Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution

Abstract

Natural killer (NK) cells have roles in immunity and reproduction that are controlled by variable receptors that recognize MHC class I molecules. The variable NK cell receptors found in humans are specific to simian primates, in which they have progressively co-evolved with MHC class I molecules. The emergence of the MHC-C gene in hominids drove the evolution of a system of NK cell receptors for MHC-C molecules that is most elaborate in chimpanzees. By contrast, the human system of MHC-C receptors seems to have been subject to different selection pressures that have acted in competition on the immunological and reproductive functions of MHC class I molecules. We suggest that this compromise facilitated the development of the bigger brains that enabled archaic and modern humans to migrate out of Africa and populate other continents.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Convergent evolution of variable NK cell receptors for MHC class I.
Figure 2: Humans KIRs recognize four epitopes of HLA-A, HLA-B and HLA-C.
Figure 3: Co-evolution of HLA-C and KIR lineage III in hominids.
Figure 4: Increased placental invasion of the uterus in primates is associated with the presence of NK cells.
Figure 5: Model for the maintenance of KIR A and B haplotypes and HLA C1 and C2 epitopes in human populations.
Figure 6: Maintaining HLA diversity during migrations that increased the geographical range of human species.

References

  1. Trowsdale, J. & Parham, P. Mini-review: defense strategies and immunity-related genes. Eur. J. Immunol. 34, 7–17 (2004).

    CAS  PubMed  Article  Google Scholar 

  2. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    CAS  Article  PubMed  Google Scholar 

  3. Flajnik, M. F. & Kasahara, M. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nature Rev. Genet. 11, 47–59 (2010).

    CAS  PubMed  Article  Google Scholar 

  4. Boehm, T. et al. VLR-based adaptive immunity. Annu. Rev. Immunol. 30, 203–220 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Moffett, A. & Loke, C. Immunology of placentation in eutherian mammals. Nature Rev. Immunol. 6, 584–594 (2006).

    CAS  Article  Google Scholar 

  6. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Dos Reis, M. et al. Phylogenomic datasets provide both precision and accuracy in estimating the timescale of placental mammal phylogeny. Proc. Biol. Sci. 279, 3491–3500 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  8. Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

    CAS  PubMed  Article  Google Scholar 

  9. Natarajan, K., Dimasi, N., Wang, J., Mariuzza, R. A. & Margulies, D. H. Structure and function of natural killer cell receptors: multiple molecular solutions to self, nonself discrimination. Annu. Rev. Immunol. 20, 853–885 (2002).

    CAS  PubMed  Article  Google Scholar 

  10. Parham, P. MHC class I molecules and KIRs in human history, health and survival. Nature Rev. Immunol. 5, 201–214 (2005).

    CAS  Article  Google Scholar 

  11. Hoglund, P. & Brodin, P. Current perspectives of natural killer cell education by MHC class I molecules. Nature Rev. Immunol. 10, 724–734 (2010).

    Article  CAS  Google Scholar 

  12. Sullivan, L. C., Clements, C. S., Rossjohn, J. & Brooks, A. G. The major histocompatibility complex class Ib molecule HLA-E at the interface between innate and adaptive immunity. Tissue Antigens 72, 415–424 (2008).

    CAS  PubMed  Article  Google Scholar 

  13. Weis, W. I., Taylor, M. E. & Drickamer, K. The C-type lectin superfamily in the immune system. Immunol. Rev. 163, 19–34 (1998).

    CAS  PubMed  Article  Google Scholar 

  14. Hammond, J. A., Guethlein, L. A., Abi-Rached, L., Moesta, A. K. & Parham, P. Evolution and survival of marine carnivores did not require a diversity of killer cell Ig-like receptors or Ly49 NK cell receptors. J. Immunol. 182, 3618–3627 (2009).

    CAS  PubMed  Article  Google Scholar 

  15. Guethlein, L. A., Abi-Rached, L., Hammond, J. A. & Parham, P. The expanded cattle KIR genes are orthologous to the conserved single-copy KIR3DX1 gene of primates. Immunogenetics 59, 517–522 (2007).

