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

Abstract

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.

Keywords: MHC; genomics; killer immunoglobulin-like receptors; natural killer cells.

Figure 1

Genomic organization of the human and rhesus macaque CD94 and NKG2 region. The maps are not to scale. Orthologous genes CD94,NKG2D,NKG2F, and NKG2A are ordered vertically.

Figure 2

Phylogenetic tree analysis of human (hs) and rhesus macaque (rh) NKG2 amino acid sequences. Sequences were aligned and neighbour‐joining trees using the Jones–Taylor–Thornton model with 1000 bootstraps were constructed. Scale bars denote substitutions per site and bootstrap support in per cent is indicated at nodes. Trees were based on (a) complete amino acid sequences, (b) transmembrane and cytoplasmic regions only, (c) C‐type lectin‐like domains only.

Figure 3

Amino acid sequence alignment of human (hs) and rhesus macaque (rh) NKG2 sequences. Identical residues are indicated by a dot and gaps by a dash. Residues known to be involved in binding of human NKG2A to HLA‐E53, 54, 55 are marked. The ITIM motifs of inhibitory receptors and the lysine residue in the transmembrane region of activating receptors are marked in yellow and red, respectively.