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Phil. Trans. R. Soc. B (2012) 367, 800–811
doi:10.1098/rstb.2011.0266
Review
Human-specific evolution of killer cell
immunoglobulin-like receptor recognition
of major histocompatibility complex
class I molecules
Peter Parham1,2,*, Paul J. Norman1,2, Laurent Abi-Rached1,2
and Lisbeth A. Guethlein1,2
1
Department of Structural Biology, and 2Department of Microbiology and Immunology,
Stanford University, Stanford, CA 94305, USA
In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals,
populations and species. Modulating these functions are conserved and variable NK-cell receptors
that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans,
for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs)
is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell
immunity—combined with the segregation on different chromosomes of variable NK-cell receptors
and their MHC class I ligands—drive an unusually rapid evolution that has resulted in unprecedented
levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to
human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and
the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the
emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two
groups of KIR haplotypes that are present in all human populations and subject to balancing selection.
Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding
KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors
with diminished capacity to bind HLA class I. Correlating with their balance in human populations,
B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence.
Evolution of the B KIR haplotypes is thus unique to the human species.
Keywords: natural killer cells; major histocompatibility complex; balancing selection
1. INTRODUCTION
From their variable cell-surface receptors, that detect
infection, cancer and other physiological perturbations, lymphocytes are divided into three broad
types. These comprise the B cells and T cells that
use gene rearrangement and somatic mutation to
diversify their variable antigen receptors (immunoglobulins and T-cell receptors (TCRs) respectively), and
the natural killer (NK) cells that do not employ these
mechanisms. In their place, NK cells use transcriptional regulation of a variety of receptor genes to
form and maintain a diverse repertoire of NK cells
with heterogeneous cell-surface phenotype [1].
NK cells exert their functional effects by physically
interacting with other types of cell, engagements that
can lead to the killing of cells damaged by infection
or malignancy, and to the secretion of cytokines that
recruit other inflammatory immune system cells [2].
NK cells contribute to innate immunity, the early
phase of an immune response, when NK-cell interactions with dendritic cells can help initiate the
adaptive immune response mediated by B and T
cells, but only if and when it is necessary. Further
distinguishing NK cells from B and T cells is their
role in placental reproduction [3]. Implantation of an
embryo into the uterus and formation of the placenta
involves interactions between maternal uterine NK
cells and foetal extra-villous trophoblast cells that
cause the latter to invade the mother’s spiral arteries
and convert them into large vessels capable of supplying the placenta with sufficient blood to nourish the
baby to term. NK cells thus make vital contributions
to the immune system and the reproductive system,
the former being essential for day-to-day survival of
human individuals, the latter for the generation-togeneration survival of human populations and the
human species.
* Author for correspondence ([email protected]).
One contribution of 14 to a Discussion Meeting Issue ‘Immunity,
infection, migration and human evolution’.
800
This journal is q 2012 The Royal Society
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Review. Coevolution of KIR and HLA class I
P. Parham et al. 801
isotype variants
HLA complex
human chromosome 6
ligands for NK cell receptors
highly
conserved
interaction
HLA-A 1243
HLA-B 1737
HLA-C 884
3
HLA-E
4
HLA-F
HLA-G 15
HLA-A, -B, -C
HLA-E
killer cell
immunoglobulin
CD94:NKG2A
-like receptors (KIRs)
natural killer complex
human chromosome 12
lectin-like NK cell receptors
highly
diversified
interaction
leucocyte receptor complex
human chromosome 19
antibody-like NK cell receptors
Figure 1. Three genetic complexes encoding cell-surface molecules involved in natural killer (NK) cell responses. Shown is a
schematic of interactions between human leucocyte antigen (HLA) class I molecules and NK-cell receptors. The chromosomal
locations of the complexes encoding them are given in the orange boxes. The number of protein variants (allotypes) for each of
the HLA class I molecules is given in the green box.
In their cell-surface phenotype and function, NK
cells are more like T cells than B cells, and more closely resemble the CD8-bearing killer T cells than the
CD4-bearing helper T cells [1]. Central to killer
T-cell biology are the interactions of ab TCRs with
small 8 – 10 amino acid peptides presented by major
histocompatibility complex (MHC) class I molecules.
In analogous fashion, NK-cell receptors for MHC
class I have similar critical influences on NK-cell
development and response. In a process known as education for human NK cells [4 – 6] and licensing for
mouse NK cells [7], developmental interactions
between MHC class I ligands and cognate NK-cell
receptors determine how mature NK cells carrying
such receptors can respond to unhealthy cells exhibiting perturbed expression of the MHC class I ligand.
