Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans

Abstract

Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

KIR2DL5 alleles mark certain combination of activating KIR genes

“…This suggests that more KIR2DL5 polymorphisms are likely to be discovered in Africans. Consistent with this finding, extensive polymorphism was also observed at the KIR3DL1/S1 locus in African populations 22 indicating …”

“…This is very different from the scenario seen in KIR3DL1, which has been shown to be highly polymorphic with enriched amino-acid substitutions in the ligand-binding loops. 22,25 Confined variations in the ligand-binding sites of KIR3DL1 have been considered to be driven by coevolving polymorphic HLA-B and HLA-A ligands. 22,26 The conserved nature of KIR2DL5 suggests the possibility that it recognizes an invariant determinant.…”

“…22,25 Confined variations in the ligand-binding sites of KIR3DL1 have been considered to be driven by coevolving polymorphic HLA-B and HLA-A ligands. 22,26 The conserved nature of KIR2DL5 suggests the possibility that it recognizes an invariant determinant. It is interesting to note that KIR2DL4 that displays limited polymorphism, [27][28][29] and shares high structural homologies to KIR2DL5, binds to the conserved non-classical HLA-G molecule.…”

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

“…A good example is KIR3DL1/S1 , which has over 100 alleles characterized (Fig. 4)60 and has three divergent allele lineages that have been maintained by balancing selection for millions of years 61. 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.…”

“…4)60 and has three divergent allele lineages that have been maintained by balancing selection for millions of years 61. 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.…”