    CAS  PubMed  Article  Google Scholar 

  16. Dobromylskyj, M. & Ellis, S. Complexity in cattle KIR genes: transcription and genome analysis. Immunogenetics 59, 463–472 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. Averdam, A. et al. A novel system of polymorphic and diverse NK cell receptors in primates. PLoS Genet. 5, e1000688 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. Shum, B. P. et al. Conservation and variation in human and common chimpanzee CD94 and NKG2 genes. J. Immunol. 168, 240–252 (2002).

    CAS  PubMed  Article  Google Scholar 

  19. Bininda-Emonds, O. R. et al. The delayed rise of present-day mammals. Nature 446, 507–512 (2007).

    CAS  PubMed  Article  Google Scholar 

  20. Gumperz, J. E., Valiante, N. M., Parham, P., Lanier, L. L. & Tyan, D. Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype. J. Exp. Med. 183, 1817–1827 (1996).

    CAS  PubMed  Article  Google Scholar 

  21. Vilches, C. & Parham, P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu. Rev. Immunol. 20, 217–251 (2002).

    CAS  PubMed  Article  Google Scholar 

  22. Cadavid, L. F. & Lun, C. M. Lineage-specific diversification of killer cell Ig-like receptors in the owl monkey, a New World primate. Immunogenetics 61, 27–41 (2009).

    CAS  PubMed  Article  Google Scholar 

  23. Perelman, P. et al. A molecular phylogeny of living primates. PLoS Genet. 7, e1001342 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Barrow, A. D. & Trowsdale, J. The extended human leukocyte receptor complex: diverse ways of modulating immune responses. Immunol. Rev. 224, 98–123 (2008).

    CAS  PubMed  Article  Google Scholar 

  25. Trowsdale, J. et al. The genomic context of natural killer receptor extended gene families. Immunol. Rev. 181, 20–38 (2001).

    CAS  PubMed  Article  Google Scholar 

  26. Wilson, M. J. et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc. Natl Acad. Sci. USA 97, 4778–4783 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. Guethlein, L. A., Older Aguilar, A. M., Abi-Rached, L. & Parham, P. Evolution of killer cell Ig-like receptor (KIR) genes: definition of an orangutan KIR haplotype reveals expansion of lineage III KIR associated with the emergence of MHC-C. J. Immunol. 179, 491–504 (2007).

    CAS  PubMed  Article  Google Scholar 

  28. Rajagopalan, S. Endosomal signaling and a novel pathway defined by the natural killer receptor KIR2DL4 (CD158d). Traffic 11, 1381–1390 (2010).

    CAS  PubMed  Article  Google Scholar 

  29. Moesta, A. K. et al. Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. J. Immunol. 180, 3969–3979 (2008).

    CAS  PubMed  Article  Google Scholar 

  30. Daza-Vamenta, R., Glusman, G., Rowen, L., Guthrie, B. & Geraghty, D. E. Genetic divergence of the rhesus macaque major histocompatibility complex. Genome Res. 14, 1501–1515 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Shiina, T. et al. Rapid evolution of major histocompatibility complex class I genes in primates generates new disease alleles in humans via hitchhiking diversity. Genetics 173, 1555–1570 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Adams, E. J. & Parham, P. Species-specific evolution of MHC class I genes in the higher primates. Immunol. Rev. 183, 41–64 (2001).

    CAS  PubMed  Article  Google Scholar 

  33. Bimber, B. N., Moreland, A. J., Wiseman, R. W., Hughes, A. L. & O'Connor, D. H. Complete characterization of killer Ig-like receptor (KIR) haplotypes in Mauritian cynomolgus macaques: novel insights into nonhuman primate KIR gene content and organization. J. Immunol. 181, 6301–6308 (2008).

