Degenerate Recognition of MHC Class I Molecules with Bw4 and Bw6 Motifs by a Killer Cell Ig-like Receptor 3DL Expressed by Macaque NK Cells

Abstract

The killer cell immunoglobulin-like receptors (KIRs) expressed on the surface of natural killer (NK) cells recognize specific major histocompatibility complex class I (MHC-I) molecules and regulate NK cell activities against pathogen-infected cells and neoplasia. In human immunodeficiency virus (HIV) infection, survival is linked to host KIR and MHC-I genotypes. In the simian immunodeficiency virus (SIV) macaque model, however, the role of NK cells is unclear due to the lack of information on KIR-MHC interactions. Here, we describe the first characterization of a KIR-MHC interaction in pig-tailed macaques (Macaca nemestrina). Initially, we identified three distinct subsets of macaque NK cells that stained ex vivo with macaque MHC-I tetramers loaded with SIV peptides. We then cloned cDNAs corresponding to 15 distinct KIR3D alleles. One of these, KIR049-4, was an inhibitory KIR3DL that bound MHC-I tetramers and prevented activation, degranulation and cytokine production by macaque NK cells after engagement with specific MHC-I molecules on the surface of target cells. Furthermore, KIR049-4 recognized a broad range of MHC-I molecules carrying not only the Bw4 motif but also Bw6 and non-Bw4/Bw6 motifs. This degenerate, yet peptide-dependent, MHC reactivity differs markedly from the fine specificity of human KIRs.

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

“…This is interpreted as a strategy to avoid immune recognition and underscores the importance of NK cells in the defence of HIV‐1 . An influence of MHC class I‐bound peptides on binding avidity of KIR3D proteins was also demonstrated in rhesus and pig‐tailed macaques . Hence, there is accumulating evidence that the repertoire of presented peptides is an important factor in the KIR‐mediated control of NK cell activity and that viruses might exploit this.…”

“…Analyses of rhesus macaque cDNA and genomic DNA revealed the presence of 22 KIR genes (Table ), which can all be assigned to established KIR lineages. Phylogenetic analyses suggest that cynomolgus macaques and pig‐tailed macaques have similar sets of KIR genes with few species‐specific differences . Similar to human KIR haplotypes, macaque KIR haplotypes also vary in gene content, giving rise to a substantial degree of genomic diversity, in particular of the KIR3D genes .…”

“…Phylogenetic analyses suggest that cynomolgus macaques and pig‐tailed macaques have similar sets of KIR genes with few species‐specific differences . Similar to human KIR haplotypes, macaque KIR haplotypes also vary in gene content, giving rise to a substantial degree of genomic diversity, in particular of the KIR3D genes . The MHC class I genes of macaques have undergone significant expansions during evolution .…”

“…In comparison to human inhibitory KIR (iKIR), the iKIR–MHC class I interactions in macaques are characterized by lower avidity and broader reactivity . Although the Bw4/Bw6 motifs play a role in binding macaque KIR3D proteins, there are some KIR3D with restricted specificity for Bw4 such as KIR3DL01 or KIR3DLW03, whereas other iKIR bind to both motifs such as KIR3DL05 or KIR049‐4 . One reason for this broader reactivity of some iKIR might be the enormous genetic diversity and copy number variation in macaque species that might favour the evolution of KIR with broad interaction specificity.…”

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

“…In the rhesus macaque, these include the identification of Mamu-A1*002 as a ligand for Mamu-KIR3DL05 by binding and cellular assays (37, 38), with additional binding partners for Mamu-KIR3DL05, -3DLW03, -3DL11 and -3DS05 revealed by staining with soluble KIR-Fc fusion proteins (38). In the pig-tailed macaque, Mane ( Ma caca ne mestrina) -A1*082 and -A1*084 were also identified as ligands for KIR049-4 (39). However, the value of most of these interactions for studying NK cell responses in KIR- and MHC class I -defined animals remains limited due to the lack of reagents for staining specific KIR on primary macaque NK cells.…”