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Lautenberg Center for General and Tumor Immunobiology, Hadassah Medical School, Jerusalem, Israel
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14 is shown to be
important in the KIR2DS4 binding to HLA-Cw4. Implications of the role
of the activating NK receptors in immunosurveillance are
discussed. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recognition of polymorphic determinants on HLA molecules by human NK cell-inhibitory receptors is mediated by three types of class I MHC-binding receptors (reviewed in Ref. 4). The Ig-like transcript 2 receptor, a member of the Ig-like transcript family of receptors (5), is able to bind to distinct class I MHC protein and to deliver an inhibitory signal (6). The C-type lectin complex CD94/NKG2A can deliver an inhibitory signal on binding to HLA-E (7, 8). Finally, members of the Ig superfamily of receptors, in particular the 58-kDa and 70-kDa NK-inhibitory receptors, containing two and three domains, respectively, can inhibit NK cell cytotoxicity when binding to the appropriate class I MHC molecules (9, 10, 11). In contrast, related 50-kDa receptors associated with DAP12 (12) augment NK cell cytotoxicity (13) and T cell proliferation (14). However, the class I MHC molecules recognized by many of these activating NK receptors and functions of activating NK receptors are currently poorly defined. Due to the possible expression of a multitude of NK receptors on any given NK cell, it is difficult to define the class I MHC-binding specificity of any given NK receptor using cellular assays with peripheral NK cells. One example of such difficulty is the analysis of the binding of killer cell Ig-like receptor two-domain short tail number 4 (KIR2DS4,3 also known as CL 39 or NKAT8) to class I MHC molecules. The expression of KIR2DS4, as well as other NK receptors, was reported on a CD4+ T cell clone (14). Enhanced proliferation was observed when this T cell clone (named TANK-1) was incubated with superantigen-coated 721.221 cells expressing Cw4 or Cw7 class I MHC proteins, but not with Cw3 or Cw6 (14). In contrast, KIR2DS4 has been postulated to interact with HLA-Cw3 (15), but again, this suggestion was based on cellular assays using NK cells expressing many NK receptors.
Here, we show binding of the KIR2DS4-Ig to HLA-Cw4, but not to HLA-Cw6, although both alleles belong to the same allotype-specific group characterized by the presence of K80 (16). We demonstrate that the W residue at position 14 of HLA-Cw4 is important in the binding of KIR2DS4 to HLA-Cw4. The binding of KIR2DS4-Ig to HLA-Cw4 was weak compared with the killer cell Ig-like receptor two-domain long tail number 1 (KIR2DL1)-Ig binding to the same HLA-C molecules. However, it was still functionally significant in that it was sufficient to inhibit the lysis of Cw4-expressing target cells by YTS cells (an NK tumor line) expressing the chimeric protein of KIR2DS4 fused to the transmembrane and cytoplasmic tail portion of KIR2DL1 (YTS/KIR2DS4*) and to cause enhancement of lysis by NK cells expressing KIR2DS4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cell lines used in this work are the class I MHC-negative human cell line 721.221 (17) and the YTS NK tumor line (a kind gift from Dr. Eshhar, The Weizmann Institute, Rehovot, Israel). Point mutation in HLA-Cw4 and HLA-Cw6 cDNA was performed by PCR. Transfection of 721.221 cells with the cDNA of various class I MHC molecules (wild-type and mutants) was performed as previously described (16). NK cells (lines and clones) were isolated from PBL using the human NK cell isolation kit and the autoMACS instrument (Miltenyi Biotec, Auburn, CA). NK cells were grown in culture as previously described (16).
mAb used in this work were mAb W632, G46-2.6, and HP1F7 directed against class I MHC molecules. mAb HP3E4 (18) and EB6 (Immunotech, Westbrook, ME) are both directed against KIR2DL1R. The HP3E4 and HP1F7 mAb were a kind gift from M. Lopez-Botet (Hospital de la Princesa, Madrid, Spain). The anti-CD99 mAb 12E7, used as a control, was a kind gift from A. Bernard (Hôpital de L’Archet, Nice, France).
