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Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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KIR2D have the intriguing and unique property, among all Ig superfamily members, of binding zinc, as shown with KIR2DL1 and KIR2DL3 (13). KIR2DL1 is specific for HLA-C allotypes that carry amino acids asparagine at position 77 and lysine at position 80, such as HLA-Cw4, whereas KIR2DL3 recognizes HLA-C with serine at 77 and asparagine at 80, such as HLA-Cw3 (4, 14, 15, 16). Potential zinc binding sites are present in the first Ig domain of KIR2D molecules, including the amino-terminal end, which corresponds to the canonical Zn-binding motif HEXXH (17). In addition to zinc binding, a role for zinc in the KIR-mediated inhibition of NK killing was demonstrated using NK clones (13). KIR-mediated inhibition of target cell lysis was prevented by the zinc chelator 1,10-phenanthroline (13). However, as 1,10-phenanthroline is membrane permeable, such cytolytic assays did not distinguish between a requirement for extracellular zinc, possibly bound to KIR, and an intracellular role for zinc bound to other molecules involved in the negative signaling pathway.
Zinc coordination in proteins can serve a structural role by stabilizing a folded conformation, or a catalytic role as part of the active site of enzymes. Zinc can also promote protein-protein interactions when it is coordinated by amino acid residues on two different molecules. From the study of several zinc-binding proteins that have been crystallized, it appears that zinc is typically coordinated by histidine, cysteine, and less commonly, aspartate and glutamate residues, with histidine being the most frequent ligand in zinc active sites (18). By analogy with known zinc-mediated receptor-ligand interactions, such as HLA-DR with the superantigen staphylococcal enterotoxin A (19), and prolactin receptor with growth hormone (20), the zinc-binding property of KIR2D suggested that zinc may be required for KIR binding to HLA-C. However, binding of a soluble KIR2DL1-Fc fusion protein to HLA-C was unaffected by chelation of zinc (C. Winter and S.R., unpublished observations). Furthermore, soluble KIR2DL1 produced in Escherichia coli could be refolded in the absence of zinc and was still competent to bind soluble HLA-C (21). Thus, a requirement for zinc in the direct interaction between KIR and HLA-C was ruled out.
At least four possible roles for zinc in KIR function can be envisaged. First, zinc may be required for the activity or the inhibition of intracellular proteins that control the negative signaling pathway. Zinc is a necessary structural component of many transcription factors and enzymes such as proteases (18, 22). Second, zinc could confer a conformation to KIR that is necessary for the delivery of a signal through the cytoplasmic tail. It is still unknown to what extent signaling through KIR occurs via receptor aggregation or via a conformational change. Third, zinc may promote oligomerization of KIR at the cell surface, which may be a necessary early step in the negative signaling cascade. Dimerization of proteins such as HIV tat and human growth hormone is zinc dependent (23, 24). Fourth, zinc might mediate intermolecular interactions between KIR and another protein that would strengthen the inhibitory signal. To distinguish between these different possibilities, mutational analysis of the putative zinc binding sites of KIR and functional reconstitution experiments in NK cells were conducted. The results definitively established a role for the zinc-binding site on KIR in the inhibitory function of this receptor. The data support a model whereby zinc bound to KIR promotes a protein-protein interaction.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The human NK cell line NK92 (a gift of H. G. Klingemann, The Terry Fox Laboratory, Vancouver, Canada) (25) was maintained in MyeloCult H5100 medium (Stem Cell Technologies, Vancouver, Canada) and supplemented with 100 U/ml rIL-2 (gift from Hoffmann-La Roche, Nutley, NJ). The HLA class I transfectants .221-Cw3 and .221-Cw4 of the B lymphoblastoid cell line 721.221 were provided by J. Gumperz and P. Parham (Stanford University, Stanford, CA). The RMA-S-Cw4 transfectant and its loading with peptide QYDDAVYKL have been described (26). The following mAbs were used: F4/326 (IgG2a) (a gift from S. Y. Yang, Memorial Sloan-Kettering Cancer Center, New York, NY) (27); the anti-KIR2D mAb HP3E4 (IgM) (a gift from M. Lopez-Botet, Hospital de la Princesa, Madrid, Spain) (28); and the anti-KIR2DL1 mAb EB6 (IgG2a) from Immunotech (Westbrook, ME). The zinc chelators polyhistidine (m.w. 5,000–15,000) and 1,10-phenanthroline were obtained from Sigma (St. Louis, MO).
cDNA and construction of mutant and chimeric constructs
The mutants H1, H2, and H1,2,3 were generated by site-directed
mutagenesis of the cDNA cl-42 (29), encoding the KIR2DL1 molecule
KIR-42, using the QuikChange site-directed mutagenesis kit (Stratagene,
La Jolla, CA). Mutant H1 was engineered by replacing the histidines at
positions 1 and 5 of KIR-42 with alanine using oligonucleotide
5'-GGGGCCTGGCCAGCTGAGGGAGTCGCCAGAAAACCT-3' and its complement.