Likewise, the strength of NK-cell effector functions
can be modulated by the strength of the avidity
between allelic variants of an NK-cell receptor and
its cognate MHC class I ligand [5,8]. Despite the striking parallels, there are many differences in the way that
NK-cell and T-cell receptors for MHC class I guide
and regulate their respective lymphocyte populations.
2. GENETIC COMPLEXES ENCODING NATURAL
KILLER CELL RECEPTORS AND LIGANDS
Identified in the 1930s as highly polymorphic antigens
that determine the rejection of transplanted tissues
and organs, MHC class I molecules were studied for
the next four decades in the non-physiological context
of clinical transplantation (reviewed by Klein [9]).
Although their physiological function of presenting
antigens to T cells unfolded in the 1970s and 1980s,
it was not until the 1990s that the important influence
that MHC class I molecules exert on NK-cell biology was appreciated [10]. The human MHC is
Phil. Trans. R. Soc. B (2012)
alternatively called the human leucocyte antigen
(HLA) complex, a name reflecting its discovery and
initial characterization using antibody-based serological assays that distinguish different antigens. The
approximately 4.8 Mb HLA complex on chromosome
6 contains many immune system genes and is the most
highly polymorphic segment of the human genome
[11,12]. Of the six expressed HLA class I genes,
HLA-A, -B and -C are extraordinarily polymorphic,
whereas HLA-E, -F and -G are conserved (figure 1).
All these genes except HLA-F have been shown to
encode ligands for NK-cell receptors. For decades,
the function of HLA-F has been an enigma, but
a recent report raises the possibility that it acts as a
kind of chaperone that retrieves other HLA class I
molecules that have become unfolded at the plasma
membrane and escorts them inside the cell [13].
Complementing the MHC are two further genetic
complexes containing families of genes that encode
NK-cell receptors: the natural killer complex (NKC) on
chromosome 12 [14] and the leucocyte receptor complex
(LRC) on chromosome 19 (figure 1) [15,16]. The NKC
encodes receptors whose ligand-binding domains have a
structure related to that of calcium-dependent carbohydrate-binding proteins called lectins. But instead of
binding to carbohydrates, the NK-cell receptors have
evolved to bind protein ligands and some of them bind
to MHC class I. Critical human NKC-encoded receptors are the heterodimeric receptors CD94:NKG2A
(an inhibitory receptor) and CD94:NKG2C (an
activating receptor), which both recognize complexes
of HLA-E and peptides derived from the leader
sequences of other HLA class I (figure 1) [17]. The
functional consequence of this composite specificity is
that CD94:NKG2 receptors are sensors that monitor
the total amount HLA class I made by a cell and how
it changes in the context of disease.
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Review. Coevolution of KIR and HLA class I
KIR locus
Y
human
Y
chimpanzee
Y
orangutan
Y
Y
gibbon
rhesus macaque
owl monkey
Y
Y
Y
mouse lemur
galago
Y
Y
pig
seal
dog
mouse
Figure 2. A variable family of KIR3DL genes is specific to the simian primates. Shown is a schematic of the KIR locus in a
variety of primate and non-primate species [19–25]. A single representative KIR haplotype is shown for each species. Grey
colour coding indicates framework genes. Other genes are coloured according to the class of receptor they encode: red, inhibitory KIR; green, activating KIR; purple, leucocyte immunoglobulin-like receptor (LILR); yellow, receptor for the Fc of IgA
(CD89); white, C, pseudogene.
The LRC encodes receptors whose ligand-binding
domains are made up from several modules each of
which is an immunoglobulin-like domain. Of particular
interest here is the diverse family of human killer cell
immunoglobulin-like receptors (KIRs), some of which
recognize the polymorphic HLA-A, -B and -C molecules. In a complementary fashion to CD94:NKG2A/
C, these KIRs monitor the presence and level of individual HLA class I allotypes on cell surfaces. Consistent
with these complementary functions, HLA-E and
CD94:NKG2 are conserved in the human population, whereas KIR and HLA-A, -B and -C are highly
diversified (figure 1) [18].
