Killer cell immunoglobulin-like receptor 3DL1 polymorphism defines distinct hierarchies of HLA class I recognition

Abstract

Rossjohn, Brooks, Vivian, and colleagues provide the most complete picture to date of the impact of KIR3DL1 polymorphism on HLA class I recognition, which can be used to both reevaluate previous work on the involvement of KIR3DL1 in disease as well as inform future disease association studies.

MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape

“…There are also well-described C-terminal escape mutations within the TW10 epitope, of which G9D has similarly been shown to abrogate KIR3DL1 recognition in a KIR3DL1-allotype dependent manner 59 . This is in-line with recent reports on KIR3DL1 allomorph specificity 60 and suggests that KIR3DL1 polymorphism may be an important determinant shaping viral fitness. Accordingly, there appears to be a molecular tension between the innate and adaptive arms of the immune system as they converge to target a common HIV-I determinant presented by HLA-B*57:01.…”

Evaluation of KIR3DL1/KIR3DS1 polymorphism in Behçet’s disease

“…Additionally, in the subset of cases with ocular disease, we observed an increase in activating KIR3DS1 alleles among both HLA-B*51 positive and HLA-B*51 negative individuals. These findings suggest that although HLA-B*51 is a known ligand for KIR3DL1, the KIR3DS1 association is not dependent on the presence of HLA-B*51 to increase the risk of ocular involvement, thus supporting a ligand-independent role for this KIR Nonetheless, given mounting evidence of allele-specific differential binding of KIRs by class I MHC molecules, 20 this study does not exclude the possibility that HLA-B*51 may influence BD risk through differential interaction with specific KIR3DL1 and/or KIR3DS1 allotypes.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…A synergy of population genetics, phylogenetic analysis and comparison of nucleotide substitution rates among codons showed that this diversity is focused towards the parts of the KIR molecule that bind the HLA class I and peptide 61. The prediction that these major lineages of KIR3DL1/S1 have distinct ligand HLA/peptide‐binding properties has been borne out with crystallographic and functional studies 35, 39, 41, 42, 62, 63, 64, 65. Expansion of the phylogenetic analyses to include other KIR molecules revealed natural selection has consistently been focused towards residues that affect interaction with the HLA class I ligand,66 as well as those that affect the signalling properties of the receptor 67…”

“…Early work showed that HLA‐Bw4 allotypes with I80 formed more potent ligands for KIR3DL1 than those with T80,119 a functional difference reinforced by associations with disease outcome 27, 58, 120, 121, 122. However, recent high‐resolution studies have identified several I80 Bw4 allotypes that are poorly recognized by KIR3DL1, providing weaker KIR3DL1 ligands than selected T80 Bw4 allotypes 39, 41, 123. Compounding the difficulty of understanding the interactions between KIRD3DL1 and Bw4 is the extensive functional polymorphism of KIR3DL1 , which changes its cell‐surface expression25, 38 and capacity to recognize the Bw4 epitope 41, 65, 123…”