Cytotoxic assays
The cytotoxic activity of YTS cells and NK cells against the various targets was assessed in 5-h 35S release assays as described previously (16). In experiments where mAb were included, the final mAb concentration was 10 µg/ml, or 1/2 dilution in cases where the mAb were used as tissue culture supernatants. In all presented cytotoxic assays, the spontaneous release was <15% of maximal release.
Ig fusion proteins
The generation of KIR2DL1-Ig and CD99-Ig fusion proteins was previously described (19). The sequence encoding the extracellular portion of KIR2DS4 protein was amplified by PCR from cDNA isolated from human NK clones. The KIR2DS4 specific primers were: 5'-primer (including HindIII site and Kozak sequence), 5'-CCCAAGCTTGGGGCCGCCACCATGTCGCTCATGGTCATCATC-3'; 3'-primer, (including BamHI site), 5'-CGGGATCCAGAACATGTAGGTGTCTGGG-3'. These PCR-generated fragments were cloned into the mammalian expression vector containing the Fc portion of human IgG1 as previously described (19). Sequencing of the constructs revealed that cDNA of all Ig fusion proteins were in frame with the human Fc genomic DNA and were identical with the reported sequences. The production of CD99-Ig, KIR2DL1-Ig, and KIR2DS4-Ig fusion proteins and the FACS staining procedure were previously described (19). All Ig fusion proteins used in this work run as a single protein band on nonreduced SDS-PAGE. The Ig fusion proteins were routinely tested on SDS-PAGE for protein degradation.
Generation of YTS cells transfected with the chimeric protein containing the extracellular portion of KIR2DS4 fused to the transmembrane and cytoplasmic tail portion of KIR2DL1
For the expression of KIR2DS4 with the transmembrane and cytoplasmic tail portion of KIR2DL1, plasmid constructs were prepared that replaced an EcoRI-AgeI fragment of the KIR2DL1 cDNA with that of the KIR2DS4 cDNA. Sequencing of the constructs revealed that KIR2DL1 cDNA was in frame with the KIR2DS4 cDNA and was identical with the reported sequences. YTS cells were transfected with the cDNA encoding for the chimeric KIR2DS4/KIR2DL1 (KIR2DS4*) protein, as previously described (20, 21).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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cDNA encoding for KIR2DS4 was amplified by PCR from peripheral NK clones and cloned into the mammalian expression vector containing the Fc portion of human IgG1 to produce the KIR2DS4-Ig fusion protein. KIR2DS4-Ig was then used to stain 721.221 cells transfected with various class I MHC proteins. Strikingly, specific KIR2DS4-Ig binding was observed only to cells expressing the Cw4 class I MHC protein (data not shown). No binding was observed to 721.221 transfected either with Cw3 or Cw7, while little or no binding was observed to 721.221 cells transfected either with HLA-Cw6 or with HLA-Cw6 in which the cysteine at position 309 was replaced by tryptophan (Cw6/C309W) (Ref. 22 and data not shown). The KIR2DL1 binds to both Cw4 and Cw6 class I MHC molecules (reviewed in Ref. 4). Indeed, efficient binding of KIR2DL1-Ig, which was about 20 times higher than that of KIR2DS4-Ig binding, was observed to 721.221/Cw4 cells (data not shown). The expression of all class I MHC molecules on the surface of 721.221 cells measured by W632 binding was similar (data not shown). KIR2DS4-Ig fusion protein did not bind to 721.221 expressing HLA-A alleles (HLA-A2) or HLA-B alleles (B7, B8, B44, B2702, B2705, B58, and B73) or to 721.221 cells expressing nonclassical class I MHC proteins (HLA-E, HLA-G, and CD1d; data not shown).
