The killer-cell immunoglobulin-like receptors of macaques

Abstract

Natural killer (NK) cells play a central role in immune responses through direct cytotoxicity and the release of cytokines that prime adaptive immunity. In simian primates, NK cell responses are regulated by interactions between two highly polymorphic sets of molecules: the killer-cell immunoglobulin-like receptors (KIRs) and their major histocompatibility complex (MHC) class I ligands. KIR-MHC class I interactions in humans have been implicated in the outcome of a number viral diseases and cancers. However, studies to address the role of KIRs in animal models have been limited by the complex immunogenetics and lack of defined ligands for KIRs in non-human primates. Due to the rapid evolution of KIRs, there is little conservation among the KIR genes of different primate species and it is not possible to predict the specificity of KIRs from known KIR-MHC class I interactions in humans. Hence, the MHC class I ligands for KIRs in species other than humans are poorly defined. Here, we review the KIR genes of the rhesus macaque, an important animal model for human immunodeficiency virus infection and other infectious diseases, and the MHC class I ligands that have been identified for KIRs in this species.

Keywords: KIR; MHC; NK cells; macaque.

Fig 1. Macaque KIR domain structure and genomic organization

(A) Schematic representation of macaque KIR molecules showing domain structure. Domains are abbreviated as follows: leader peptide (LP), immunoglobulin-like domains (D0-D2), transmembrane region (T), stem (ST) and cytoplasmic region (C). Note: Mamu-KIR1D has a frameshift in the final third of the D2 domain, resulting in a novel domain and truncation at a final length of 244 amino acids. (B) KIR gene content from representative haplotypes observed in rhesus macaques. KIR genes are indicated along the top axis. The identity of the allele is indicated within the schematic boxes if it was determined. The physical map of gene order is arbitrary and brackets indicate gene duplication. Due to limitations in the technique used to generate the first 9 haplotypes, Mamu-KIR2DL04 could not be detected and dotted lines indicate the potential presence of this gene. While Mamu-KIR3DL20 was not detected in any of these haplotypes either, these were generated from cDNA and this KIR can be present as a pseudogene. Dotted lines indicate this possibility.

Fig. 2. Polymorphisms in the D1 domain of Mamu-KIR3DL05 account for preferential binding to Mamu-A1*002-bound peptides

(A) Residues corresponding to surface exposed loops of the D1 domain (L2 and L3) that differ between Mamu-KIR3DL05*008 and mmKIR3DL05x (red) were mapped onto the three-dimensional crystal structure of KIR3DL1 (cyan) bound to HLA-B*57 (blue) (19). The HLA-B*57-bound peptide is indicated in yellow and the positions of the D0, D1 and D2 domains of KIR3DL1 relative to the α1 and α2 domains of HLA-B*57 are labeled. (B) Jurkat cells expressing L2 and L3 recombinants of Mamu-KIR3DL05*008 and mmKIR3DL05x were stained with Mamu-A1*002 tetramers folded with the SIV Gag GY9 and Nef YY9 peptides and an antibody to the HA tag engineered into the D0 domain to confirm cell surface expression (54).

Fig. 3. Divergence of the surfaces of Mamu-KIR3DL01 and human KIR3DL1 predicted to contact Bw4 ligands

(A) Alignment of five allotypes of Mamu-KIR3DL01 to human KIR3DL1 with residues predicted to contact MHC class I ligands based on the KIR3DL1-HLA-B*57 crystal structure shaded in gray (19, 53). (B) Surface projection of human KIR3DL1 with HLA-B*57-contact residues that are conserved in Mamu-KIR3DL01*001 indicated in red and residues that differ indicated in yellow (53). Copyright 2014. The American Association of Immunologists, Inc.