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Humans Differ from Other Hominids in
Lacking an Activating NK Cell Receptor
That Recognizes the C1 Epitope of MHC
Class I
Achim K. Moesta, Thorsten Graef, Laurent Abi-Rached,
Anastazia M. Older Aguilar, Lisbeth A. Guethlein and Peter
Parham
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J Immunol 2010; 185:4233-4237; Prepublished online 27
August 2010;
doi: 10.4049/jimmunol.1001951
http://www.jimmunol.org/content/185/7/4233
The Journal of Immunology
Humans Differ from Other Hominids in Lacking an
Activating NK Cell Receptor That Recognizes the C1 Epitope
of MHC Class I
Achim K. Moesta, Thorsten Graef, Laurent Abi-Rached, Anastazia M. Older Aguilar,
Lisbeth A. Guethlein, and Peter Parham
T
he killer cell Ig-like receptors (KIR) are a family of
diverse immunoreceptors that modulate NK cell function
through recognition of MHC class I (1). In higher primates
the role of KIR is analogous to that of rodent Ly49 receptors (2, 3).
Of four human KIR lineages, lineages II and III include the KIR
specific for polymorphic HLA-A, HLA-B, and HLA-C. Dominant
are the C1 and C2 epitopes borne by HLA-C and recognized by
lineage III KIR; the most numerous lineage comprising two genes
encoding inhibitory C1 (KIR2DL2/3) and C2 (KIR2DL1) receptors
and five genes encoding activating receptors (KIR2DS1, 2, 3, 4, and
5). Although the importance of inhibitory KIR for NK cell biology is
well established, the contributions of the activating KIR remain
poorly understood. Pointing to their relevance are correlations with
a variety of clinical conditions (4).
The five activating lineage III KIR comprise three groups.
One group consists of KIR2DS1 and KIR2DS2, which have similar extracellular domains to inhibitory KIR2DL1 and KIR2DL2/3,
respectively. Consistent with this relationship, KIR2DS1 recognizes
Department of Structural Biology and Department of Microbiology and Immunology,
School of Medicine, Stanford University, Stanford, CA 94305
Received for publication June 11, 2010. Accepted for publication July 12, 2010.
This work was supported in part by National Institutes of Health Grant AI022039 (to
P.P.), a Ruth L. Kirschstein National Research Service Award from the National
Institutes of Health (to A.M.O.A.), and a National Science Foundation Graduate
Fellowship (to A.K.M.).
Address correspondence and reprint requests to Dr. Peter Parham, Department of
Structural Biology, Stanford University, Fairchild D-159, 299 Campus Drive West,
Stanford, CA 94305. E-mail address: [email protected]
The online version of this article contains supplemental material.
Abbreviation used in this paper: KIR, killer cell Ig-like receptor.
Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1001951
C2 but has lower avidity than does KIR2DL1 due to replacement
of Thr70 with lysine (5–7). Despite this attenuation, KIR2DS1 influences NK cell education and response in a C2-dependent manner (8, 9). In contrast, KIR2DS2 has no demonstrable interaction
with C1+ HLA-C, an abrogation due to replacement of Phe45 with
tyrosine (10, 11). Because activating KIR were derived from
their paired inhibitory receptors by recombination, the subsequent acquisition of substitutions that reduce ligand binding
was likely a consequence of natural selection (12).
The C1 and C2 specificities of KIR2DL2/3 and KIR2DL1 are
determined by lysine and methionine at position 44, respectively
(13). The second group of activating lineage III KIR, formed by
KIR2DS3 and KIR2DS5, has threonine at position 44. These divergent KIR are not paired with inhibitory receptors, but they are
similar to each other. Distinguishing KIR2DS3 is its absence from
the NK cell surface and retention inside the cell (14). KIR2DS5
reaches the NK cell surface and transduces activating signals when
cross-linked with anti-KIR Ab, but a physiological ligand has yet
to be identified (15). KIR2DS4, the most divergent lineage III KIR,
forms the third group. This activating receptor binds HLA-A11 and
subsets of C1+ and C2+ HLA-C with moderate avidity, and it can
activate NKL cells on engagement of HLA-A11 (16).