Two main conclusions can be drawn from the above experiments. 1) The
KIR2DS4-Ig protein specifically binds to 721.221/Cw4 but not to
721.221/Cw6 cells and thus can discriminate between the two alleles
that belong to the same allotype group characterized by the presence of
K80 (16). 2) The binding of KIR2DS4-Ig to 721.221/Cw4
cells is much weaker than that of KIR2DL1-Ig. Thus, the question arises
as to whether the low level of binding between KIR2DS4 and 721.221/Cw4
is sufficient to induce cellular response. An NK tumor line, YTS, was
infected with the cDNA encoding for KIR2DS4, KIR2DS2, and CD16 using
the retroviral vector pBABE as previously described (20).
Although surface expression of all receptors was detected using the mAb
HP3E4, GL183, and 3G8 for KIR2DS4, KIR2DS2, and CD16, respectively,
none of the transfectants was able to induce lysis in redirected
killing assays against P815 cells using appropriate mAb (data not
shown). This may be because the signaling pathway, which these
receptors use to enhance NK cytotoxicity, is impaired in YTS cells. In
contrast, inhibition of lysis of 721.221/Cw4 and Cw6 cells was observed
when YTS infected with cDNA encoding for KIR2DL1 (YTS/KIR2DL1) were
used (Ref. 20 and Figs. 2
and 3), thus indicating that the inhibitory
signal cascade is functioning in YTS cells.
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). In contrast,
YTS/KIR2DL1 cells were positively stained with both mAb (Fig. 1). No
staining was observed to YTS or to YTS/MOCK cells (Fig. 1). Thus, mAb
HP3E4 can recognize the extracellular portion of KIR2DS4.
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). YTS/MOCK lysed all target cells
tested to the same extent (Fig. 2, top). Efficient
inhibition of YTS/KIR2DL1 lysis was observed when cells were incubated
with either 721.221/Cw4 or 721.221/Cw6 cells in all E:T ratios tested
(Fig. 2, middle). In contrast, inhibition of YTS/KIR2DS4*
was observed only when target cells expressing HLA-Cw4 were used (Fig. 2, bottom). Correlating to the weak staining of 221/Cw4 by
KIR2DS4-Ig compared to KIR2DL1-Ig (Fig. 6), the inhibition
of YTS/KIR2DS4* was weaker than that observed with YTS/KIR2DL1 (Fig. 2). The results presented above suggest that the interaction between
the KIR2DS4* and the HLA-Cw4 molecules is sufficient to transmit the
inhibitory signal. To test whether this inhibition is indeed the result
of the binding of the extracellular portion of KIR2DS4 to the HLA-Cw4,
mAb HP3E4, shown to bind KIR2DS4 in Fig. 1, was used to block the
KIR2DS4 protein binding to HLA-Cw4. HP3E4 was indeed able to reverse
the inhibition mediated by 721.221/Cw4 cells, whereas a control mAb
12E7 had no effect (Fig. 3).
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The functional relevance of the above observation suggesting a
specific interaction between KIR2DS4 and HLA-Cw4 was tested by using NK
clones derived from various healthy donors. NK clones were generated as
described in Materials and Methods. Two hundred fifty
independent NK clones were tested in killing experiments against
various class I MHC-transfected target cells. Three killing phenotypes
were observed with regard to the killing of 721.221/Cw4 cells, of which
three representatives are shown in Fig. 4. NK clone 3 was stained equally
brightly with mAb EB6 and HP3E4. This clone probably expresses KIR2DS1,
because activation of lysis was observed against 721.221/Cw4 and
721.221/Cw6 cells, and both EB6 and HP3E4 mAb blocked the enhancement
of lysis (Fig. 4, top). Among the 250 NK clones
tested, 5 (2%) were stained brightly with mAb HP3E4 and dimly with mAb
EB6 (representative NK clone 6 is seen in Fig. 4, middle). This unique staining suggests the existence
of KIR2DS4 (Fig. 1). Indeed, enhancement of lysis of
721.221/Cw4 cells only was observed when cells were incubated with all
five clones mentioned. The addition of HP3E4 mAb blocked this
enhancement, whereas EB6 or 12E7 mAb had no effect (representative NK
clone 6 is seen in Fig. 4, middle). This is in
agreement with our above observation suggesting that the ligand for
KIR2DS4 is the HLA-Cw4 only. Finally, inhibition of lysis was observed
when 721.221/Cw4 and 721.221/Cw6 cells were tested against NK clone 52.