3. COUNTERPARTS TO THE HUMAN KILLER
CELL IMMUNOGLOBULIN-LIKE RECEPTOR
FAMILY ARE PRESENT ONLY IN SIMIAN
PRIMATES
Comparing a range of mammalian species has shown
that most of them do not have a diversified family of
KIR genes (figure 2). For example, the KIR locus
appears deleted from dog and cat genomes; and in
the mouse genome, the two KIR genes are not in the
LRC but on the X chromosome [26], with only one
of them being expressed by NK cells [27]. Seals have
a single, conserved and functional KIR gene [19]; but
in prosimians, the single KIR gene is non-functional
[20]. To date, diversified families of KIR genes have
been found only for simian primates (monkeys,
apes and the human species) and cattle, a ruminant
[20–22,28–33]. However, the primate and cattle KIR
families diverged 135 million years ago, prior to the
radiation of placental mammals. At that time an
ancestral KIR gene duplicated to form two daughter
genes: KIR3DL and KIR3DX [34,35]. Subsequently,
Phil. Trans. R. Soc. B (2012)
the KIR3DL gene exclusively expanded in the simian
primates, whereas the KIR3DX gene degenerated
to become a pseudogene. Conversely, the KIR3DX
gene expanded in cattle (and probably related ruminant
species), whereas KIR3DL remained a single-copy
gene. Although cattle and simian primates both have
diverse KIR gene families, they are clearly the products
of independent expansions [34]. Further emphasizing
the restriction of diverse KIR3DL to the simian primates, prosimian primates have expanded and
diversified the CD94 and NKG2 families of NKC
genes in the context of their non-functional KIR [20].
Particularly extreme in their divergence from the
human situation are rodents (for example mouse and
rat), who use diverse families of NKC-encoded Ly49
receptors as their variable NK-cell receptors for MHC
class I [36,37]. In contrast to the flourishing Ly49
gene families of rodents, the single human Ly49 gene
is non-functional [38].
4. KILLER CELL IMMUNOGLOBULIN-LIKE
RECEPTORS RECOGNIZE FOUR MUTUALLY
EXCLUSIVE EPITOPES OF HUMAN LEUCOCYTE
ANTIGEN CLASS I
HLA-E is highly selective in binding peptides derived
from HLA class I leader sequences [39]. Consequently,
the CD94:NKG2A/C receptors are highly peptidespecific. The interactions of KIR with HLA class I are
also sensitive to the sequence of the bound peptides
[40–43]. Three-dimensional structures show that the
KIR-binding site on the HLA class I molecule overlaps
with that of the ab TCR, and involves the face formed
by the exposed parts of the a helices of the a1 and a2
domains and of the outstretched peptide gripped
between them (figure 3) [44]. Direct contact is possible
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P. Parham et al. 803
C1
Bw4
a1 helix
80
A11
83
HLA-A
Bw4
C1
C2
A3
HLA-B
HLA-C
Figure 4. The specificity of KIR recognition of HLA
class I. The pie charts show the frequency of HLA class I
allotypes carrying the A3/11, orange; Bw4, green; C1,
blue; and C2, red, epitopes. Population frequencies were
obtained from http://www.allelefrequencies.net [51].
a2 helix
KIR binding
site
TCR binding
site
Figure 3. Killer cell immunoglobulin-like receptor (KIR) and
the ab T-cell receptor (TCR) bind to overlapping sites on
human leucocyte antigen (HLA) class I. The areas of KIR
and TCR binding to MHC class I are given by the red and
green lines, respectively. HLA class I residues involved in
direct contact [44,45] are shown on the ribbon diagram of
the a1 and a2 domains in red for KIR binding, green for
TCR binding, and yellow for binding to both KIR and
TCR. Shown are position 80, the residue that determines
the C1 and C2 specificities of lineage III KIR [44,46], and
position 83 that is critical for the binding of lineage II KIR
to the Bw4 epitopes of HLA-A and HLA-B [41,47]. The
HLA structure used to produce the ribbon diagram was
PDB ID:1EFX.
with peptide residues seven and eight, and indirect
effects may also arise from other peptide positions that
interact with the pockets of the HLA class I binding
groove [47]. Although not well studied, the peptide sensitivity of KIR binding to HLA class I appears to vary
with the KIR. For example, KIR3DL2 binding to
HLA-A3 and HLA-A11 appears to be very peptidedependent, because only one peptide (derived from
Epstein–Barr virus (EBV)) has been shown to be permissive for the interaction [43]. Less fastidious are the
HLA-C-specific KIRs, for which around 40 per cent
of the peptides that bind to HLA-C are compatible
with KIR interaction [40,48–50]. That the KIR- and
ab TCR-binding sites physically overlap raises the
possibility that the individual selection pressures exerted
on HLA class I by T-cell and NK-cell immunity can
compete with each other (figure 3). In other words, a
variant HLA class I selected for its beneficial T-cell
response to one infection might have detrimental consequences for a subsequent NK-cell response against
another infectious agent, and vice versa.