MHC-C mediated regulation of NK cells evolved in hominids
(humans and great apes), with C1-mediated regulation arising several
million years before C2-mediated regulation. In modern human
populations both activating and inhibitory C2 receptors are functional, whereas natural selection has reduced C1-mediated regulation
to the inhibitory receptor. To see if this asymmetry in NK cell regulation by C1 and C2 is human-specific, or a more general phenomenon, we studied activating lineage III KIR in the most closely
related hominid species: chimpanzee and gorilla (17, 18).
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Modulation of human NK cell function by killer cell Ig-like receptors (KIR) and MHC class I is dominated by the bipartite
interactions of inhibitory lineage III KIR with the C1 and C2 epitopes of HLA-C. In comparison, the ligand specificities and
functional contributions of the activating lineage III KIR remain poorly understood. Using a robust, sensitive assay of KIR
binding and a representative panel of 95 HLA class I targets, we show that KIR2DS1 binds C2 with ∼50% the avidity of
KIR2DL1, whereas KIR2DS2, KIR2DS3, and KIR2DS5 have no detectable avidity for C1, C2, or any other HLA class I
epitope. In contrast, the chimpanzee has activating C1- and C2-specific lineage III KIR with strong avidity, comparable to
those of their paired inhibitory receptors. One variant of chimpanzee Pt–KIR3DS2, the activating C2-specific receptor, has
the same avidity for C2 as does inhibitory Pt–KIR3DL4, and a second variant has ∼73% the avidity. Chimpanzee Pt–
KIR3DS6, the activating C1-specific receptor, has avidity for C1 that is ∼70% that of inhibitory Pt–KIR2DL6. In both
humans and chimpanzees we observe an evolutionary trend toward reducing the avidity of the activating C1- and C2-specific
receptors through selective acquisition of attenuating substitutions. However, the extent of attenuation has been extreme in
humans, as exemplified by KIR2DS2, an activating C1-specific receptor that has lost all detectable avidity for HLA class I.
Supporting such elimination of activating C1-specific receptors as a uniquely human phenomenon is the presence of a highavidity activating C1-specific receptor (Gg–KIR2DSa) in gorilla. The Journal of Immunology, 2010, 185: 4233–4237.
4234
HUMAN-SPECIFIC EVOLUTION OF ACTIVATING MHC-C–SPECIFIC KIR
Materials and Methods
Single-Ag bead analysis of KIR–Fc specificity
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KIR–Fc fusion proteins were made, assessed for conformational integrity, and
assayed for binding to LABScreen single-Ag bead sets (One Lambda, Canoga
Park, CA) as described (16, 19, 20). Binding of W6/32 Ab was used as
a positive control and to normalize for bead-to-bead variation in the amount
of HLA class I displayed. Each KIR–Fc protein was assayed a minimum
of three times in independent experiments for binding to 95 HLA class I
allotypes.
The HLA class I proteins used to coat the beads were isolated from a panel
of transfected cell lines, each made from the class I-deficient B cell line 221
and expressing a different HLA class I allele (21). Consequently, the target
HLA class I molecules carry a repertoire of bound peptides that is representative of those presented by HLA on the surface of the human B cell lines
commonly used as NK cell targets. The bead sets were initially developed
for high-resolution analysis of the HLA class I specificity of mAbs and
human alloantisera (21). The 95 HLA class I allotypes present in the bead
sets were chosen to represent the variation in structure and serology as well
as the common variants of HLA-A, HLA-B, and HLA-C. It is well established that there is a good correlation between the results obtained with direct
binding to single-Ag beads and those obtained with conventional serology
using the complement-dependent cytotoxicity of human lymphocytes and
with direct Ab binding to cells (22). Such correlations strongly indicate that
the representation of complexes of class I HLA and peptide by the beads is
comparable to that of normal human cells.
transfectants of the 221 HLA class I-deficient B cell line and have
a heterogeneity of bound peptides that is comparable to that of
normal human cells. The advantage of this assay is that it allows KIR
specificity and avidity to be defined with much greater precision and
confidence than was previously possible (16). Consequently, it was
Cytotoxicity assays
Killing of 221 target cells (expressing a single HLA class I variant) by NKL
effector cells (expressing a single KIR) was assayed as described (19, 20).
