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J Immunol. 2018 Apr 15;200(8):2640-2655. doi: 10.4049/jimmunol.1701780. Epub 2018 Mar 16.

Different Selected Mechanisms Attenuated the Inhibitory Interaction of KIR2DL1 with C2+ HLA-C in Two Indigenous Human Populations in Southern Africa.

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Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.
Department of Ecology and Evolution, Stony Brook University, Stony Brook, NY 11794.
Colorado Center for Personalized Medicine, University of Colorado, Denver, CO 80045.
Department of Biostatistics, University of Colorado, Denver, CO 80045.
South African Medical Research Council Centre for Tuberculosis Research, Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa.
Department of Biology, Stanford University, Stanford, CA 94305.
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, National University of Singapore, Singapore 119077, Singapore.
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore 117609, Singapore.
Section of Ophthalmology, Department of Medicine, Fukuoka Dental College, Fukuoka 814-0193, Japan; and.
Section of Immunology, Imperial College London, London SW7 2BX, United Kingdom.
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;


The functions of human NK cells in defense against pathogens and placental development during reproduction are modulated by interactions of killer cell Ig-like receptors (KIRs) with HLA-A, -B and -C class I ligands. Both receptors and ligands are highly polymorphic and exhibit extensive differences between human populations. Indigenous to southern Africa are the KhoeSan, the most ancient group of modern human populations, who have highest genomic diversity worldwide. We studied two KhoeSan populations, the Nama pastoralists and the ≠Khomani San hunter-gatherers. Comprehensive next-generation sequence analysis of HLA-A, -B, and -C and all KIR genes identified 248 different KIR and 137 HLA class I, which assort into ∼200 haplotypes for each gene family. All 74 Nama and 78 ≠Khomani San studied have different genotypes. Numerous novel KIR alleles were identified, including three arising by intergenic recombination. On average, KhoeSan individuals have seven to eight pairs of interacting KIR and HLA class I ligands, the highest diversity and divergence of polymorphic NK cell receptors and ligands observed to date. In this context of high genetic diversity, both the Nama and the ≠Khomani San have an unusually conserved, centromeric KIR haplotype that has arisen to high frequency and is different in the two KhoeSan populations. Distinguishing these haplotypes are independent mutations in KIR2DL1, which both prevent KIR2DL1 from functioning as an inhibitory receptor for C2+ HLA-C. The relatively high frequency of C2+ HLA-C in the Nama and the ≠Khomani San appears to have led to natural selection against strong inhibitory C2-specific KIR.

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