The interaction between KIR and HLA class I
is relatively rigid, involving little accommodation
through conformational change [44]. Only a fraction
of the HLA-A, -B and -C variants interact with KIRs
and these all carry one of four mutually exclusive epitopes (A3/11, Bw4, C1 and C2) that are structural
variations on a theme (figure 4). These epitopes are
alternatively referred to as KIR ligands, particularly in
the clinical literature pertaining to bone marrow transplantation and the role of donor-derived NK cells
in improving the survival of transplanted patients
Phil. Trans. R. Soc. B (2012)
[52–55]. That all HLA-C allotypes have either the C1
or C2 epitope, whereas only 45 per cent of HLA-A
and 36 per cent of HLA-B allotypes are KIR ligands, is
consistent with HLA-C having evolved to be a superior
and more specialized ligand for KIR [56,57]. This distribution also shows how a majority of HLA-A and -B
allotypes do not function as KIR ligands and are thus
free to evolve exclusively under pressure from the
T-cell response. HLA-C is of more recent origin than
HLA-A and -B and probably evolved from an HLAB-like ancestor that carried the C1 epitope [58].
Studies to compare the HLA class I specificities of
mutant human and ape KIRs show that hominoid
KIRs are inherently restricted to recognizing HLA
class I allotypes carrying the A3/11, Bw4, C1 or C2 epitope, further emphasizing the partition of HLA-A and
-B allotypes into those that serve as KIR ligands and
those that cannot [56,57].
5. POPULATION BIOLOGY AND GENETICS
OF KILLER CELL IMMUNOGLOBULIN-LIKE
RECEPTORS
There are 13 expressed human KIR genes and two KIR
pseudogenes (figure 5). KIR2DS1, 2, 3, 4 and 5 are
dedicated activating receptors, whereas KIR2DL1,
2DL2/3 and 2DL5 are dedicated inhibitory receptors.
KIR2DL4 has potential for both activating and inhibitory functions, whereas KIR3DL1/S1 is unusual in
having mutually exclusive subsets of allotypes with activating (KIR3DS1) and inhibitory (KIR3DL1) function
[59]. Haplotypes of the KIR locus differ in their content
of KIR genes [33], an important feature that is illustrated
for several common KIR haplotypes in figure 5 [23].
Three conserved genes (KIR3DL3, 2DL4 and 3DL2)
form the common framework that defines two regions
of gene-content diversity, one in the centromeric part
of the locus and the other in the telomeric part [60].
Only five of the 13 human KIRs have been demonstrated to recognize HLA class I: A3/11 by KIR3DL2
[61], Bw4 by KIR3DL1 (but not KIR3DS1) [62,63],
C2 by KIR2DL1 and 2DS1 [64], C1 and some C2 by
KIR2DL2/3 [46,65], a mix of some C1, some C2 and
A11 by KIR2DS4 [66] and HLA-G by KIR2DL4 [67]
(table 1). In contrast, KIR2DS2, 2DS3, 2DS5, 2DL5,
3DS1 and 3DL3 remain orphan receptors for which
no ligand has yet been identified. In the case of
KIR2DS2, it is likely that at one time it did bind to
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P. Parham et al.
Review. Coevolution of KIR and HLA class I
KIR
haplotype
B
A
Cen
Tel
3DL3
2DS2
2DL2L3
2DL5C
2DS3S5C
2DP1
2DL1
3DP1
2DL4
3DL1S1
B01
B01
B01
B01
B01
B01
B03
B02
B02
B02
B02
B02
B02
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
B01
B01
B01
A01
A01
A01
A01
B01
B01
B01
A01
A01
A01
B01
B01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
A01
*0030102
*0030103
*00301
*0030104
*0140203
*0040202
par t
*0030101
*00801
*0140202
*0040201
*0140201
*036
*0090102
*01001
*00201
*00206
*00802
*0090102
*0090101
*0010102
*0010105
*0010105
*0010112
*0010111
*0010109
2*0010101
2*0010102
2*0010106
2*0010107
2*0010105
2*0010104
3*010
2*0030101
2*0030107
2*0030106
2*0030105
2*0010103
2*0030104
3*0010102
3*0010105
3*0010101
3*0010106
3*0010108
3*0010102
3*0010104
3*0010103
3*0010107
3*0010109
3*00101 10
3*0020102
3*0020103
3*006
*0020103
*0020105
*0020107
*0020107
*0080101
*004
*00601
3*0010301
3*0010301
3*0010301
3*0010302
5*007
5*006
5*010
*0010201
*0010201
*0010202
*0010203
*010
*009
*006
*0040101
*0040101
*0040101
*007
*0040102
*1201
*010
*0030101
*0030102
*0030102
*0030101
*0030402
*0030401
*00902
*002
*0090103
*0090101
*007
*001
*0090102
*0030205
*0030202
*0030201
*00303
*0030202
*0030202
*0030204
*0030202
*008
*010
*0030206
*006
*006
*0030203
*00501
*00501
*00501
*00602
*011
*011
*0080203
*00501
*00501
*00501
*0010201
*00602
*0080105
*0010308
*00501
*0080101
*0010202
*0010201
*0010303
*011
*0010305
*0010307
*011
*0010201
*0010304