Inhibitory versions of short-tailed receptors were constructed by fusing exons
encoding their extracellular domains with exons encoding the transmembrane
and cytoplasmic portions of their related inhibitory receptors. Redirected
cytotoxicity assays using mouse P815 target cells were performed as described
(16) with Ab preincubation for 30 min. mAbs specific for KIR (NKVFS1),
NKG2D, and 2B4 (CD244) (BD Biosciences, San Jose, CA) were included,
singly and in combination, at 10 mg/ml final concentration for each Ab.
Untransfected 221 target cells and untransduced NKL cells were controls.
Assays were replicated three or more times and included triplicates for each
condition.
Results
Exploration of KIR specificity and avidity for HLA class I has been
previously carried out using small numbers of target HLA class I
variants (7, 10, 13). Recently, we developed a new sensitive and
quantitative assay that measures the binding of KIR–Fc fusion proteins to beads coated with a representative set of 95 HLA class I
variants (20). The target HLA class I molecules are purified from
FIGURE 1. Binding of human activating lineage III KIR to C2+ HLA-C
and to C1+ HLA-B and HLA-C. C2 binding is normalized to that of inhibitory KIR2DL1; C1 binding is normalized to that of inhibitory KIR2DL3.
FIGURE 2. Binding of chimpanzee and gorilla activating lineage III
KIR to C1 and C2. A and B, Binding of chimpanzee KIR with C1 and C2
specificity, respectively. Data are normalized as described in the legend to
Fig. 1. C, Comparison of the binding of gorilla Gg–KIR2DSa and human
KIR2DL3 to HLA-A, HLA-B, and HLA-C allotypes.
The Journal of Immunology
essential to reevaluate the HLA class I specificities of the human
activating lineage III KIR before comparing them to their chimpanzee counterparts.
KIR2DS1 is C2-specific, but 2DS2, 2DS3, and 2DS5 have little
or no avidity for HLA class I
Activating chimpanzee lineage III KIR exhibit high avidity for
C1 or C2
Chimpanzee Pt–KIR3DS6 and Pt–KIR3DS2 Fc-fusion proteins were
analyzed for binding to the 95 HLA class I variants and compared
with the closely related inhibitory receptors Pt–KIR2DL6v and Pt–
KIR3DL4, respectively. Activating Pt–KIR3DS6 and inhibitory Pt–
KIR2DL6v both showed a specificity similar to human KIR2DL3 for
the C1 epitope carried by eight HLA-C and two HLA-B allotypes,
consistent with all three KIR having Lys44. Except C*1601, for
which the binding was comparable, activating Pt–KIR3DS6 bound
less strongly to the C1 epitopes (∼70%) than did inhibitory Pt–
KIR2DL6v (Fig. 2A). This reduced avidity must arise from the single
amino acid difference in their ligand-binding domains, replacement
of Leu83 for valine in Pt–KIR3DS6; of note, a second allotype of the
inhibitory receptor, Pt–KIR2DL6, has Leu83 like Pt–KIR3DS6, but
differs at position 68 (Supplemental Fig. 1). In comparison with its
human counterpart, KIR2DS2, chimpanzee Pt–KIR3DS6 is seen to
be a strong C1 receptor. Pt–KIR3DS6 and Pt–KIR2DL6 are adjacent
genes in the chimpanzee KIR locus (Fig. 3). This arrangement is
similar to that of human KIR2DS2 with KIR2DL2, with the latter
being allelic to KIR2DL3 and also encoding an inhibitory C1specific receptor.
