Abstract
The activity and function of natural killer (NK) cells are modulated through the interactions of multiple receptor families, of which some recognize MHC class I molecules. The high level of MHC class I polymorphism requires their ligands either to interact with conserved epitopes, as is utilized by the NKG2A receptor family, or to co-evolve with the MHC class I allelic variation, which task is taken up by the killer cell immunoglobulin-like receptor (KIR) family. Multiple molecular mechanisms are responsible for the diversification of the KIR gene system, and include abundant chromosomal recombination, high mutation rates, alternative splicing, and variegated expression. The combination of these genetic mechanisms generates a compound array of diversity as is reflected by the contraction and expansion of KIR haplotypes, frequent birth of fusion genes, allelic polymorphism, structurally distinct isoforms, and variegated expression, which is in contrast to the mainly allelic nature of MHC class I polymorphism in humans. A comparison of the thoroughly studied human and macaque KIR gene repertoires demonstrates a similar evolutionarily conserved toolbox, through which selective forces drove and maintained the diversified nature of the KIR gene cluster. This hypothesis is further supported by the comparative genetics of KIR haplotypes and genes in other primate species. The complex nature of the KIR gene system has an impact upon the education, activity, and function of NK cells in coherence with an individual’s MHC class I repertoire and pathogenic encounters. Although selection operates on an individual, the continuous diversification of the KIR gene system in primates might protect populations against evolving pathogens.
Highlights
The innate and adaptive arms of the immune system are interconnected, and feature several effector functions that provide efficient and specific protection against infection and tumor formation
THE killer cell immunoglobulin-like receptor (KIR) GENE ALLELIC REPERTOIRE IS EXPANDED BY POINT MUTATIONS. Another level of variation is displayed by allelic polymorphisms, which is explained to a large extent by the occurrence of single nucleotide polymorphisms (SNP; Figure 2B)
The KIR gene system is well studied in humans, and reveals multiple mechanisms that contribute to the plasticity of this immunogenetic cluster (Figure 2)
Summary
The innate and adaptive arms of the immune system are interconnected, and feature several effector functions that provide efficient and specific protection against infection and tumor formation. The gene is fixed in most primate species, and its function is currently unknown [10] This lineage is, expanded in cattle, and encodes multiple inhibitory and a single activating functional KIR3DX receptor, which interact with an expanded repertoire of classical MHC molecules [11, 12]. More extensive and species-specific expansions are reported for KIR genes that cluster into lineages II and III (Table 1), and the data suggest that this coincides with the evolution of their MHC class I ligands. The expanded MHC repertoire in macaques probably propelled the extensive expansion and differential expression of their lineage
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