Mutant H2 was engineered by replacing the histidines at positions 36
and 40 of KIR-42 with alanine using oligonucleotide
5'-GTCATGTTTGAAGCCTTCCTTCTGGCCAGAGAGGGG-3' and its complement.
Mutant H1,2,3 was generated by sequentially mutating the histidines
described in H1 and H2 and additionally mutating a third pair of
histidines at positions 55 and 56 using oligonucleotides
5'-CTCATTGGAGAAGCCGCTGATGGGGTCTCC-3' and its complement. Mutations
were confirmed by sequencing, and the mutants H1, H2, and H1,2,3 were
cloned into the plasmid pSC66 and used to generate recombinant vaccinia
viruses, as described (30). The chimeric KIR-42-ITAM and H1,2,3-ITAM
receptors were produced by ligation of fragments encoding the
extracellular and transmembrane regions of KIR-42 and H1,2,3 with the
ITAM-containing cytoplasmic region of the 
-chain of Fc
RI. The
cytoplasmic tail of the FcRI- was amplified from a cDNA encoding
FcRI- (a gift from M.-H. Jouvin, Beth Israel Hospital, Boston,
MA) using the forward primer 5'-TCCTCTACCTTAGGCTGAAGATCCAAGTGC-3'
containing a Bsu36I site, and reverse primer
5'-CATCTATTGAATTCCTACTGGTGGTGGTTTCT-3' containing a stop codon followed
by an EcoRI site. The fragments encoding KIR-42 and H1,2,3
used for ligation were amplified from the plasmid pSPORT-p58-cl42 or
pSPORT-p58-H1,2,3 using the forward primer
5'-AGCTCCCGGAGCTCCTATGACATG-3' containing a SalI site, and
the reverse primer 5'-GCAGCAGGATCCCCTAAGGAGAAAGAAGAGGAG-3'
containing a Bsu36I site for cloning into pBluescript. The
SacI-EcoRV fragment containing the chimeric
receptors was excised from pBluescript and subcloned into the
SacI-StuI site of pSPORT-cl-42 and H1,2,3 to
generate KIR-42-ITAM and H1,2,3-ITAM. These chimeric cDNA molecules
(see Fig. 1
) were then subcloned into the
plasmid pSC66 and used to generate recombinant vaccinia viruses, as
described (30).
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The construction of soluble KIR-42-Fc fusion protein of KIR fused to the Fc portion of human IgG1 has been described (4). The sequences encoding the extracellular portions of the mutant KIR-42 molecules generated in this study, namely H1, H2, and H1,2,3, were amplified by PCR. For H1 and H1,2,3, the forward primer used was 5'-CAGGGGGCGCTAGCGCATGAGGGAGTCGCCAGAAAACC-3' containing an NheI site, and the reverse primer used was 5'-GAGGTCCCAGGATCCGCATGATGCAGGTGTCTGGGGTTACC-3' upstream of the transmembrane and containing a BamHI site. For H2, the forward primer was 5'-CAGGGGGCGCTAGCGGCTGAGGGAGTCCACAGAAAACC-3', and the reverse primer was the same as that used for H1 and H1,2,3. These PCR-generated NheI-BamHI fragments were cloned into the expression vector CD51neg (a gift from B. Seed, MGH Cancer Center, Charlestown, MA). COS-7 cells were transfected with these cDNAs, and supernatants were harvested and affinity purified on protein A-Sepharose, as previously described (4). Protein concentrations were determined using the Micro bicinchoninic acid assay (Pierce, Rockford, IL). The HLA-Cw4-transfected and untransfected 721.221 cells were incubated for 30 min at 4°C with 40 µg/ml of the purified KIR-Fc fusion proteins KIR-42-Fc, H1-Fc, H2-Fc, and H1,2,3-Fc. The cells were then washed and incubated with Fc-specific, FITC conjugates of goat anti-human IgG Abs (Jackson ImmunoResearch, West Grove, PA) for 30 min at 4°C. Fluorescence of 5000 cells was analyzed by flow cytometry on a FACScan (Becton Dickinson, Mountain View, CA).