*0080204
*0010306
*0130101
*0130101
*0130101
*0070102
*0050102
*0050102
*063
*0130101
*0130103
*0130101
*0290101
*0070101
*0010102
*014
*0130102
*0010101
*0150201
*0150203
*025
*0050101
*008
*01701
*0050102
*0290102
*062
*00401
*0150202
*0090103
*0090101
*012
*048
*00101
*019
*005
*0010101
*0010110
*0010108
*0010107
*0010102
*0010106
*0020107
*0020104
*0020101
*008
*0020106
*0020103
*0020103
*005
*0020105
*0020109
*0020108
*004
*0030102
*007
*025
*0030207
*0030201
*0030208
*0030205
*0030203
*0030206
*0030204
*0030209
*0030210
*0030204
*0020102
*0020103
*00303
2DL5T
2DS3S5T
*0010102 5*0020102
*0050101 3*0020101
*0050101 3*0020103
2DS1
2DS4
*0020102
*0020104
*0020104
*0040102
*010
*010
*0060101
*0010101 5*0020101
*0050104 3*0020102
*0010103 5*0020104
*0020101
*0020106
*0020103
*0010109
*0040101
*0030103
typing
typing
*0050103 3*0020101
par t
*0020105
*0030101
*0010101
*0010107
*0010104
*010
*0030104
*0010108
*010
*0010102
*0010106
*0060102
*0010105
3DL2
*0070101
*0070103
*0070103
*008
*010
*010
*00202
*006/007
*0070102
*018
*0020103
*008
*0010102
*056
*0070102
*0010101
*0020104
*0020105
par t
*0010302
*00901
*023
*010
*0020106
*00903
*00501
*0020102
Figure 5. Killer cell immunoglobulin-like receptor (KIR) haplotypes vary in both gene content and allelic diversity. Shown are
the gene and allele content of 27 KIR haplotypes for which complete sequences have been determined [23]. Haplotypes are
grouped by gene content (A or B haplotypes) and then further subdivided by their centromeric (Cen) and telomeric (Tel)
gene-content motifs. Framework genes are shaded in grey, A haplotype characteristic genes/alleles in red and B haplotype
characteristic genes/alleles in blue. Partial sequences are indicated by stippling and ‘part’ indicates where allelic identity was
not fully determined. ‘Typing’ indicates that the KIR gene was determined to be present by genotyping.
Table 1. Human leukocyte antigen epitopes recognized by killer cell immunoglobulin-like receptor.
HLA class I ligand
KIR
A3
A11
Bw4
3DL1
3DS1
3DL2
3DL3
2DL1
2DL2/3
2DS1
2DS2
2DS3
2DS4
2DS5
2DL4
2DL5
HLA class I but was then actively selected to lose that
function [68,69].
Population studies provide an alternative approach
for assessing the functional benefit of the enigmatic
orphan KIR. To date, approximately 200 populations
have been studied for KIR gene content (http://www.
allelefrequencies.net [51]). With the exception of
KIR2DS3 and KIR2DL5B, which are absent from
some Amerindian tribes [70,71], all populations have
significant frequencies for all the KIR genes. Likewise,
all populations have both inhibitory KIR3DL1 that
binds to Bw4 [62] and activating KIR3DS1 that
does not bind Bw4 or other HLA class I [63]. Such
Phil. Trans. R. Soc. B (2012)
C1
C2
G
unknown
some
some
some
retention, particularly in the case of Amerindian populations who have experienced successive population
bottlenecks and severe epidemics of infectious disease,
is unlikely to have occurred by chance and argues that
the orphan KIRs serve useful functions, but this need
not necessarily involve interaction with HLA class I. A
precedent is set by KIR3DL2, which in addition to
recognizing the A3/11 epitope of HLA class I [61]
also recognizes microbial products and carries them
inside cells for possible delivery to Toll-like receptors
[72,73]. That loss of KIR2DS3 and KIR2DL5B has
been tolerated by some populations could reflect the
sequence similarities of these KIRs with KIR2DS5
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centromeric
3DL3
telomeric
2DS2 2DL2/3 2DL5B 2DS3/5 2DP1
2DL1
3DP1
2DL4 3DL/S1 2DL5A 2DS3/5
B
2DL2
3DS1
A
2DL3
3DL1
0
25
50
P. Parham et al. 805
75
100
125
length (kb)
150
2DS1
haplotype
2DS4
3DL2
2DS5
175
200
length frequency
(kb)
(%)
157
47
143
46
225
Figure 6. Group A and B haplotypes are present at very even frequencies in the Yucpa Amerindians. The structures of the two
Yucpa KIR gene-content haplotypes are shown [70,75]. Genes are coloured according to the binding specificity of the encoded
receptor. Green denotes KIRs that bind HLA class I. Yellow denotes KIRs that do not bind HLA class I. Grey denotes KIR for
which ligands are unknown. White denotes pseudogenes. Dots indicate absence of a gene. The KIR locus is situated at
chromosome 19q13.4; its centromeric boundary corresponds to 0 kb in the horizontal scale and its telomeric end to 230 kb.