    CAS  PubMed  Article  Google Scholar 

  34. Blokhuis, J. H., van der Wiel, M. K., Doxiadis, G. G. & Bontrop, R. E. The mosaic of KIR haplotypes in rhesus macaques. Immunogenetics 62, 295–306 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  35. Kruse, P. H., Rosner, C. & Walter, L. Characterization of rhesus macaque KIR genotypes and haplotypes. Immunogenetics 62, 281–293 (2010).

    PubMed  Article  Google Scholar 

  36. Abi-Rached, L., Moesta, A. K., Rajalingam, R., Guethlein, L. A. & Parham, P. Human-specific evolution and adaptation led to major qualitative differences in the variable receptors of human and chimpanzee natural killer cells. PLoS Genet. 6, e1001192 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. Older Aguilar, A. M. et al. Coevolution of killer cell Ig-like receptors with HLA-C to become the major variable regulators of human NK cells. J. Immunol. 185, 4238–4251 (2010).

    CAS  PubMed  Article  Google Scholar 

  38. Moesta, A. K., Abi-Rached, L., Norman, P. J. & Parham, P. Chimpanzees use more varied receptors and ligands than humans for inhibitory killer cell Ig-like receptor recognition of the MHC-C1 and MHC-C2 epitopes. J. Immunol. 182, 3628–3637 (2009).

    CAS  PubMed  Article  Google Scholar 

  39. Graef, T. et al. KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C. J. Exp. Med. 206, 2557–2572 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Hilton, H. G. et al. Mutation at positively selected positions in the binding site for HLA-C shows that KIR2DL1 is a more refined but less adaptable NK cell receptor than KIR2DL3. J. Immunol. 189, 1418–1430 (2012).

    CAS  PubMed  Article  Google Scholar 

  41. Saulquin, X., Gastinel, L. N. & Vivier, E. Crystal structure of the human natural killer cell activating receptor KIR2DS2 (CD158j). J. Exp. Med. 197, 933–938 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Winter, C. C., Gumperz, J. E., Parham, P., Long, E. O. & Wagtmann, N. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J. Immunol. 161, 571–577 (1998).

    CAS  PubMed  Google Scholar 

  43. Abi-Rached, L. et al. A small, variable, and irregular killer cell Ig-like receptor locus accompanies the absence of MHC-C and MHC-G in gibbons. J. Immunol. 184, 1379–1391 (2010).

    CAS  PubMed  Article  Google Scholar 

  44. Uhrberg, M. et al. Human diversity in killer cell inhibitory receptor genes. Immunity 7, 753–763 (1997).

    CAS  PubMed  Article  Google Scholar 

  45. Bari, R. et al. Significant functional heterogeneity among KIR2DL1 alleles and a pivotal role of arginine 245. Blood 114, 5182–5190 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Pyo, C. W. et al. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus. PLoS ONE 5, e15115 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Anton, S. C. Natural history of Homo erectus. Am. J. Phys. Anthropol. 122 (Suppl. 37), 126–170 (2003).

    Article  Google Scholar 

  48. Robson, S. L. & Wood, B. Hominin life history: reconstruction and evolution. J. Anat. 212, 394–425 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  49. Hollenbach, J. A. et al. Report from the killer immunoglobulin-like receptor (KIR) anthropology component of the 15th International Histocompatibility Workshop: worldwide variation in the KIR loci and further evidence for the co-evolution of KIR and HLA. Tissue Antigens 76, 9–17 (2010).

    CAS  PubMed  Google Scholar 

  50. Gendzekhadze, K. et al. Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands. Proc. Natl Acad. Sci. USA 106, 18692–18697 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. King, A. et al. Evidence for the expression of HLAA-C class I mRNA and protein by human first trimester trophoblast. J. Immunol. 156, 2068–2076 (1996).

    CAS  PubMed  Google Scholar 

  52. Apps, R. et al. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology 127, 26–39 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Moffett-King, A. Natural killer cells and pregnancy. Nature Rev. Immunol. 2, 656–663 (2002).