65Zn blot assay
The Fc portion of human IgG1 (control), wild-type KIR-42-Fc, and mutant H1,2,3-Fc fusion proteins (5 µg and 10 µg of each) were dried down onto nitrocellulose filters. Filters were incubated with metal-binding buffer (MBB: 100 mM Tris-HCl, pH 6.8, 50 mM NaCl) for 30 min at room temperature. The blot was incubated in 50 µCi of 65ZnCl2 (3.31 Ci/g) in 7.5 ml MBB for 1 h at room temperature. After three washes in MBB, the filter was subjected to autoradiography.
Peptide-binding assay for stabilization of HLA-C surface expression
RMA-S transfectants were plated at 2.5 x 105 cells/well in a 48-well plate in a final volume of 0.5 ml. Cells were incubated for 18 h at 25°C. Peptide (100 µM final concentration) was added at the onset of culture, and again 16 h later. Cells were harvested, washed with PBS containing 2% FCS, and divided into two aliquots. One aliquot was used to measure the surface levels of class I molecules on peptide-loaded RMA-S transfectants, as described previously (26). The second aliquot was used for targets in the cytotoxicity assay described below.
Vaccinia virus infections and cytotoxicity assays
Purified viruses encoding KIR-42, H1, H2, H1,2,3, KIR-42-ITAM, and H1,2,3-ITAM were used to infect the human cell line NK92, as described (4). Lysis of B cell targets by human NK92 cells was measured in a 4-h 51Cr release assay, as described (4). The RMA-S-Cw4 target cells were incubated with peptide, as described above, and labeled overnight at 25°C with Na51Cr (50 µCi/well; Amersham, Arlington Heights, IL). Targets were washed and resuspended at a final concentration of 2.5 x 104 cells/ml, and 100 µl was added to an equal volume of NK92 cells. The assay was incubated at 37°C for 3 h, and 51Cr release was measured as previously described (31). mAbs and zinc chelators were added at the onset of the cytotoxicity assays and were present throughout the assay.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To test whether the requirement for zinc in the KIR-mediated
inhibition of NK cells reflects a need for zinc inside or outside the
cells, the membrane-nonpermeable zinc chelator polyhistidine was used.
The recombinant vaccinia virus expression system in NK cells (4) was
used to study the effect of zinc on KIR2DL1, the well-defined
HLA-Cw4-specific KIR2D encoded by cDNA cl-42 (refered to in this study
as KIR-42; see Fig. 1
). KIR-42 was expressed in the cell line NK92 and
tested for its ability to inhibit lysis of HLA-Cw4 targets in the
presence of polyhistidine (Fig. 2).
Inhibition of lysis of HLA-Cw4-bearing targets was reversed in the
presence of 10 µg/ml polyhistidine (corresponding to approximately 1
µM polymer or 100 µM histidine). Similarly, the KIR-42-specific mAb
HP3E4 interfered with the inhibition provided by HLA-Cw4-bearing
targets (Fig. 2). Thus, the data suggest that extracellular zinc is
required for the inhibition of NK cells by KIR-42. The
membrane-permeable zinc chelator 1,10-phenanthroline also compromised
KIR-42 function in this reconstitution system (data not shown), as
described earlier with NK clones (13).
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To directly test whether zinc bound to KIR is necessary for
inhibition of NK cells, several histidine residues that were potential
zinc binding sites on KIR were replaced by alanine. A total of six
histidines in the first Ig domain, included in the three histidine
pairs HEGVH (amino acids 1–5), HFLLH (amino acids 36–40), and HH
(amino acids 55–56), were replaced to produce mutant H1,2,3 (Fig. 1).
Soluble forms of wild-type KIR-42 and of mutant H1,2,3 were produced as
fusion proteins with the Fc portion of human IgG1 to assess their zinc-
and HLA-C-binding potential. Binding of 65Zn to proteins
attached on nitrocellulose filters was measured in a zinc-blot assay
(Fig. 3A). While there was no
zinc binding by the control Fc protein (Fig. 3A,
left), wild-type KIR-42-Fc bound zinc (Fig. 3A,
center) to an extent comparable with that obtained with
thermolysin, a protein known to bind zinc via the HEXXH motif (data not
shown). In contrast, the mutant H1,2,3-Fc protein exhibited greatly
reduced zinc binding (Fig. 3A, right).
Competition studies indicated that metal binding was specific.
Zn2+ and, to a lesser extent, Ni2+ competed for
the binding of 65Zn, whereas Ca2+ and
Mg2+ did not, even at 10-fold higher concentrations (data
not shown).