and KIR2DL5A, respectively. For KIR2DS3, its poor
folding in the endoplasmic reticulum and inability to
reach the NK cell surface could also be a factor [74].
On the basis of KIR gene content, two groups of KIR
haplotype have been defined. This concept is well illustrated by the Yucpa population of Amerindians who
have only two major KIR gene-content haplotypes, one
of group A and one of group B, which are present at
roughly equal frequencies (figure 6). Differences of
gene content are seen in both the centromeric and telomeric regions; and at the allele level, the two haplotypes
have no KIR factor in common [75]. The group A haplotype has a content of seven genes of which six encode
KIRs that bind HLA class I and the seventh
(KIR3DL3) has not been tested. The group B KIR haplotype has nine expressed KIRs, of which three bind
HLA class I (KIR2DL2, 2DL4 and 3DL2), four do
not bind HLA class I (KIR2DS2, 3DS1, 2DL5A and
2DS5), and KIR3DL3 remains uncertain. Thus, a
major difference between the two haplotypes is that the
A haplotype is enriched for KIRs that bind HLA class
I, whereas the B haplotype is enriched for KIRs that
have either lost that function or never had it. This
effect is also seen at the allelic level for genes that are
common to A and B haplotypes. The Yucpa B haplotype
lacks the KIR2DL1 gene, but that is not the case for all B
haplotypes. However, the common KIR2DL1 allele of
B haplotypes is KIR2DL1*004 which has attenuated
signalling function compared with the common
KIR2DL1*003 allele of the A haplotype [76]. Such functional difference between allotypes of the A and B KIR
haplotypes is particularly extreme for the KIR3DL1/S1
gene, where A haplotype inhibitory KIR3DL1 binds
the Bw4 epitope and is polymorphic, whereas B haplotype KIR3DS1 does not bind Bw4 and is practically
monomorphic. By some margin, the genetics and functional effects of KIR polymorphism have been more
extensively studied for KIR3DL1/S1 than for other
KIR genes and are the subject of a recent review [12].
The central region of the KIR locus between 3DP1
and 2DL4 is a major site of reciprocal combination.
This mechanism has re-assorted centromeric and telomeric gene-content motifs to form recombinant
haplotypes that combine an A haplotype centromeric
motif with a B haplotype telomeric motif, and vice
Phil. Trans. R. Soc. B (2012)
versa [23,77]. The convention has been to describe
all such recombinant haplotypes as B haplotypes,
reserving the A haplotype designation for haplotypes
that have both a centromeric and a telomeric A
motif. In disease-association studies, the effects of
the B motifs appear dominant as is consistent with
them having loss of function [78].
6. MAJOR DIFFERENCES IN HUMAN
AND CHIMPANZEE KILLER CELL
IMMUNOGLOBULIN-LIKE RECEPTORS
Comparing the KIR locus in different species of simian
primate shows an extraordinary degree of species specificity that attests to the rapid and variable evolution of
KIR (figure 2). Phylogenetic analysis of the nucleotide
sequences encoding simian primate KIR shows they
form four discrete lineages that have coevolved with
their target epitopes [21]. Presence in Old World monkeys
of multiple HLA-A- and -B-like loci is associated with an
expansion of lineage II KIR related to the human lineage
II KIR3DL1 and 3DL2 that recognize the Bw4 and A3/
11 epitopes, respectively. Likewise, the emergence of an
HLA-C orthologue in orangutans is associated with
expansion of lineage III KIR related to the human lineage
III KIR2DL1, 2DS1 and 2DL2/3 that recognize HLA-C.
As the chimpanzee is the living species most closely related
to humans, we have extensively studied the function and
population biology of chimpanzee KIR, so as to provide
a valid assessment of what features of the human system
are shared with other species and what features are
unique (figure 7).
