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.
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We thank all donors, phlebotomists and colleagues involved in sample preparation; D. Koechlein, M. Lawson and members of N. Pourmand's laboratory for technical advice; and M. Carrington, S. Cooper and D. Middleton's laboratories for further samples. M.G. is a Howard Hughes graduate scholar and D.K. a Boehringer Ingelheim Fonds graduate scholar. S.S. is a Wellcome Trust Training fellow, and P.J.N. is a Lymphoma Research Foundation fellow. This work was supported grants to P.P. from the US National Institutes of Health (AI17892, AI24258 and AI64520) and by the Leukaemia and Lymphoma Society of the USA.
The authors declare no competing financial interests.
Supplementary Figures 1–6, Supplementary Table 1, Supplementary Methods (PDF 339 kb)
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