The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

Abstract

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...

KIR3DL01 Recognition of Bw4 Ligands in the Rhesus Macaque: Maintenance of Bw4 Specificity since the Divergence of Apes and Old World Monkeys

“…As products of the extensively duplicated and highly polymorphic Mamu-B genes, the diversity of these molecules reflects the diversity of Mamu-KIR3DL01, which is the most polymorphic of the rhesus macaque KIRs (32). Mamu-KIR3DL01 is also one of the most commonly expressed rhesus macaque KIRs (expressed by approximately 85–95% of Indian-origin animals (31–33, 42)), and is thus likely to play a significant role in regulating NK cell responses in a majority of animals. Therefore, the identification of MHC class I ligands for Mamu-KIR3DL01 is especially important for investigating the role of NK cells in vaccine and pathogenesis studies in rhesus macaques.…”

“…In accordance with KIR and MHC class I co-evolution, macaques lack lineage III KIR genes, which encode KIR2DL/S specific for HLA-C (29, 30), and instead have an expanded repertoire of KIR3DL/S genes characterized by extensive polymorphism (20, 29–32). Indeed, 19 distinct KIR3DL/S genes have been identified in rhesus macaques (31, 33). …”

KIR3DL01 upregulation on gut natural killer cells in response to SIV infection of KIR- and MHC class I-defined rhesus macaques

“…However, these findings do not necessarily preclude a contribution of peptides to the evasion of NK cell responses. Rhesus macaques typically express six to thirteen different KIRs [36,40], and the ligands for most of these receptors remain undefined. Macaque NK cells also express other more conserved inhibitory and activating receptors, such as CD94/NKG2 heterodimers and natural cytotoxicity receptors (NCRs) that may influence responses to viral infection.…”

“…Macaques accordingly lack KIR2DL/S genes that encode receptors for HLA-C, but have an expanded complement of highly polymorphic KIR3DL/S genes [33–37]. Phylogenetic and segregation analyses support the existence of 22 KIR genes in macaques [35,36,38]; however, as a consequence of the rapid pace of KIR evolution, only two of these genes ( Mamu-KIR2DL04 and - KIR3DL20 ) have recognizable human orthologs [1,2,39–41]. Thus, it is not possible to predict the ligands for macaque KIRs based on sequence similarity with their human counterparts.…”

Characterisation of mouse monoclonal antibodies against rhesus macaque killer immunoglobulin-like receptors KIR3D

“…Rhesus macaque KIR genes and haplotypes turned out to be at least as polymorphic and diverse as their human counterparts (Blokhuis et al 2011; Kruse et al 2010; Moreland et al 2011; Hershberger et al 2001). Whereas members of all KIR lineages known in Old World monkeys and apes/humans are present, a particular expansion of lineage II KIR , i.e.…”