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

Nature Reviews Immunology volume 13, pages 133–144 (2013)Cite this article

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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.

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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.

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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.

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  1. Peter Parham is at the Department of Structural Biology, Stanford University, Fairchild D-157, 299 Campus Drive West, Stanford, California 94305, USA.,

    Peter Parham

  2. Ashley Moffett is at the Department of Pathology and Centre for Trophoblast Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.,

    Ashley Moffett

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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.

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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

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