As expected, this clone was stained equally brightly with EB6 and HPE4
mAb (Fig. 4, bottom), suggesting the existence of the
KIR2DL1.
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It has been demonstrated that peptides bound in the groove can
influence recognition by NK receptors (23, 24, 25). Thus, the
binding of KIR2DS4 to HLA-Cw4, but not -Cw6 could be the result of the
influence of the repertoire of peptides bound by -Cw4 vs -Cw6. All four
HLA-C molecules (Cw3, Cw4, Cw6, and Cw7) analyzed here exhibit related
peptide motifs, although each allelic product shows individual
characteristics in their fine specificity of peptide binding
(26). Alternatively, and perhaps more likely, given the
limited effect of peptides on NK recognition (23, 24), it
is possible that KIR2DS4 binds to the class I MHC proteins on a site
that is different from the one identified for the inhibitory NK
receptors KIR2DL1 and KIR2DL2 (16, 27, 28). Indeed, the
KIR2DS4* inhibition could not be blocked with any of the anti-HLA
mAb tested including HP1F7, G46-2.6, W632, and W632 F(ab')2
(data not shown). Moreover, comparison of the amino acid sequences of
all known HLA-C proteins characterized by the presence of K80 revealed
the existence of a pair of residues that can be found in HLA-Cw4 only
(S11 and W14; Fig. 5A). The
location of both residues is shown in Fig. 5C. Although S11
can also be found in the sequence of other HLA-C alleles that belong to
the other allotype-specific group, characterized by the presence of N80
(e.g., Cw0101, Cw0102, Cw1402, and Cw1403), W14 is unique to HLA-Cw4
(Fig. 5A).
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). Whereas binding of the
KIR2DL1-Ig fusion was observed to all HLA-Cw4 proteins (wild-type and
mutants), binding of KIR2DS4-Ig was observed to 721.221/Cw4 and
721.221/Cw4 S11A but not to 721.221/Cw4 W14R (Fig. 6), thus suggesting
that residue W14 is important in the KIR2DS4 binding to HLA-Cw4. To
further demonstrate the importance of residue W14 in the binding to
HLA-Cw4, we mutated by PCR residue R14 in HLA-Cw6 cDNA to W (Cw6 R14W).
cDNA was sequenced and transfected into 721.221 cells. Whereas
KIR2DL1-Ig fusion protein binds all HLA-Cw4 and HLA-Cw6 expressing
cells, including wild types and mutants, binding of KIR2DS4-Ig was
observed only to cells expressing HLA-C alleles containing the W14
residue, including the 721.221/Cw6 R14W cells (Fig. 6).
The functional relevance of the above observation, suggesting the
involvement of W14 in the binding to KIR2DS4, was tested by using NK
clones derived from various healthy donors. NK clones that were
activated by HLA-Cw4 but not by HLA-Cw6 and that stained brightly with
HP3E4 mAb (data not shown) were tested against various
transfectants. One representative clone is shown in Fig. 7A. Enhancement of lysis was
observed with 721.221/Cw4 cells, but not with 721.221, 721.221/Cw3, and
721.221/Cw6 transfectants (Fig. 7A). In agreement with the
FACS staining results, mutations in residue 14 affect the lysis of the
target cells. Enhancement of lysis was not observed against target
cells expressing HLA-C alleles containing the R14 residue, i.e.,
721.221/Cw4 W14R, 721.221/Cw6 transfectant (these cells do not bind
KIR2DS4-Ig (Fig. 6)). In contrast, activation of lysis was observed
when 721.221/Cw4, 721.221/Cw6 R14W, or 721.221/Cw4 S11A cells were used
(all cells bind KIR2DS4-Ig (Figs. 6 and 7A)). In all targets
in which activation of lysis was observed, the activation could be
blocked with HP3E4 mAb but not with EB6 mAb or 12E7 mAb, suggesting the
involvement of KIR2DS4 (Fig. 7A). Similar results were
obtained when the YTS/KIR2DS4* cells were used as effector cells.
