strategy for surviving epidemic infections. [3] but they are also involved with the vascularisation process during placentation, and thus contribute to reproductive success [4]. The education and activation state of the NK-cell is determined by the interactions of its receptors with their cognate ligands [5]. It is the shift in equilibrium of inhibitory and activating receptor signaling that ultimately leads to NK-cell activation in the form of cytokine production, cytotoxicity, or priming of the adaptive immune system [6].Killer cell immunoglobulin-like receptors (KIRs) may influence this balance through interactions with their ligands, the MHC molecules, which are called human leukocyte antigens 2719(HLA) in humans. Since both the HLA system and the KIR gene complex are characterized by variation in locus content, and segregate independent of each other, the potential array of interactions can vary considerably between individuals. Understanding the evolution and complexity of these receptor systems has broad medical relevance, since particular combinations of KIR and HLA alleles are associated with the outcome of viral infection, relapse of leukemia after transplantation, susceptibility to autoimmune disease, and successful pregnancy [7][8][9][10]. Because of its close evolutionary relationship to humans, and evidenced by similar immunological responses, the rhesus macaque (Macaca mulatta) is an important animal model to study the onset, progression, and outcome of infectious diseases, experimentally induced autoimmunity, and transplantation [11][12][13]. Moreover, certain human pathogens or their simiantrophic family members have adapted to primates as their natural host, and may show a host-specific pathology. Since in an experimental setting the onset of disease or the actual challenge with a pathogen can be controlled, it is possible to stu...

The major histocompatibility complex class I gene repertoire was investigated in a large panel of rhesus macaques of Chinese origin. As observed in Indian animals, subjects of Chinese derivation display Mamu-B gene copy number variation, and the sum of expressed genes varies among haplotypes. In addition, these genes display differential transcription levels. The majority of the Mamu-B alleles discovered during this investigation appear to be unique for the population studied. Only one particular Mamu-B haplotype is shared between Indian and Chinese animals, and it must have been present in the progenitor stock. Hence, the data highlight the fact that most allelic polymorphism, and most of the Mamu-B haplotypes themselves, are of relatively recent origin and were most likely generated after the separation of the Indian and Chinese rhesus macaque populations.

In humans, the classical antigen presentation function of major histocompatibility complex (MHC) class I molecules is controlled by the human leukocyte antigen HLA -A, HLA-B and HLA-C loci. A similar observation has been made for great apes and Old World monkey species. In contrast, a New World monkey species such as the cotton-top tamarin (Saguinus oedipus) appears to employ the G locus for its classical antigen presentation function. At present, little is known about the classical MHC class I repertoire of the common marmoset (Callithrix jacchus), another New World monkey that is widely used in biomedical research. In the present population study, no evidence has been found for abundant transcription of classical I class genes. However, in each common marmoset, four to seven different G-like alleles were detected, suggesting that the ancestral locus has been subject to expansion. Segregation studies provided evidence for at least two G-like genes present per haplotype, which are transcribed by a variety of cell types. The alleles of these Caja-G genes cluster in separate lineages, suggesting that the loci diversified considerably after duplication. Phylogenetic analyses of the introns confirm that the Caja-G loci cluster in the vicinity of HLA-G, indicating that both genes shared an ancestor. In contrast to HLA-G, Caja-G shows considerable polymorphism at the peptide-binding sites. This observation, together with the lack of detectable transcripts of A and B-like genes, indicates that Caja-G genes have taken over the function of classical class I genes. These data highlight the extreme plasticity of the MHC class I gene system.

The interaction of killer-cell immunoglobulin-like receptors (KIR) and their respective major histocompatibility complex (MHC) ligands can alter the activation state of the natural killer (NK) cell. In both humans and rhesus macaques, particular types of non-classical MHC class I molecules are predominantly expressed on the trophoblast. In humans, human leukocyte antigen G has been demonstrated to act as a ligand for KIR2DL4, present on all NK cells, whereas Mamu-AG may execute a similar function in rhesus macaques. During primate evolution, orthologues of KIR2DL4 appear to have been highly conserved, suggesting strong purifying selection. A cohort of 112 related and unrelated rhesus macaques of mostly Indian origin were selected to study their KIR2DL4 genes for the occurrence of polymorphism. Comparison of the proximal region provided evidence for strong conservative selection acting on the exons encoding the Ig domains. As is found in humans, in the Indian rhesus macaque population, two different KIR2DL4 entities are encountered, which differ for their intra-cellular signalling motifs. One genotype contains a complex mutation in the distal region of exon 9, which negates a serine/threonine kinase site. Furthermore, both allelic entities are present in a distribution, which suggests that balancing selection is operating on these two distinct forms of KIR2DL4.

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