Although both humans and chimpanzees have 13 KIR
genes, only 3DL3, 2DL4, 2DL5 and 2DS4 are orthologous [30]. The framework of the KIR locus in the two
species is similar but the distribution of genes within
this framework is qualitatively different (figure 8)
[24,79]. Whereas the variable gene content in the
human KIR locus is evenly distributed between the centromeric and telomeric regions, all 10 chimpanzee KIR
genes that contribute to variable gene content are
packed together in the centromeric region. This leaves
the telomeric region empty except for the 3DL1/2 lineage
II framework gene which encodes a receptor having a
specificity for MHC-A and MHC-B that combines
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806
P. Parham et al.
Review. Coevolution of KIR and HLA class I
KIR
divergence time
from human
(million years)
prosimians
one pseudogene
58–69
New World monkeys
expansion of a
novel lineage
40–45
expansion of
lineage II
28–30
contraction of
KIR locus
19–24
first expansion
of lineage III
14–18
MHC class I isotype
primate species
E
G
Old World monkeys
A
B
C
Bw6
inactive
Bw4
Bw6
gibbons
Bw4
C1
Bw6
orangutans
Bw4
Bw6
gorillas
(C1)
C2
Bw4
C1
Bw6
chimpanzees
C2
Bw4
C1
Bw6
humans
cognate receptor
in human
CD94:
NKG2
lineage I
KIR
lineage II
KIR
further
expansion of
lineage III
Bw4
C2
lineage II
and III KIR
lineage III
KIR
10–12
7–10
elaboration of
group A and B
haplotypes
Figure 7. Coevolution of KIR with cognate MHC class I ligands. In the columns corresponding to E, A, B, C and G, coloured
boxes indicate the presence in other primate species of one or more counterparts to the corresponding human HLA class I
isotype. The cognate NK-cell receptor for each HLA class I is shown at the bottom of the column. In the column under
‘KIR’, characteristic features of the KIR in each non-human primate species are given. Bw4 /Bw6 and C1/C2 are pairs of
mutually exclusive epitopes at HLA-B and HLA-C, respectively.
chimpanzee
FCAR
LILR
C1
3DL3
C2
C1
3DL1/2
2DL4
C2
C2
C2
C1
C2
3DS2 2DL9
2DS2
C1
C1
3DS6 2DL6
2DL5 2DL8
2DL2
2DL5B 2DS3/5
C2
C2
C2
3DL5 3DL4
2DS4 2DL7
3DS1 2DL5A 2DS3/ 5 2DS1
C2
C1
3DL3
3DL2
3DP1 2DL4
FCAR
LILR
C1
2DL3
C2
2DP1
2DL1
human
3DL1
2DS4
Figure 8. Variation in the chimpanzee KIR locus is restricted to the centromeric interval. This diagram compares the
organization and gene-content variability of the chimpanzee and human KIR loci. The branching pathways represent different
gene-content motifs and they are combined to produce different KIR haplotypes. Framework genes are coloured grey; chimpanzee-specific lineage III KIR specific for the C1 and C2 epitopes of HLA-C, green; genes characteristic of human A
haplotype, red; genes characteristic of human B haplotypes, blue; 2DP1 and 2DL1 in humans have been coloured grey indicating their presence both on A and B haplotypes. Adapted from Abi-Rached et al. [79]. C1 or C2 in a gene box denotes the
receptor’s epitope specificity.
elements of the Bw4 and A3/11 specificities of human
lineage II KIR3DL1 and 3DL2, respectively [80]. All
nine of the chimpanzee lineage III bind HLA class I, compared with only three of six human lineage III [58,69]. In
addition to an orthologue of human 2DS4, the
Phil. Trans. R. Soc. B (2012)
chimpanzee has a battery of three C1-specific KIRs
(one activating and two inhibitory) and five C2-specific
KIRs (one activating and four inhibitory) that vary in
both signalling and ligand-binding domains, and display
more allelic variability than their human counterparts
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Review. Coevolution of KIR and HLA class I
P. Parham et al. 807
0.7
(a)
(b)
HLA-C2 frequency
0.6
0.5
0.4
0.3
0.2
0.1
n = 58, b = –1.3, r2 = 0.6116, p < 0.0001
0
0.3
0.4
0.5
0.6
0.7
KIR A haplotype frequency
0.8
African east southeast
Asian
Asian
southwest Oceanian South
Hispanic European
Asian
Amerindian
Figure 9. Worldwide inverse correlation in human populations between the frequencies of the C2 epitope of HLA-C and the
group A KIR haplotype. (a) Compares the frequencies of HLA-C2 and the KIR A haplotype for 58 populations. (b) How the
HLA-C2 and KIR A frequencies vary with the geographical origin of populations. (a, b) The populations are colour coded by
geographical region. Frequency data for HLA-C2 and KIR A haplotypes were obtained from http://www.allelefrequencies.net
(accessed 20 July 2010). KIR A haplotype frequency was calculated from the KIR A/A genotype frequency assuming the
Hardy– Weinberg equilibrium in the population. Regression analysis was performed using SAS v. 9.2 and the result is
shown in (a).