Inhibition of YTS/KIR2DS4* lysis was observed when cells were incubated
with 721.221/Cw4, 721.221/Cw4 S11A, and 721.221/Cw6 R14W, whereas
incubation with 721.221, 721.221/Cw3, 721.221/Cw6, and 721.221/Cw4 W14R
had no effect (Fig. 7B). Abolishment of the inhibition was
observed when the YTS/KIR2DS4* cells were incubated with HP3E4 mAb, but
not with EB6 mAb or 12E7 mAb.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and that binding is
dependent on residue W14 (Figs. 6 and 7). This is in agreement with
previous results demonstrating no binding of soluble KIR2DS4 to either
Cw6 or Cw7 class I MHC proteins (29). This
surprising result is particularly interesting because the key residues
which determine the binding site for KIR2DL1 and KIR2DL2 on the HLA-C
(Refs. 16, 27, 28 and Fig. 5, A and C) are
identical in both HLA-Cw4 and -Cw6. It thus suggests that KIR2DS4 binds
to HLA-Cw4 on a binding site that is different from the binding site to
KIR2DL1. Indeed, changing of the W14 residue in Cw4 to R abolished
recognition by KIR2DS4-Ig but not by KIR2DL1-Ig (Fig. 6). The second
conclusion is that the binding of KIR2DS4-Ig to Cw4 is much
weaker than that observed with KIR2DL1-Ig (Figs. 2 and 6). Few
experiments have been reported analyzing the binding of activating NK
receptors to class I MHC proteins. A soluble form of the activating NK
receptor molecule EB6ActI (KIR2DS1) bound very weakly to
HLA-Cw4-expressing cells (30). The molecular basis for the
lack of binding of CL 49 (KIR2DS2) to various class I-transfected cells
was localized to the presence of tyrosine in position 45 (29, 31). Phenylalanine occupies this position in all other
two-domain-activating or inhibitory receptors. The same authors
(31) could not detect binding of KIR2DS4 to any of the
class I transfectants tested, including Cw4. This might be due to the
lower concentration of KIR2DS4-Ig used to stain the transfectants,
i.e., 50 µg/ml in Ref. 31 vs 100 µg/ml in this work, as well as to
a higher cell-protein ratio that could have been used that might
be sufficient to detect binding of KIR2DL1-Ig to Cw4, but not
enough to detect binding of KIR2DS4-Ig to the same cells. Indeed, in
the current work, binding of KIR2DS4-Ig to 721.221/Cw4 cells is
diminished at 12.5 µg/ml, whereas binding of KIR2DL1-Ig to the same
cells is still detected even at a concentration as low as 1.5 µg/ml
(data not shown).
The molecular basis for the unique binding of KIR2DS4 to HLA-Cw4 and
not -Cw3, -Cw6, or -Cw7, is unclear. The K residue at position 44 of
KIR2DL2 was reported to be critical for the binding of this receptor to
HLA-Cw3 (28, 32). KIR2DS4 contains the KFN amino acid
residues at positions 44–46 (Fig. 5B), which is a hybrid of
the amino acids found in the same position in KIR2DL1 (MFN) and KIR2DL2
(KFK). Molecular modeling of KIR2DS4 receptor based on the crystal
structure of KIR2DL1 predicted that the surface potential of
KIR2DS4 is dramatically different from that of KIR2DL2
(29). Moreover, the mAb EB6, which recognizes an epitope
important for the binding of KIR2DL1 to HLA-Cw4 (33), does
not recognize KIR2DS4 (Fig. 1). This suggests that the site on these
two NK receptors involved in the binding to HLA-C is distinct. Residues
at positions 67–70, GPMM, found in KIR2DL2, which binds to HLA-Cw3,
can also be found in KIR2DS4 (Fig. 5B). Some of these
residues were also reported to be important in the HLA-C binding
(28, 30, 32). Thus, of seven amino acid residues that are
found in the two regions of KIR sequences reported to be important in
HLA-Cw4 binding (30, 31, 32), only three, namely, F45, N46,
and M69, are found in KIR2DS4. This might account for the weak
interaction observed between KIR2DS4 and HLA-Cw4 (Figs. 2 and 6). In
addition, the crystal structure of KIR2DL2 in complex with HLA-Cw3 was
recently solved (28). Sixteen contact residues were
identified in the KIR2DL2 protein interacting with HLA-Cw3 (Ref. 28 and
Fig. 5B). Among these residues, three were unique for
KIR2DS4 only, namely, P71, V72, and A184. Site-directed mutagenesis
analysis of these residues would determine their involvement in the
KIR2DS4 binding to HLA-Cw4.