    CAS  Article  Google Scholar 

  54. Bulmer, J. N. & Sunderland, C. A. Immunohistological characterization of lymphoid cell populations in the early human placental bed. Immunology 52, 349–357 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Hanna, J. et al. Decidual NK cells regulate key developmental processes at the human fetal–maternal interface. Nature Med. 12, 1065–1074 (2006).

    CAS  PubMed  Article  Google Scholar 

  56. King, A. & Loke, Y. W. Uterine large granular lymphocytes: a possible role in embryonic implantation? Am. J. Obstet. Gynecol. 162, 308–310 (1990).

    CAS  PubMed  Article  Google Scholar 

  57. Koopman, L. A. et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J. Exp. Med. 198, 1201–1212 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Manaster, I. & Mandelboim, O. The unique properties of uterine NK cells. Am. J. Reprod. Immunol. 63, 434–444 (2010).

    CAS  PubMed  Article  Google Scholar 

  59. Sharkey, A. M. et al. Killer Ig-like receptor expression in uterine NK cells is biased toward recognition of HLA-C and alters with gestational age. J. Immunol. 181, 39–46 (2008).

    CAS  PubMed  Article  Google Scholar 

  60. Trowsdale, J. & Moffett, A. NK receptor interactions with MHC class I molecules in pregnancy. Semin. Immunol. 20, 317–320 (2008).

    CAS  PubMed  Article  Google Scholar 

  61. Hiby, S. E. et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. J. Clin. Invest. 120, 4102–4110 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Hiby, S. E. et al. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Hum. Reprod. 23, 972–976 (2008).

    CAS  PubMed  Article  Google Scholar 

  63. Hiby, S. E. et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J. Exp. Med. 200, 957–965 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Schonberg, K., Sribar, M., Enczmann, J., Fischer, J. C. & Uhrberg, M. Analyses of HLA-C-specific KIR repertoires in donors with group A and B haplotypes suggest a ligand-instructed model of NK cell receptor acquisition. Blood 117, 98–107 (2011).

    PubMed  Article  CAS  Google Scholar 

  65. Chazara, O., Xiong, S. & Moffett, A. Maternal KIR and fetal HLA-C: a fine balance. J. Leukoc. Biol. 90, 703–716 (2011).

    CAS  PubMed  Article  Google Scholar 

  66. Single, R. M. et al. Global diversity and evidence for coevolution of KIR and HLA. Nature Genet. 39, 1114–1119 (2007).

    CAS  PubMed  Article  Google Scholar 

  67. Dring, M. M. et al. Innate immune genes synergize to predict increased risk of chronic disease in hepatitis C virus infection. Proc. Natl Acad. Sci. USA 108, 5736–5741 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004).

    CAS  Article  PubMed  Google Scholar 

  69. Cheent, K. & Khakoo, S. I. Natural killer cells and hepatitis C: action and reaction. Gut 60, 268–278 (2010).

    PubMed  Article  CAS  Google Scholar 

  70. Wauquier, N., Padilla, C., Becquart, P., Leroy, E. & Vieillard, V. Association of KIR2DS1 and KIR2DS3 with fatal outcome in Ebola virus infection. Immunogenetics 62, 767–771 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. McGrew, W. C. In search of the last common ancestor: new findings on wild chimpanzees. Phil. Trans. R. Soc. 365, 3267–3276 (2010).

    CAS  Article  Google Scholar 

  72. White, T. D. et al. Ardipithecus ramidus and the paleobiology of early hominids. Science 326, 75–86 (2009).

    CAS  PubMed  Google Scholar 

  73. DeGiorgio, M., Jakobsson, M. & Rosenberg, N. A. Out of Africa: modern human origins special feature: explaining worldwide patterns of human genetic variation using a coalescent-based serial founder model of migration outward from Africa. Proc. Natl Acad. Sci. USA 106, 16057–16062 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Crompton, R. H. et al. Human-like external function of the foot, and fully upright gait, confirmed in the 3.66 million year old Laetoli hominin footprints by topographic statistics, experimental footprint-formation and computer simulation. J. R. Soc. Interface 9, 707–719 (2012).