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B). The H1,2,3-Fc mutant bound to HLA-Cw4 as
well as KIR-42-Fc, even at suboptimal concentrations (Fig. 3C). Thus, the histidine residues that control zinc binding
to KIR are not required for KIR binding to HLA-C. Impaired inhibitory function of KIR-42 lacking the zinc binding site
To test whether mutation of the zinc-binding motifs had an effect
on the inhibitory potential of KIR, KIR-42 and the mutant H1,2,3 were
expressed by recombinant vaccinia viruses in NK cells (Fig. 4A). NK92, an NK cell line
that lacks endogenous KIR-42 expression (32), was used to express these
recombinant receptors and was tested for its ability to kill 721.221
target cells transfected with either HLA-Cw4 (ligand for KIR-42) or
HLA-Cw3 (an allotype recognized by other KIR2D receptors). As expected,
KIR-42 provided specificity for HLA-Cw4 on target cells, resulting in
inhibition of lysis (Fig. 4B). In contrast, expression of
the mutant H1,2,3 resulted in a partial inhibition of lysis of target
cells bearing HLA-Cw4. The residual inhibition mediated by mutant
H1,2,3, similar to that observed after chelating zinc (Fig. 2) (13),
was observed reproducibly and is not due to lower expression of H1,2,3
(Fig. 4A). This residual inhibition was not reversed to
complete lysis by the addition of the zinc chelator polyhistidine (data
not shown). These data suggest that zinc, although not absolutely
required, contributes to the inhibition of NK cells by KIR-42.
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-chain of the FcRI receptor (Fig. 1).
To detect an activation signal in NK cells, it was necessary to use
target cells that are not normally lysed by NK92 cells, such as the
mouse TAP-deficient cell line RMA-S (26). Direct binding of soluble
KIR2D to transfected RMA-S cells expressing HLA-C allotypes is
dependent on the addition of specific exogenous peptides (26). Thus,
RMAS-Cw4 cells loaded with the specific peptide QYDDAVYKL were tested
for their ability to activate the lytic function of NK92 cells
expressing KIR-42, H1,2,3, and the ITAM-containing forms of these
receptors (Fig. 5A). NK92
cells, either uninfected or infected with recombinant vaccinia viruses
expressing any one of these receptors, were unable to bind empty
HLA-Cw4 molecules and lyse RMAS-Cw4 cells (Fig. 5B). Upon
peptide-induced stabilization of surface HLA-Cw4 molecules, activation
of the lytic function of NK92 cells was observed after infection with
vaccinia viruses encoding KIR-42-ITAM and H1,2,3-ITAM, but not KIR-42
and H1,2,3 (Fig. 5B). Despite a lower level of surface
expression as compared with that of KIR-42-ITAM, the mutant H1,2,3-ITAM
was equally competent to activate NK92 cells. Thus, removal of
zinc-binding site(s) on KIR-42 expressed on NK cells affected neither
ligand binding nor the ability to transduce an activation signal. These
results point to a specific role for the zinc-binding histidines in the
inhibitory function of KIR-42.
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During the course of this work, structural data on KIR-42 became
available (33). The position of several histidine residues in the
three-dimensional structure of KIR-42, including those at residues
36–40 (HFLLH) and 55–56 (HH), was not favorable to zinc binding. In
contrast, the first five amino acids of KIR-42, which correspond to the
zinc-binding motif HEXXH, are not visible in the crystal structure and
may be disordered (33). Furthermore, the amino-terminal end of KIR-42
lies at an edge of the molecule, in a position seemingly well suited
for intermolecular interactions. To test whether this N-terminal HEGVH
motif is indeed necessary for KIR function, mutant H1 (HEGVH
AEGVA)
was generated (Fig. 1). Mutant H2 (HFLLHAFLLA) was generated to
compare mutant H1 with a KIR-42 molecule that had a very similar
mutation, but at a position not favored structurally to bind zinc.
Soluble forms of mutants H1 and H2 were produced to evaluate binding to
HLA-C. As expected, given the normal binding of mutant H1,2,3-Fc (Fig. 3), both H1-Fc and H2-Fc bound to HLA-Cw4 expressed on transfected
.221-Cw4 cells (Fig. 6A).
Mutants H1 and H2 were expressed in NK92 cells using the vaccinia virus
expression system. Whereas mutant H2 retained the inhibitory function
upon specific recognition of HLA-Cw4, mutant H1 was greatly impaired in
the inhibitory function, despite a similar surface expression level
(Fig. 6B). Thus, the histidines of the prototypic
zinc-binding motif HEGVH at the N terminus of KIR-42 contribute to the
inhibitory function of KIR-42.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A role for zinc bound to KIR2D molecules was deduced from mutagenesis of the KIR-42 zinc binding site. Both the H1,2,3 and the H1 mutants showed impaired inhibitory potential compared with wild-type KIR-42. Despite the substitution of six histidine residues by alanines, the zinc-binding-deficient mutant H1,2,3 was fully competent to bind HLA-C and to transmit an activation signal through an ITAM-containing artificial cytoplasmic tail upon recognition of HLA-C molecules on target cells. In agreement with this, earlier work had shown that folding of a soluble KIR-42 and binding to a soluble form of HLA-C occurred in the absence of zinc (21). Therefore, the zinc dependence of the inhibitory function of KIR lies downstream of ligand binding.