The third conclusion is that the low binding affinity between the
activating NK receptor KIR2DS4 and HLA-Cw4 is likely to be sufficient
for the function of this receptor (
Figs. 2–4 and 7). Accumulating
evidence suggests that activating NK receptors can function on binding
to various class I molecules. A correlation between the expression of
p50 receptor stained with EB6 mAb and enhanced cytotoxicity against
Cw4-expressing target cells was observed (13). Enhanced
proliferation was observed when a T cell clone (TANK-1) positive for
KIR2DS4 expression was incubated with superantigen-coated 721.221
expressing Cw4 or Cw7 class I MHC proteins, but not with Cw3 or Cw6
(14). This last observation (14) seems to be
in contrast with the results presented here demonstrating binding of
KIR2DS4 to HLA-Cw4 only. However, as the field developed and more
sequence information became available, a later analysis using
additional PCR primers revealed that the TANK-1 clone expresses mRNA
for other NK receptors (29). Using YTS cells transfected
with KIRD2S4 and KIR2DS4-Ig protein, it is now clear that KIR2DS4 binds
to HLA-Cw4-expressing cells only.
Finally, a model for the interplay of NK-activating and inhibitory receptors can be speculated. Inhibitory receptors bind with higher affinity to MHC class I proteins but have a higher threshold for the number of MHC molecules required for triggering signaling, whereas the activating receptors bind with lower affinity and have a lower threshold for triggering signaling. Thus, on recognition of normal MHC expression, signaling through the inhibitory receptors dominates, whereas on recognition of reduced class I MHC expression, e.g. in viral-infected cells, the activating NK receptors dominate the NK cell response. Alternatively, it might be that the activating NK receptors function only in cases where allele-specific down-regulation can be observed, e.g., after HIV infection (20) or tumor spread (reviewed in Ref. 34). In these situations, after down-regulation of HLA molecules for which specific inhibitory NK receptors are present, activating NK receptors may be triggered via other HLA molecules remaining on the cell surface.
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Acknowledgments |
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Footnotes |
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2 Address correspondence to Dr. Ofer Mandelboim, Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Jerusalem 91120, Israel. E-mail address: oferman{at}md2.huji.ac.il
3 Abbreviation used in this paper: KIR2DS4, killer cell Ig-like receptor two-domain short tail number 4; KIR2DL1, killer cell Ig-like receptor two-domain long tail number 1. Other moieties are similarly abbreviated.
Received for publication June 1, 2000. Accepted for publication April 13, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T. Gonen-Gross, H. Achdout, R. Gazit, J. Hanna, S.'a. Mizrahi, G. Markel, D. Goldman-Wohl, S. Yagel, V. Horejsi, O. Levy, et al. Complexes of HLA-G Protein on the Cell Surface Are Important for Leukocyte Ig-Like Receptor-1 Function J. Immunol., August 1, 2003; 171(3): 1343 - 1351. [Abstract] [Full Text] [PDF]
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G. Markel, N. Lieberman, G. Katz, T. I. Arnon, M. Lotem, O. Drize, R. S. Blumberg, E. Bar-Haim, R. Mader, L. Eisenbach, et al. CD66a Interactions Between Human Melanoma and NK Cells: A Novel Class I MHC-Independent Inhibitory Mechanism of Cytotoxicity J. Immunol., March 15, 2002; 168(6): 2803 - 2810. [Abstract] [Full Text] [PDF]
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