Different selected mechanisms attenuated the inhibitory interaction of KIR2DL1 with C2 + HLA-C in two indigenous human populations in Southern Africa

Neda Nemat-Gorgani, Hugo G. Hilton, Brenna M. Henn, Meng Lin, Christopher R. Gignoux, Justin W. Myrick, Cedric J. Werely, Julie M. Granka, Marlo Möller, Eileen G. Hoal, Makoto Yawata, Nobuyo Yawata, Lies Boelen, Becca Asquith, Peter Parham, Paul J. Norman

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2640-2655
Number of pages16
JournalJournal of Immunology
Volume200
Issue number8
DOIs
Publication statusPublished - Apr 15 2018
Externally publishedYes

Fingerprint

HLA-C Antigens
Southern Africa
Population Groups
Haplotypes
Ligands
HLA-A Antigens
HLA-B Antigens
Population
Natural Killer Cell Receptors
Placentation
Genetic Selection
Cell Communication
Natural Killer Cells
Genetic Recombination
Genes
Reproduction
Sequence Analysis
Alleles
Genotype
Mutation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Different selected mechanisms attenuated the inhibitory interaction of KIR2DL1 with C2 + HLA-C in two indigenous human populations in Southern Africa . / Nemat-Gorgani, Neda; Hilton, Hugo G.; Henn, Brenna M.; Lin, Meng; Gignoux, Christopher R.; Myrick, Justin W.; Werely, Cedric J.; Granka, Julie M.; Möller, Marlo; Hoal, Eileen G.; Yawata, Makoto; Yawata, Nobuyo; Boelen, Lies; Asquith, Becca; Parham, Peter; Norman, Paul J.

In: Journal of Immunology, Vol. 200, No. 8, 15.04.2018, p. 2640-2655.

Research output: Contribution to journalArticle

Nemat-Gorgani, N, Hilton, HG, Henn, BM, Lin, M, Gignoux, CR, Myrick, JW, Werely, CJ, Granka, JM, Möller, M, Hoal, EG, Yawata, M, Yawata, N, Boelen, L, Asquith, B, Parham, P & Norman, PJ 2018, ' Different selected mechanisms attenuated the inhibitory interaction of KIR2DL1 with C2 + HLA-C in two indigenous human populations in Southern Africa ', Journal of Immunology, vol. 200, no. 8, pp. 2640-2655. https://doi.org/10.4049/jimmunol.1701780
Nemat-Gorgani, Neda ; Hilton, Hugo G. ; Henn, Brenna M. ; Lin, Meng ; Gignoux, Christopher R. ; Myrick, Justin W. ; Werely, Cedric J. ; Granka, Julie M. ; Möller, Marlo ; Hoal, Eileen G. ; Yawata, Makoto ; Yawata, Nobuyo ; Boelen, Lies ; Asquith, Becca ; Parham, Peter ; Norman, Paul J. / Different selected mechanisms attenuated the inhibitory interaction of KIR2DL1 with C2 + HLA-C in two indigenous human populations in Southern Africa In: Journal of Immunology. 2018 ; Vol. 200, No. 8. pp. 2640-2655.
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AU - Nemat-Gorgani, Neda

AU - Hilton, Hugo G.

AU - Henn, Brenna M.

AU - Lin, Meng

AU - Gignoux, Christopher R.

AU - Myrick, Justin W.

AU - Werely, Cedric J.

AU - Granka, Julie M.

AU - Möller, Marlo

AU - Hoal, Eileen G.

AU - Yawata, Makoto

AU - Yawata, Nobuyo

AU - Boelen, Lies

AU - Asquith, Becca

AU - Parham, Peter

AU - Norman, Paul J.

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N2 - 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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