Human-Specific Evolution and Adaptation Led to Major
Qualitative Differences in the Variable Receptors of
Human and Chimpanzee Natural Killer Cells
Laurent Abi-Rached1, Achim K. Moesta1, Raja Rajalingam2, Lisbeth A. Guethlein1, Peter Parham1*
1Department of Structural Biology, Stanford University School of Medicine, Stanford, California, United States of America, 2UCLA Immunogenetics Center, Department of
Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, United States of America
Natural killer (NK) cells serve essential functions in immunity and reproduction. Diversifying these functions within
individuals and populations are rapidly-evolving interactions between highly polymorphic major histocompatibility
complex (MHC) class I ligands and variable NK cell receptors. Specific to simian primates is the family of Killer cell
Immunoglobulin-like Receptors (KIR), which recognize MHC class I and associate with a range of human diseases. Because
KIR have considerable species-specificity and are lacking from common animal models, we performed extensive comparison
of the systems of KIR and MHC class I interaction in humans and chimpanzees. Although of similar complexity, they differ in
genomic organization, gene content, and diversification mechanisms, mainly because of human-specific specialization in
the KIR that recognizes the C1 and C2 epitopes of MHC-B and -C. Humans uniquely focused KIR recognition on MHC-C,
while losing C1-bearing MHC-B. Reversing this trend, C1-bearing HLA-B46 was recently driven to unprecedented high
frequency in Southeast Asia. Chimpanzees have a variety of ancient, avid, and predominantly inhibitory receptors, whereas
human receptors are fewer, recently evolved, and combine avid inhibitory receptors with attenuated activating receptors.
These differences accompany human-specific evolution of the A and B haplotypes that are under balancing selection and
differentially function in defense and reproduction. Our study shows how the qualitative differences that distinguish the
human and chimpanzee systems of KIR and MHC class I predominantly derive from adaptations on the human line in
response to selective pressures placed on human NK cells by the competing needs of defense and reproduction.
Citation: Abi-Rached L, Moesta AK, Rajalingam R, Guethlein LA, Parham P (2010) Human-Specific Evolution and Adaptation Led to Major Qualitative Differences
in the Variable Receptors of Human and Chimpanzee Natural Killer Cells. PLoS Genet 6(11): e1001192. doi:10.1371/journal.pgen.1001192
Editor: Harmit S. Malik, Fred Hutchinson Cancer Research Center, United States of America
Received August 2, 2010; Accepted October 1, 2010; Published November 4, 2010
Copyright: ? 2010 Abi-Rached et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported by National Institutes of Health grants AI24258 and AI22039 to PP; the authors also acknowledge the support of the Yerkes
Center Base Grant RR000165. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: email@example.com
Natural killer (NK) cells are lymphocytes that contribute to both
the immune and reproductive systems. NK cells provide first-line,
innate immune defense against infection  and cancer , and
through interaction with dendritic cells  help initiate the
second-line, adaptive immune response . During embryo
implantation and placentation, NK cells control the trophoblast-
mediated widening of maternal blood vessels necessary to nourish
the fetus throughout pregnancy . Controlling both NK cell
development and effector function is a variety of interactions
between NK cell receptors and their ligands , the class I
molecules of the major histocompatibility complex (MHC): called
the HLA complex in humans. Some interactions are conserved,
such as that between human HLA-E and the CD94:NKG2A
receptor , whereas others are highly variable, notably those
between HLA-A, B, C and killer cell immunoglobulin-like
receptors (KIR) . Pointing to the clinical importance of these
interactions, various combinations of HLA and KIR factors
associate with the outcome of viral infection, susceptibility to
autoimmune disease, relapse of leukemia following therapeutic
transplantation, and reproductive success [9–11].