[79]. Importantly, however, the chimpanzee KIR haplotypes do not divide into two groups as is the case for the
human KIR haplotypes.
7. AN EVOLUTIONARY COMPROMISE FOR
HUMAN KILLER CELL IMMUNOGLOBULIN-LIKE
RECEPTORS THAT WAS NOT MADE
BY CHIMPANZEE KILLER CELL
IMMUNOGLOBULIN-LIKE RECEPTORS
In the context of hominoid evolution, during which
HLA-C evolved specifically as a KIR ligand and the
C1 epitope preceded the C2 epitope by several million
years, the chimpanzee KIR locus has taken this
progression to a higher level than the human KIR
locus. The majority of chimpanzee KIRs are HLA-C
receptors and the C2-specific receptors outweigh the
C1-specific receptors in number. In contrast, the
human system represents a less robust or compromised system in which the group A KIR haplotypes
are more similar to the chimpanzee KIR haplotypes,
whereas the group B KIR haplotypes have accumulated genes encoding KIRs with reduced or no
binding to HLA class I.
Common disorders of reproduction, such as preeclampsia, spontaneous abortion and foetal growth
restriction, have been associated with pregnancies in
which the mother is homozygous for group A KIR
haplotypes and the foetus has HLA-C bearing the
C2 epitope [81,82]. This combination implicates
interactions between foetal C2 and maternal inhibitory
C2-specific KIR2DL1 in the disease-causing mechanism. Consistent with this model, activating C2-specific
KIR2DS1 is a protective factor on maternal B KIR
haplotypes [83]. Indicating that these pregnancy
disorders have been a major selective force on
human populations is the observed inverse correlation
Phil. Trans. R. Soc. B (2012)
between the frequencies of C2 bearing HLA-C and
group A KIR haplotypes (figure 9). This correlation
strongly argues that pressure from human reproduction drove the evolution of the group B KIR
haplotypes.
The common disorders of pregnancy are associated
with insufficient invasion of the uterus by foetal extravillous trophoblast cells, which enlarge maternal blood
vessels called spiral arteries so that they will be
capable of supplying the growing baby with sufficient
nutrition [3]. This remodelling function of the trophoblast appears to be guided through physical and
chemical interactions with specialized uterine NK
cells of the mother, which have phenotypic and functional properties that are different from those of the
majority of blood NK cells [84]. Extra-villous trophoblast uniquely expresses an abundance of HLA-C
but not HLA-A and -B [85]. Thus, the underlying disease-causing mechanism probably involves interaction
between C2-bearing HLA-C on the foetal trophoblast
and KIR2DL1 on the maternal uterine NK cells. That
this type of interaction has been attenuated in humans,
by evolution of the group B KIR haplotypes, but not
in chimpanzees indicates a selective pressure that
demanded an ever-increasing supply of maternal
blood to feed the foetus. An important difference
that distinguishes human and chimpanzee evolution,
since they last shared a common ancestor more
than 6 Myr ago, is that the adult human brain is now
more than three times the size of an adult chimpanzee
brain [86]. The evolution of ever-bigger brains would
have been energetically expensive, necessitating continual improvement of the supply of maternal blood
to the placenta. This improvement seems to have
been accomplished by the evolution of the KIR B haplotypes that have an activating C2-specific KIR that
counters the effect of inhibitory KIR2DL1, and a
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808
P. Parham et al.
Review. Coevolution of KIR and HLA class I
series of inhibitory KIRs, including allotypes of
KIR2DL1 [76], that have been selected for attenuation or loss of function [23].
NK cells have been strongly implicated in providing
immunity against viral infections [87]. For example, a
person lacking NK cells was susceptible to fulminating
herpes virus infection and eventually died of disease
caused by EBV [88]. Relatively few studies have been
performed to correlate the progress of viral infection
with KIR and HLA type [89,90], but the evidence as
it stands indicates that the group A KIR haplotype,
and by implication all chimpanzee KIR haplotypes,
evolved to mount defence against infection. The
human immune system appears to have made a compromise between KIRs that are beneficial for fighting
infection and those that facilitate reproduction, an evolutionary compromise that the chimpanzee has not had
to make. This difference may in part explain why chimpanzees are relatively resistant to a variety of infections
that plague the modern human population [91].
This work was supported by NIH grants nos. AI17892 and
AI22039 to P.P.
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