Similar comparison of activating Pt–KIR3DS2 and inhibitory Pt–
KIR3DL4 showed that they both bound strongly to C2+ HLA-C
allotypes and to no other HLA class I (Fig. 2B), with their C2
specificity being consistent with presence of Met44 in both KIR. In
addition to identical specificity, Pt–KIR3DS2 and Pt–KIR3DL4
bound individual C2+ allotypes with equivalent avidity. Thus, the
single difference in their ligand-binding domains, at position 51
(Supplemental Fig. 1), was not selected to reduce the activating
receptor’s avidity for ligand. The Pt–KIR3DS2v allotype differs from
Pt–KIR3DS2 by two substitutions in D1 and four in D2 (Supplemental Fig. 1). The Pt–KIR3DS2v fusion protein has the same
C2 specificity as Pt–KIR3DS2, but its avidity for each of the C2+
HLA-C allotypes was reduced to ∼73% that of Pt–KIR3DS2. Thus,
KIR3DS2v is likely to be a product of natural selection for reduced
receptor avidity. Although Pt–KIR3DS2 and Pt–KIR3DL4 are paired
high-avidity C2 receptors, their genes are separated by up to six
other KIR genes and they lack linkage disequilibrium (Fig. 3). This
arrangement resembles that of the human KIR2DL1 and KIR2DS1
genes, present in different halves of the human KIR locus and separated by a comparable number of other KIR genes. Pt–KIR3DS2
is now adjacent and in linkage disequilibrium with Pt–KIR2DL9
(Fig. 3), a divergent form of inhibitory C2 receptor with Glu44 and
differing from Pt–KIR3DS2 by 29 aa substitutions in the Ig-like
domains.
In conclusion, the chimpanzee has pairs of activating and inhibitory receptors that recognize C1 and C2. One variant of the
activating C2 receptor has the same strong avidity as does the inhibitory receptor, while a second variant is ∼27% less avid. To
a similar extent the activating C1 receptor is less avid than its inhibitory counterpart. This trend, in which natural selection acts to
weaken the activating receptor relative to the inhibitory receptors,
has been observed for other paired immunoreceptors (23).
Gorilla Gg–KIR2DSa is an activating receptor with high
avidity for C1
Of six gorilla lineage III KIR, Gg–KIR2DSa with Lys44 is the only
activating KIR and a candidate C1 receptor (18). As seen in Fig. 2C, the
Gg–KIR2DSa fusion protein binds only to C1+ HLA-B and HLA-C
allotypes, and it thus has C1 specificity similar to KIR2DL3, Pt–
KIR2DL6, and Pt–KIR3DS6. However, Gg–KIR2DSa and KIR2DL3
exhibit significant avidity differences for individual C1+ allotypes,
with the extreme cases being HLA-C*1203, which binds weakly to
KIR2DL3 but strongly to Gg–KIR2DSa, and HLA-C*0102, which
binds weakly to Gg–KIR2DSa but strongly to KIR2DL3. In our
hands, Gg–KIR2DSa is the only KIR that binds well to HLAC*1203. This unique reactivity correlates with Ala73 in HLA-C
(present only in C*12 and the structurally divergent C*07) and
Arg71 in Gg–KIR2DSa, a unique residue at a position that influences
KIR specificity (16). On average, the binding of Gg–KIR2DSa
to C1+ allotypes was about half that of KIR2DL3. However, in
comparison with human KIR2DS2 (Fig. 1), Gg–KIR2DSa is an
activating receptor with high avidity for C1.
Pt–KIR3DS2 and Pt–KIR3DS6 recognize MHC-C to
control NK cell function
To assess the functional influence of interactions between MHC
class I and activating chimpanzee KIR, the ligand-binding domains
of Pt–KIR3DS2 and Pt–KIR3DS6 were grafted onto the signaling
FIGURE 3. The genomic organization of the chimpanzee and human KIR loci. Shown are composite haplotypes containing all known KIR genes. Inhibitory
and activating lineage III genes are colored red and blue, respectively. Conserved framework genes are colored green; other genes and the 2DP1 pseudogene are
white. Double-headed arrows connect the paired receptors. †Denotes that KIR2DS2 has lost all detectable avidity for C1.
