KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV

Abstract

Natural killer (NK) cells recognize “self” HLA via killer Ig-like receptors (KIR). Homeostatic HLA expression signals for inhibition via KIR, and downregulation of HLA, a common consequence of viral infection, allows NK activation. Like HLA, KIR are highly polymorphic, and allele combinations of the most diverse receptor-ligand pair, KIR3DL1 and HLA-B, correspond to hierarchical HIV control. We used primary cells from healthy human donors to demonstrate how subtype combinations of KIR3DL1 and HLA-B calibrate NK education and their consequent capacity to eliminate HIV-infected cells. High-density KIR3DL1 and Bw4-80I partnerships endow NK cells with the greatest reactivity against HLA-negative targets; NK cells exhibiting the remaining KIR3DL1/HLA-Bw4 combinations demonstrate intermediate responsiveness; and Bw4-negative KIR3DL1+ NK cells are poorly responsive. Cytotoxicity against HIV-infected autologous CD4+ T cells strikingly correlated with reactivity to HLA-negative targets. These findings suggest that the programming of NK effector function results from defined features of receptor and ligand subtypes. KIR3DL1 and HLA-B subtypes exhibit an array of binding strengths. Like KIR3DL1, subtypes of HLA-Bw4 are expressed at distinct, predictable membrane densities. Combinatorial permutations of common receptor and ligand subtypes reveal binding strength, receptor density, and ligand density to be functionally important. These findings have immediate implications for prognosis in patients with HIV infection. Furthermore, they demonstrate how features of KIR and HLA modified by allelic variation calibrate NK cell reactive potential.

Sequence and Phylogenetic Analysis of the Untranslated Promoter Regions for HLA Class I Genes

“…The lack of allele-specific expression along with the stability of HLA-B mRNA expression levels suggests that trans, rather than cis polymorphism may modify HLA-B expression. Although we find no evidence for HLA-B lineage specific mRNA expression differences, recent reports suggest that cell surface expression levels of HLA-B do vary in a lineage-specific manner to some extent (47, 48), which may result from lineage-specific translational events. Using three antibodies (Tu149, B1.23.2 and 22E1), Chappell et al showed that the surface expression levels of HLA-B*57, -B*27, -B*07 and -B*35 inversely correlated with promiscuity of peptide binding (48), where B*57 was expressed at the highest level, followed by B*27, B*07, and B*35 in descending order.…”

Memory responses of natural killer cells

“…Several studies have demonstrated an important role for NK cells in control of HIV infection, and specific combinations of KIR and HLA haplotype have been implicated in protection against primary infection or progression to AIDS [90–95]. Studies in rhesus macaques have also shown associations between NK cell phenotypes and disease progression following SIV infection [96, 97].…”

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…”