Given that proper folding and ligand binding of KIR-42, and the ability of KIR-42 to deliver an activation signal through an ITAM-containing cytoplasmic tail upon binding to HLA-C on target cells, are zinc-independent properties, the specific effect of zinc is best explained by a zinc-mediated interaction of KIR-42 with proteins that contribute to the negative signal. Zinc bound to KIR-42 may either mediate a protein interaction directly, or it may induce a conformation of KIR2D that is necessary for a protein interaction. By analogy with nerve growth factor (34), it is also possible that a N-terminal zinc-dependent conformation prevents an interaction with another protein. Several possibilities that could facilitate inhibition of NK cells through a zinc-mediated interaction with KIR-42 can be considered. First, receptors that activate NK cytotoxicity may interact with KIR to facilitate their own inhibition. Second, KIR-42 may interact with itself. Third, other proteins may interact with KIR-42 to strengthen the inhibitory signal.
Coligation of KIR with activating receptors appears to be necessary for inhibition (35), presumably because the required activity of the KIR-associated tyrosine phosphatase SHP-1 (5) needs to be localized near the activation signal. It is still unknown whether and how KIR interacts with receptors that activate NK cells. Zinc may facilitate such an interaction. However, many structurally unrelated proteins, such as the Ig-like CD16 and the lectin-like CD69, can trigger NK cells (3). It is therefore unlikely that zinc could mediate an interaction between KIR2D and each of these different activating receptors, unless it mediates an interaction with a common intermediate.
Dimerization or multimerization of KIR2D may be a requirement for an effective negative signal, as it often is for signal transduction mediated by other receptors (36). However, zinc-dependent oligomerization was not observed in studies of soluble rKIR-42 produced in E. coli. Such soluble KIR-42 remained monomeric in the presence or the absence of zinc, as judged by size exclusion (21). It remains possible that such a zinc-mediated KIR dimerization occurs at the surface of NK cells, but only after KIR binding to HLA-C to avoid constitutive dimerization.
The third hypothesis proposes that zinc mediates the interaction of KIR2D with another protein. Such a protein could be a coreceptor for KIR2D that provides an accessory function in the inhibition of NK cells, a ligand for KIR on target cells that enhances KIR function, or a protein that interferes with KIR function by binding to KIR in the absence of zinc. Preliminary biochemical experiments have failed to date to reveal a zinc-dependent protein interaction with KIR2D. A low affinity interaction, or a transient interaction dependent on target cell recognition by NK cells, could explain the lack of detection.
The protein interaction proposed by this hypothesis would be distinct
from the KIR-42 dimerization or heterodimerization suggested by the
three-dimensional structure of KIR-42 (33). The high resolution x-ray
structure of KIR-42 revealed that this molecule belongs to the
hemopoietic receptor family that includes cytokine and growth hormone
receptors. All of the members of this receptor family form either
homodimers (e.g., growth hormone and erythropoietin receptors) or
heterodimers (e.g., IL receptors) upon ligand binding. A similar
dimerization of KIR2D upon binding to HLA-C on target cells would
involve contacts along one face of the second Ig domain (33). The HEGVH
zinc-binding motif on KIR2D that contributes to inhibition of NK
cytotoxicity is located away from this hypothetical dimerization site,
and at some distance from the HLA-C binding site (Fig. 7). Thus, a protein interacting with the
N-terminal end of KIR2D via zinc would not interfere with HLA-C binding
or receptor dimerization. The first five HEGVH amino acids of KIR-42
were not visible in the crystal structure, indicating they may be
disordered (33). Conceivably, these amino acids could gain an ordered
structure upon zinc binding or upon a zinc-mediated interaction with a
protein, as has been observed or postulated for other proteins that
bind zinc at their N terminus, such as HIV integrase (37) and nerve
growth factor (34).
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: KIR, killer cell-inhibitory receptor; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; KIR2D, killer cell-inhibitory receptor with two Ig domains; MBB, metal-binding buffer; PFU, plaque-forming unit.
Received for publication February 5, 1998. Accepted for publication April 6, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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