The human KIR locus combines gene content variability with
allelic polymorphism [8,12]. This diverse family of NK cell
receptor genes is restricted to simian primates, having expanded
from a single copy KIR3DL gene during the last ,40–58 million
years . In rodents, where KIR genes are expressed in the
brain, but not by NK cells , the Ly49 gene family
independently evolved as a variable family of NK cell receptors
for MHC class I . Prosimians have a single, non-functional
KIR3DL gene, but a diversified system of CD94 and NKG2 genes
. Also having a single KIR3DL gene, cattle expanded and
diversified the distantly related KIR3DX gene , which in
humans is non-functional. This strong element of species-specific
evolution likely reflects the variety and inconstancy of selection
imposed on NK cells by immune defense and reproduction; the
former being essential for individuals to survive, the latter being
necessary for the survival of populations and species . In this
context of rapidly evolving NK cell receptors, the study of
chimpanzees, our closest living relatives, becomes an imperative,
not only for clinical studies in which the chimpanzee is the
preferred animal model, for example hepatitis C virus infection
, but also for defining those aspects of NK cell function that
are unique to the human species .
PLoS Genetics | www.plosgenetics.org1November 2010 | Volume 6 | Issue 11 | e1001192
HLA-A, B, C and G serve as ligands for human KIR . HLA-
G expression is restricted to trophoblast and thus dedicated to
functions associated with pregnancy . Of the highly polymor-
phic genes, only HLA-C is present on trophoblast and able to
interact with the KIR of uterine NK cells . HLA-A, B and C
are expressed by almost all cells of the body and can thus
contribute in general to NK cell responses against infection and
cancer. Although the chimpanzee has well-defined orthologs of all
the human HLA class I genes , exploratory studies of
chimpanzee KIR cDNA and one KIR haplotype [23,24], raised
intriguing possibilities: first that only a small minority of KIR genes
is shared by humans and chimpanzees; and second, that the
organization of KIR genes into haplotypes is qualitatively different
in the two species. To test these hypotheses we performed
extensive analysis of chimpanzee KIR haplotype structure and
variation, permitting definitive genetic and functional comparison
with the human KIR system.
Chimpanzee KIR haplotypes do not divide into functional
groups like human A and B haplotypes
From sequence analysis of cDNA  and three KIR haplotypes
(Figure 1A), we defined 13 chimpanzee KIR genes. Typing a panel
of 39 individuals identified 16 genotypes (Figure 1B), for which the
component KIR haplotypes were deduced (Figure 1C). Both in
number and gene content difference, chimpanzee KIR genotypes
are within the human range (Figure 1D). Common to the human
and chimpanzee KIR loci are three conserved, framework regions
separated by centromeric and telomeric intervals of variable gene
content . Whereas the human variable KIR genes are evenly
distributed between the two intervals, their chimpanzee counter-
parts are restricted to the centromeric interval, leaving the
telomeric interval both short and empty (Figure 2A).
Although human and chimpanzee each have ten variable KIR
genes, only 2DL5 and 2DS4 are held in common. These two genes
distinguish the human group A and B KIR haplotypes, a difference
correlating with a wide range of clinical effects . KIR2DL5 is
the only inhibitory KIR restricted to B haplotypes, 2DS4 the only
activating KIR of A haplotypes (Figure 2A and 2B). Whereas
human 2DS4 is restricted to the telomeric region and present on
,50% of KIR haplotypes, chimpanzee 2DS4 is restricted to the
centromeric region (Figure 2B) and present on only 8% of
haplotypes (Figure 1C). Also varying between species are the
location of 2DL5 and its linkage disequilibrium (LD). Restricted to
the centromeric region, chimpanzee 2DL5 has absolute LD with
inhibitory KIR2DL8, whereas human 2DL5 has absolute LD with
activating KIR2DS3/S5 and is alternatively found in the
centromeric region, the telomeric region, or both (Figure 2A
and 2B). Thus human-specific evolution of the KIR locus involved
‘colonization’ of the telomeric region of the KIR locus, with
assembly of A and B haplotype gene-content motifs around the
2DS4 and 2DL5 genes, respectively. Consequently, human KIR
haplotypes all have 2DS4 and/or 2DL5, while almost half the
chimpanzee haplotypes (44%; arithmetic sum of the individual
frequencies of haplotypes 1, 6, 9 and 15) lack both of them.