    PubMed  Article  Google Scholar 

  75. Franciscus, R. G. When did the modern human pattern of childbirth arise? New insights from an old Neandertal pelvis. Proc. Natl Acad. Sci. USA 106, 9125–9126 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. Rosenberg, K. & Trevathan, W. Birth, obstetrics and human evolution. BJOG 109, 1199–1206 (2002).

    PubMed  Article  Google Scholar 

  77. Weaver, T. D. & Hublin, J. J. Neandertal birth canal shape and the evolution of human childbirth. Proc. Natl Acad. Sci. USA 106, 8151–8156 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. Leonard, W. R., Snodgrass, J. J. & Robertson, M. L. Effects of brain evolution on human nutrition and metabolism. Annu. Rev. Nutr. 27, 311–327 (2007).

    CAS  PubMed  Article  Google Scholar 

  79. Vallender, E. J., Mekel-Bobrov, N. & Lahn, B. T. Genetic basis of human brain evolution. Trends Neurosci. 31, 637–644 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Carter, A. M. & Pijnenborg, R. Evolution of invasive placentation with special reference to non-human primates. Best Pract. Res. Clin. Obstet. Gynaecol. 25, 249–257 (2011).

    PubMed  Article  Google Scholar 

  81. DeSilva, J. & Lesnik, J. Chimpanzee neonatal brain size: implications for brain growth in Homo erectus. J. Hum. Evol. 51, 207–212 (2006).

    PubMed  Article  Google Scholar 

  82. Hublin, J. J. Out of Africa: modern human origins special feature: the origin of Neandertals. Proc. Natl Acad. Sci. USA 106, 16022–16027 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. McDougall, I., Brown, F. H. & Fleagle, J. G. Stratigraphic placement and age of modern humans from Kibish, Ethiopia. Nature 433, 733–736 (2005).

    CAS  PubMed  Article  Google Scholar 

  84. Cann, R. L., Stoneking, M. & Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987).

    CAS  PubMed  Article  Google Scholar 

  85. Prugnolle, F., Manica, A. & Balloux, F. Geography predicts neutral genetic diversity of human populations. Curr. Biol. 15, R159–R160 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. Moreau, C. et al. Deep human genealogies reveal a selective advantage to be on an expanding wave front. Science 334, 1148–1150 (2011).

    CAS  PubMed  Article  Google Scholar 

  87. Mulligan, C. J., Hunley, K., Cole, S. & Long, J. C. Population genetics, history, and health patterns in native americans. Annu. Rev. Genomics Hum. Genet. 5, 295–315 (2004).

    CAS  PubMed  Article  Google Scholar 

  88. Mourant, A. E., Kopec, A. C. & Domaniewska-Sobczak, K. The Distribution of the Human Blood Groups and Other Polymorphisms (Oxford Univ. Press, 1976).

    Google Scholar 

  89. Belich, M. P. et al. Unusual HLA-B alleles in two tribes of Brazilian Indians. Nature 357, 326–329 (1992).

    CAS  PubMed  Article  Google Scholar 

  90. Watkins, D. I. et al. New recombinant HLA-B alleles in a tribe of South American Amerindians indicate rapid evolution of MHC class I loci. Nature 357, 329–333 (1992).

    CAS  PubMed  Article  Google Scholar 

  91. Garber, T. L. et al. HLA-B alleles of the Cayapa of Ecuador: new B39 and B15 alleles. Immunogenetics 42, 19–27 (1995).

    CAS  PubMed  Article  Google Scholar 

  92. Little, A. M. et al. HLA class I diversity in Kolla Amerindians. Hum. Immunol. 62, 170–179 (2001).

    CAS  PubMed  Article  Google Scholar 

  93. Cadavid, L. F. & Watkins, D. I. Heirs of the jaguar and the anaconda: HLA, conquest and disease in the indigenous populations of the Americas. Tissue Antigens 50, 702–711 (1997).