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KIR2DS1, 2DS2, 2DS3, and 2DS5 Fc-fusion proteins were tested for
binding to 29 HLA-A, 50 HLA-B, and 16 HLA-C allotypes and
compared to the high-avidity inhibitory receptors, C1-specific
KIR2DL3 and C2-specific KIR2DL1 (Fig. 1). Of the four activating
receptors, only 2DS1 gave strong reactions. It bound the seven C2+
HLA-C allotypes at 20–65% the KIR2DL1 level. In contrast, 2DS2,
2DS3, and 2DS5 gave very weak reactions with no general preference for C1+ or C2+ allotypes. Weak binding of the four KIR2DS Fcfusion proteins to HLA-C*1203 is not significant because the normalizing KIR2DL3 control also binds this allotype poorly (20).
KIR2DS2–Fc selectively bound to HLA-C*1601, albeit weakly,
suggesting that this reaction is specific. No reactions with HLA-A
and HLA-B were observed. We observe that KIR2DS1 has significant avidity for the range of C2+ HLA-C, whereas 2DS2, 2DS3,
and 2DS5 have little or no detectable avidity for any HLA class I.
These results affirm and extend the observations from previous analyses of limited numbers of HLA class I variants (7, 10, 13).
4235
4236
HUMAN-SPECIFIC EVOLUTION OF ACTIVATING MHC-C–SPECIFIC KIR
domains of their paired inhibitory receptors Pt–KIR3DL4 and Pt–
KIR2DL6v, respectively. NKL cells expressing these chimeric KIR
were tested for their capacity to kill class I-deficient 221 cells and 221
transfectants expressing C1+ or C2+ chimpanzee MHC class I allotypes. Comparison was made with NKL cells expressing the natural
inhibitory receptors Pt–KIR3DL4 and Pt–2DL6v (Fig. 4).
The killing of 221 target cells by NKL cells transfected with
chimeric Pt–KIR3DS2 was inhibited by the presence of C2+ MHC-C
at the target cell surface (Fig. 4A, left panel) but not by the presence
of C1+ MHC-C (Fig. 4A, right panel). This pattern of C2-mediated
inhibition mimics that of NKL cells expressing Pt–KIR3DL4. Conversely, killing of 221 target cells by NKL cells expressing chimeric
Pt–KIR3DS6 was inhibited by the presence of C1 on the target cell
surface but not C2 (Fig. 4A, right panel). These results show that the
extracellular domains of Pt–KIR3DS6 and Pt–KIR3DS2 are binding
sites for cell surface-associated MHC-C ligands that can signal an
inhibitory NK cell response; they also imply that natural Pt–KIR3DS2
and Pt–KIR3DS6 can engage their cognate ligands on target cells and
generate an activating signal in chimpanzee NK cells.
Pt–KIR3DS2 was expressed in NKL cells and tested for its potential to induce killing in a redirected cytotoxicity assay using
P815 target cells and monoclonal anti-KIR Ab (NKVFS1). NKL
cells expressing Pt–KIR3DS2 killed P815 target cells in the
presence of anti-KIR Ab (Fig. 4B, upper left panel) but not in its
absence (Fig. 4B, upper right panel). The extent of activation was
comparable to that induced by the combination of anti-NKG2D
and anti-2B4 Abs (Fig. 4B, lower left panel). In contrast, parental
NKL cells or NKL cells expressing inhibitory Pt–KIR3DL4 were
not induced to kill P815 cells in the presence of anti-KIR Ab.
Also, the combination of all three Abs did not significantly increase cytotoxicity over that seen with anti-KIR alone, and was
only slightly higher than that observed for parental NKL cells,
suggesting that anti-KIR is sufficient to induce maximal killing in
this assay (Fig. 4B, lower right panel). Conversely, for NKL cells
expressing Pt–KIR3DL4, the inhibitory signals induced by antiKIR antagonized the activating effects of Ab-mediated crosslinking of NKG2D and 2B4.
Discussion
Our study definitively shows that no human activating KIR is a C1
receptor, whereas KIR2DS1 recognizes C2 with reduced avidity
(∼50%) compared with inhibitory KIR2DL1. The corresponding
chimpanzee receptor (Pt–KIR3DS2) has two variants, one as strong
as its paired inhibitory C2-specific receptor (Pt–KIR3DL4) and the
other with reduced affinity (73%), as for KIR2DS1. Whereas human KIR2DS2 has no detectable avidity for C1, its chimpanzee
counterpart (Pt–KIR3DS6) binds C1 with ∼70% of the avidity of its
paired inhibitory receptor (Pt–KIR2DL6). In both human and
chimpanzee the trend is for activating receptors to have reduced
avidity relative to the inhibitory receptors. However, only for the
human activating C1 receptor has this reached the extreme where
the function appears lost. As for chimpanzee, gorilla has a strong
activating C1 receptor, whereas orangutan has paired activating and
inhibitory receptors with identical, strong avidities for C1 (24).
Thus, human appears unique among hominid species in having no
functional C1-specific activating receptor. A weak reactivity with
HLA-C*1601 shows that KIR2DS2 has a narrowed specificity for
HLA-C, raising the possibility that it is also highly dependent on
the peptide bound by MHC-C. Thus, we cannot rule out the possibility that KIR2DS2 functions in the presence of peptides presented by HLA-C in infected or malignant cells but not B cell lines.
FIGURE 4. Functional analysis of chimpanzee activating KIR. A, Results
of cytotoxic assays in which the target cells are 221 cells expressing either C1+
or C2+ MHC class I, and the effector cells are NKL cells expressing inhibitory
chimpanzee KIR or chimeric proteins carrying the D0, D1, and D2 domains of
activating KIR with the transmembrane and cytoplasmic domains of the
paired inhibitory receptor. Shown is the capacity of the C2 (left) and C1 (right)
epitopes to engage the chimeric receptors and prevent NKL cell-mediated
lysis of 221 target cells. B, Results of cytotoxic assays in which the target cells
are P815 cells and the effector cells are NKL cells and NKL cells transduced
with activating Pt–KIR3DS2 or inhibitory Pt–KIR3DL4 that react with the
anti-KIR Ab, NKVSF1. Assays were carried out in the presence or absence of
mAbs directed against KIR, NKG2D, and 2B4.
The C1 epitope and its cognate KIR arose several million years
before C2 and C2-specific KIR, an ancestral state retained in the
modern orangutan (25). That chimpanzee retains strong activating C1and C2-specific receptors shows that loss of activating C1 receptor is
a product of human-specific evolution. A key feature of KIR2DS2 is
the almost total linkage disequilibrium with KIR2DL2, a divergent
allele of the KIR2DL2/3 gene having higher avidity for C1 than
KIR2DL3 (20). Thus, the inactivation of the activating C1 receptor is
associated with increased avidity of the inhibitory C1 receptor. Studies
showing that KIR2DS1 counterbalances KIR2DL1 in NK cell development and function (8) suggest that elimination of the equivalent
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Pt–KIR3DS2 activates NKL cells in a redirected cytotoxicity
assay
The Journal of Immunology
KIR2DL2/3 counterbalance could have an effect on NK cell education
in C1-expressing individuals that increases the frequency and potency
of NK cells expressing KIR2DL2.
KIR2DS2 and KIR2DL2 are characteristic centromeric genes of
the group B KIR haplotypes that are substituted by KIR2DL3 on
group A haplotypes. Differences between the group A and B KIR
haplotypes correlate with a wide range of clinical conditions. For
example, the beneficial effect of donor B haplotypes in unrelated
HLA-matched bone marrow transplantation for acute myelogenous
leukemia (26) is principally due to the presence of centromeric motifs
containing KIR2DS2 and KIR2DL2 (27). A further feature of these
centromeric B haplotype motifs are variants of KIR2DL, such as
KIR2DL1*004, which are reduced in their capacity to educate
KIR2DL1-expressing NK cells in C2-bearing individuals (28). Such
linkage disequilibrium points to a process of coevolution that has
modified the functions of both the C1 and C2 receptors encoded on the
B haplotypes. This process also appears to be human-specific because
in no other primate species examined do the KIR haplotypes divide
into two functionally distinctive groups analogous to human A and B.
The authors have no financial conflicts of interest.
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Disclosures
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