Chimpanzee lineage III KIR are more numerous and
functional MHC-C receptors than their human
The ten variable chimpanzee KIR form five pairs within the
centromeric region (Figure 1C and Figure 2A). As shown in
Figure 1B, Pairs 2, 3 and 4 at high phenotype frequency are flanked
on the centromeric side by Pair 1 of intermediate frequency and on
thetelomericside byPair5oflowfrequency.Because Pairs1,3,and
5 have absolute or very high LD (Figure 1C), gene-content diversity
of chimpanzee KIR haplotypes derives from asymmetric recombi-
nation between seven units, these three high LD pairs and the
individual genes of Pairs 2 and 4. In humans, a similar number of
units is divided between the centromeric and telomeric regions and
separated by a unique and repetitive sequence that facilitates
symmetric recombination  (Figure 2A). Thus recombination of
centromeric and telomeric gene-content motifs, a major component
of human KIR haplotype diversification, is not a significant feature
of the chimpanzee system.
Eight variable chimpanzee lineage III KIR have no human
equivalents and represent lineage III KIR encoding high-avidity
receptors for the C1 and C2 epitopes of MHC-C. Two inhibitory
and one activating KIR are C1-specific, four inhibitory and one
activating KIR are C2-specific [27,28]. Contrasting with this
battery of potent MHC-C receptors is the set of six variable
human lineage III KIR without chimpanzee equivalents. These
comprise high-avidity inhibitory receptors for C1 (2DL2/3) and
C2 (2DL1), a C2 receptor with lower avidity (2DS1) and three
KIR with no detectable binding to HLA class I (2DS2, 2DS3, and
2DS5) . The lineage III KIR expansion associated with
hominid evolution and ‘first’ detected in the orangutan  was
further elaborated in chimpanzee and human, but in distinctive
ways. Whereas the chimpanzee retains a diversity of strong
inhibitory and activating MHC-C receptors, the human system is
characterized by a reduced number of inhibitory receptors and a
variety of activating receptors with loss of function .
Recombination of ligand-binding and signaling domains
diversifies chimpanzee KIR function
The 3DL3 and 2DL8 genes are represented on each of the
sequenced KIR haplotypes by alleles that encode the same
Natural killer (NK) cells are versatile lymphocytes that make
essential contributions to immune defense and placental
reproduction. Essential to NK cell development, diversifi-
cation and function are variable families of surface
receptors that recognize equally variable determinants of
polymorphic major histocompatibility complex (MHC) class
I molecules, better known as the tissue types matched in
clinical organ transplantation. These ligand-receptor inter-
actions evolve rapidly, exhibiting much species specificity
and convergent evolution. Consequently, mice represent a
poor model, because their receptors are so disparate from
the independently evolved human counterparts that are
restricted to simian primates. To identify unique and
shared aspects of human NK cell biology, we have defined
the genomics, population biology, and immunology of
variable chimpanzee NK cell receptors and ligands to a
level permitting accurate, informed comparison with the
well-characterized human system. In both receptors and
ligands there are dramatic, qualitative differences between
humans and chimpanzees. We show these differences
arose during human evolution from the last common
system remained relatively stable. That two so closely
related species exhibit major differences in NK cell
receptors and ligands testifies to the strong and varying
selection imposed by the different demands and compet-
ing needs of defense and reproduction.
while the chimpanzee
Major Human and Chimpanzee Immune Divergence
PLoS Genetics | www.plosgenetics.org2November 2010 | Volume 6 | Issue 11 | e1001192
Major Human and Chimpanzee Immune Divergence
PLoS Genetics | www.plosgenetics.org3November 2010 | Volume 6 | Issue 11 | e1001192
Conceived and designed the experiments: LAR PP. Performed the
experiments: LAR. Analyzed the data: LAR. Wrote the paper: LAR PP.
Contributed to the MHC analysis and KIR typing study: AKM.
Contributed to the chimpanzee KIR typing analysis: RR. Contributed to
the analysis of the KIR genomic sequences and to the human-chimpanzee
haplotype comparisons: LAG.
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