    CAS  PubMed  Article  Google Scholar 

  94. Parham, P. et al. Episodic evolution and turnover of HLA-B in the indigenous human populations of the Americas. Tissue Antigens 50, 219–232 (1997).

    CAS  PubMed  Article  Google Scholar 

  95. Mellars, P. Neanderthals and the modern human colonization of Europe. Nature 432, 461–465 (2004).

    CAS  PubMed  Article  Google Scholar 

  96. Mellars, P. & French, J. C. Tenfold population increase in Western Europe at the Neandertal-to-modern human transition. Science 333, 623–627 (2011).

    CAS  PubMed  Article  Google Scholar 

  97. Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Abi-Rached, L. et al. The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334, 89–94 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Reich, D. et al. Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania. Am. J. Hum. Genet. 89, 516–528 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Boyington, J. C. & Sun, P. D. A structural perspective on MHC class I recognition by killer cell immunoglobulin-like receptors. Mol. Immunol. 38, 1007–1021 (2002).

    CAS  PubMed  Article  Google Scholar 

  101. Kaiser, B. K., Pizarro, J. C., Kerns, J. & Strong, R. K. Structural basis for NKG2A/CD94 recognition of HLA-E. Proc. Natl Acad. Sci. USA 105, 6696–6701 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. Petrie, E. J. et al. CD94–NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence. J. Exp. Med. 205, 725–735 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Hansasuta, P. et al. Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur. J. Immunol. 34, 1673–1679 (2004).

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank L. Guethlein (Stanford) for her invaluable contributions to drafting the figures and preparing the manuscript. The authors also thank G. Burton (Cambridge) for advice and helpful discussions. Research from P.P.'s laboratory that is reviewed in this article was supported by grants from the US National Institutes of Health. A.M.'s laboratory is supported by the Wellcome Trust, the British Heart Foundation and the Centre for Trophoblast Research, University of Cambridge.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter Parham.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Peter Parham's homepage

Glossary

Adaptive introgression

The process by which a mating between two species, or two geographically or culturally separated populations, leads to the acquisition of functionally advantageous gene variants. Under natural selection these new variants rise to much higher frequency in their new 'home' species than genes that provide little or no advantage.

Balancing selection

For certain genetic traits there are two or more alternative forms that provide complementary functions that are sufficiently valuable that they are maintained as a balanced polymorphism in the population. The most obvious example of a balanced polymorphism is that between X and Y chromosomes. Without both women (XX) and men (XY) a population cannot survive to the next generation. HLA class I, KIR and numerous other immune-system genes are maintained as balanced polymorphisms.

Genetic drift

A process associated with small populations in which random events, as opposed to natural selection, lead to a polymorphic variant either rising to high frequency and being fixed or being driven to low frequency and eliminated from the population.

KIR lineages I, II, III and V

The evolution of gene families of the immune system is always associated with the individual members acquiring functional and structural differences that define different phylogenetic lineages. In the KIR gene family the different lineages are associated with recognition of different MHC class I ligands.

Population bottlenecks

Periods during which a population suffers a substantial reduction in size, and as a consequence loses potentially valuable genetic diversity. Epidemics of infectious disease and conflicts between warring populations can create population bottlenecks.

Prosimian primates

Modern primate species, such as lemurs and lorises, that more closely resemble ancestral primates than do the simian primates. With the exception of the Madagascar lemurs, they have largely been replaced by the simian primates and the extant species are nocturnal.

Simian primates

Simian primates comprise monkeys, apes and humans. They are characterized by good eyesight and flexible hands and feet. The only nocturnal species of simian primate are the owl monkeys (Aotus spp.) of South and Central America.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Parham, P., Moffett, A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat Rev Immunol 13, 133–144 (2013). https://doi.org/10.1038/nri3370

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3370

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing