By
From the Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852
Natural killer (NK) cells in mice and humans express a number of structurally diverse receptors that inhibit target cell lysis upon recognition of major histocompatibility complex (MHC) class I molecules expressed on targets. The contribution of peptide to the structural features of class I required for NK cell inhibition appears to vary depending on the type of receptor engaged. Thus, while there is no peptide specificity in NK inhibition mediated by Ly-49A in the mouse, human histocompatibility antigen (HLA)-B*2705-specific NK clones displayed selectivity for peptides. In this report, we examine the role of peptide in the recognition of HLA-C by the defined killer cell inhibitory receptor (KIR) cl42 with established specificity for HLA-Cw4. Binding of soluble KIR cl42 molecules to HLA-Cw4 expressed on transporter associated with antigen presentation (TAP)-deficient RMA-S cells occurred only upon exogenous peptide loading. Moreover, there was peptide selectivity in that certain substitutions at positions 7 and 8 of the nonamer peptide QYDDAVYKL abolished Cw4 interaction with KIR cl42 despite similar surface expression of HLA-C. The specificity of this direct interaction between peptideloaded HLA-Cw4 on RMA-S cells and soluble KIR cl42 correlated with recognition by NK clones in that they were inhibited only by HLA-Cw4 loaded with the appropriate peptides.
NK cells lyse cellular targets such as certain tumor cells
or virus-infected cells. NK-mediated lysis of normal
cells is prevented by inhibitory receptors on NK cells that
recognize MHC class I molecules on target cells (1, 2).
MHC class I molecules consist of a trimolecular complex of
a polymorphic heavy chain, Mouse NK cells express inhibitory type II transmembrane glycoproteins called Ly-49 that bind H-2 ligands (1).
Studies on the role of peptide in the recognition of H-2Dd
by Ly-49A+ NK cells revealed that H-2Dd expressed on
transporter associated with antigen presentation (TAP)-deficient cells confers protection from NK-mediated lysis only
after loading with peptide but regardless of the sequence of
the bound peptide (3, 4). Thus, there is no apparent peptide specificity for the mouse inhibitory receptor Ly-49A
and the contribution of the peptide bound to H-2Dd is to ensure proper folding and reasonable cell surface expression.
Human NK cells express at least two different types of
inhibitory receptors that are involved in the specific recognition of HLA-A, -B, and -C allotypes on target cells. One
type belongs to the C-type lectin family and consists of the
type II glycoprotein CD94 covalently associated with structurally heterogeneous members of the NKG2 receptor family
(5, 6). The HLA ligands for CD94-NKG2 are not clearly
established but appear to include polymorphic HLA-A, -B,
and -C molecules (5, 7). There is no information on the
role of peptide in the recognition of HLA ligands by the CD94-NKG2 complex. The second type of NK receptors
is the p58/p70 family of receptors, called killer cell inhibitory receptors (KIR) that are type I transmembrane glycoproteins of the immunoglobulin superfamily (8).
Whereas the p70 receptors are specific for certain HLA-A and
-B alleles (11), members of the p58 group discriminate
among defined HLA-C allotypes (allotypes with N77K80, including Cw2, Cw4, Cw5, Cw6 versus allotypes with
S77N80, such as Cw1, Cw3, Cw7, Cw8) (13, 16, 17).
In contrast with Ly-49 on mouse NK cells, there is some
degree of peptide selectivity in the recognition of HLAB*2705 by NK clones expressing p70 (18, 19). This peptide discrimination can be mediated by a single p70 KIR,
cl11 (20). Single-amino acid substitutions along a protective peptide identified residues at positions P7 and P8 as
critical for NK recognition of HLA-B*2705 (19). However, there is no data on whether these substitutions affected direct binding of the p70 KIR to HLA-B*2705.
Recognition of empty HLA-C molecules expressed by
TAP-deficient cells indicated that bound peptide was not
required for the inhibition of CTL or NK-mediated lysis
(21, 22) by HLA-C. However, the identity of the inhibitory receptor(s) (e.g., KIR, CD94-NKG2) was not established in these studies.
In this study, we investigated the role of peptide in the
recognition of HLA-C by KIR cl42, a receptor previously
shown to be specific for HLA-Cw4 by binding studies and
by functional reconstitution experiments (13). We used a
direct in vitro binding assay to show that the recognition of
HLA-Cw4 by KIR cl42 is dependent on the presence of
peptide in the groove. Moreover, there is peptide selectivity, because certain peptides that stabilized HLA-Cw4 surface expression on the TAP-deficient RMA-S cells did not
render these molecules competent to interact with KIR cl42.
NK Clones and Target Cells.
CD3 Peptides, Antibodies, and Immunostaining.
Peptides were synthesized and purified as described (26). Purity was confirmed by analytical reverse phase HPLC and by mass spectrometry. QYDDAVYKL is a consensus peptide that binds Cw*0401 with an
IC50 value of 18 nM (27). It contains residues present in the endogenous peptides bound to Cw*0401, as determined by pool sequencing (28). The anchor motif for peptides bound to Cw*0401
was proposed to be Y,P at position 2, V,I,L at position 6 and
L,F,M at position 9 (27, 28). The following mAbs were used:
F4/326 (IgG2a), a gift from S.Y. Yang (Memorial Sloan-Kettering Cancer Center, New York); HP3E4 (IgM), a gift from M. Lopez-Botet (Hospital de la Princesa, Madrid, Spain); DX22
(IgG1), a gift from L. Lanier (DNAX, Palo Alto, CA). 1 × 105
cells were incubated for 30 min on ice with primary mAb,
washed in PBS containing 2% FCS, and stained with FITC-conjugated goat anti-mouse IgG+IgM (Jackson ImmunoResearch
Laboratories, Inc., West Grove, PA). Cells were washed twice
and analyzed on a FACScan® (Becton Dickinson, Mountain
View, CA). To test the binding of cl42-Ig (13) to RMA-S transfectants in the absence or presence of peptides, cells were incubated with 100 µg/ml of KIR cl42-Ig (or control cl43-Ig) for 30 min on ice, followed by staining with a fluoresceinated goat anti-
human Fc-specific reagent as previously described (13). Cells
were then washed and analyzed by flow cytometry.
Peptide Binding Assay for Stabilization of HLA-C Surface Expression.
RMA-S transfectants were plated at 2.5 × 105 cells/well
in a 48-well plate in a final volume of 0.5 ml. Cells were incubated for 24 h at 25°C. Peptide (100 µM final concentration) was
added at the onset of culture and again 8 h later. Cells were harvested, washed in PBS containing 2% FCS, and divided into
three aliquots. One aliquot was used to measure the surface levels
of class I molecules on peptide-loaded RMA-S transfectants as
described above. The second aliquot was used to test for binding
of KIR cl42-Ig to peptide-loaded RMA-S as described above.
The third aliquot was used as targets in the cytotoxicity assay described below.
Cytotoxicity Assay.
HP3E4+, DX22+ NK clones were tested
for killing at several effector to target ratios in duplicate wells. NK
clones were resuspended at the desired concentration in a medium consisting of Iscove's modified essential medium with 10%
FCS, 2 mM glutamine, and 50 U/ml rIL-2 (Hoffman-La Roche)
and plated in V-bottomed 96-well plates in a final volume of 100 or 50 µl in the presence of mAb. Target cells were incubated
with peptide as described above and labeled overnight during the
incubation at 25°C with sodium 51Cr (50 µCi/well; Amersham,
Arlington Heights, IL). Targets were washed and resuspended at a
final concentration of 2.5 × 104 cells/ml and 100 µl were added
to the NK clones. The assay was incubated at 37°C for 3 h and
51Cr release was measured as previously described (23). mAbs
were added at the onset of the assay and were present throughout
the assay.
TAP-deficient RMA-S cells previously
transfected with human
A panel of 16 different amino acid substitutions in the
QYDDAVYKL peptide were synthesized and tested for
their capacity to bind to Cw4 molecules on the surface of
RMA-S-Cw4 cells as assessed by flow cytometry using
mAb F4/326 (Table 1; Fig. 2). Each residue in the peptide
was substituted for other amino acids that had been identified as being either dominant or strong signals by pool sequencing (28). Additional substitutions of amino acids at
P7 and P8 for negatively charged residues were chosen to
test whether P7 and P8 were important for NK recognition, as had been observed in the recognition of HLAB*2705 by NK cells (19). Most of the substitutions in the
peptide sequence did not affect binding to HLA-Cw4 molecules on RMA-S-Cw4, as judged by the increase in HLA-Cw4 at the cell surface. Peptides with substitutions
that failed to increase the cell surface level of HLA-Cw4
included proline for tyrosine at P2. This was surprising, because proline at P2 was proposed to be an auxiliary anchor
for the Cw4 binding motif (28). However, it is possible
that B*3503-bound peptides contributed to the proline signal at P2, because C1R cells expressing low levels of
B*3503 were used as a source of HLA-Cw4 for pool sequencing (28). Substitution of aspartic acid at P3 and P4 with histidine and proline also abolished binding. Substitutions D3A and D4A pinpointed the importance of aspartic
acid at position 3 for binding.
Table 1.
Stabilization of HLA-Cw4 Molecules on RMA-S Cells
2-microglobulin (
2m), and
an intracellularly derived short peptide. MHC class I recognition is mediated by a number of structurally diverse inhibitory receptors present on NK cells in mice and humans. The effect of peptide binding on the structural nature of
the class I molecule recognized by the different receptors
on NK cells is not well defined. Does peptide fulfill only a
generic role in providing proper conformation and adequate cell surface expression of MHC molecules or do receptors on NK cells bind to specific conformational determinants on MHC class I induced only by certain peptides?
CD56+ NK cells were
obtained from PBMC, cloned by limiting dilution, and maintained as previously described (20, 23). The TAP-deficient cell
line RMA-S transfected with the human
2m gene (referred to as
RMA-S below) was obtained from P. Cresswell (Yale University,
New Haven, CT) (24). This line was transfected with the cDNA
constructs RSV.5gpt-Cw4 and RSV.5gpt-Cw8. A SalI-HpaI fragment containing either the HLA-Cw*0401 cDNA or the
HLA-Cw*0802 cDNA (obtained from R. Biassoni, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy) was cloned into the
SalI-HpaI sites of vector RSV.5gpt (25). Cells were electroporated at 250 V, 960 µF with 20 µg of these constructs. 48 h later,
cells were selected with 10 µg/ml mycophenolic acid and 10 µg/ml
xanthine and plated in V-bottomed 96-well plates at 103 cells/well.
Cells were screened by flow cytometry using the mAb F4/326
and subcloned. Clones with the highest class I expression were used
for the experiments described here.
Cell Surface Expression of HLA-Cw4 and HLA-Cw8 in
RMA-S Cells.
2m (24) (referred to in this report
as RMA-S) were used for transfections with HLA-Cw*0401
or HLA-Cw*0802 cDNA. HLA-Cw*0401 belongs to the
group of HLA-C allotypes with amino acids N77K80, and
HLA-Cw*0802 belongs to the group with amino acids
S77N80. Transfectants were incubated at 25°C to faciliate
surface expression of empty HLA-C molecules, screened by
flow cytometry using the HLA-C-reactive mAb F4/326, and
subcloned. One clone each, expressing high cell surface levels of either HLA-Cw4 or HLA-Cw8 at 25°C, was chosen for
further study (Fig. 1). RMA-S-Cw4 transfectants were incubated with the peptide QYDDAVYKL, a high affinity
consensus peptide that bound Cw*0401 (27). Peptide loading resulted in a dramatic increase in cell surface expression
of HLA-Cw4 as depicted by the greater than fivefold increase in fluorescence intensity. This peptide did not affect
the cell surface expression of HLA-Cw8 (see Fig. 2).
Fig. 1.
Surface HLA-C expression on RMA-S transfectants. RMA-S
cells and RMA-S transfected with HLA-Cw4 and HLA-Cw8 were incubated at 25°C for 24 h and stained with HLA-C-reactive mAb F4/326.
The peptide QYDDAVYKL was added at 100 µM to RMA-S-Cw4 (bottom). The mean fluorescence intensity for each profile is given in the top right corner.
[View Larger Version of this Image (0K GIF file)]
Fig. 2.
Interaction of peptide-stabilized surface HLA-C with cl42-
Ig. Cells were incubated with peptides (100 µM) for 24 h at 25°C and
tested for induction of HLA-C surface expression (closed bars) or KIR
cl42-Ig binding (open bars). The data are represented as mean fluorescence
intensity. The cl42-Ig binding to peptide Cw4#1 A5R was not done in
this particular experiment. In other experiments, binding was comparable
to that seen with peptide Cw4#1. Three other experiments gave similar
results.
[View Larger Version of this Image (0K GIF file)]
Peptide
Sequence
Relative
surface levels*
Cw4#1
QYDDAVYKL
1
Cw4#1
Q1S
SYDDAVYKL
1.01
Cw4#1
Y2P
QPDDAVYKL
0.11
Cw4#1
D3D4HP
QYHPAVYKL
0
Cw4#1
D3A
QYADAVYKL
0.13
Cw4#1
D4A
QYDAAVYKL
0.49
Cw4#1
A5R
QYDDRVYKL
0.75
Cw4#1
V6G
QYDDAGYKL
0.84
Cw4#1
Y7A
QYDDAVAKL
1.04
Cw4#1
Y7E
QYDDAVEKL
0.86
Cw4#1
K8H
QYDDAVYHL
0.88
Cw4#1
K8F
QYDDAVYFL
0.97
Cw4#1
K8S
QYDDAVYSL
0.83
Cw4#1
K8R
QYDDAVYRL
1.11
Cw4#1
K8E
QYDDAVYEL
0.94
Cw4#1
K8D
QYDDAVYDL
1.05
Cw4#1
L9F
QYDDAVYKF
0.77
Cw4#2
SFNCGGEFF
1.09
*
Surface levels of HLA-Cw4 are expressed relative to that induced by
peptide Cw4#1. It is calculated as follows:
.
To assess the role of peptide in the direct recognition of HLA-C by p58 KIR receptors, we examined the interaction between peptide-loaded RMA-S-Cw4 and cl42-Ig, a soluble KIR that was previously shown to bind HLA-Cw4 expressed by 721.221 cells (13). Peptideloaded RMA-S-Cw4 cells were incubated with cl42-Ig and cl43-Ig, specific for HLA-Cw3 (29), and binding was detected by flow cytometry. The first striking observation was that cl42-Ig did not bind to HLA-Cw4 molecules in the absence of peptide (Fig. 2). However, there was good binding of cl42-Ig to RMA-S-Cw4 cells loaded with the consensus peptide QYDDAVYKL. As expected, there was no binding of cl43-Ig to peptide-loaded RMA-S-Cw4 (data not shown). Most of the peptides that stabilized surface expression of HLA-Cw4 on RMA-S-Cw4 cells also permitted interaction with cl42-Ig. However, peptides Y7E, K8E, and K8D were not recognized by cl42-Ig even though they stabilized surface expression of HLA-Cw4 as well as the consensus peptide, QYDDAVYKL. This second striking result highlights the importance of residues at P7 and P8 of the Cw4-bound peptide in the interaction between KIR-cl42 and HLA-Cw4. Importantly, this result suggests that the lack of binding to empty HLA-C on RMA-S-Cw4 cells was not simply due to the lower surface expression of HLA-C on these cells but to a requirement for peptide in the recognition by KIR. The HLA-Cw4- restricted T cell epitope peptide SFNCGGEFF (30) that bound RMAS-Cw4 as well as QYDDAVYKL (Table 1) was also tested. Cl42-Ig did not bind RMA-S-Cw4 molecules loaded with this peptide (data not shown). The negatively charged E at P7 may be responsible for the lack of recognition by KIR cl42. Thus, as was seen in studies with HLA-B*2705, side chains P7 and P8 were identified as being important in the recognition of HLA-Cw4 by KIR cl42. Side chain P8 of nonamer peptides bound to HLAB*2705 contacts residues 76, 77, and 80 of the class I heavy chain (19). It is likely that side chain P8 of HLA-Cw4- bound peptides is also in proximity to these residues, two of which form the basis for the distinction among HLA-C allotypes by NK cells (17, 22, 31).
Our data show that peptide is not required merely to ensure adequate levels of surface HLA-Cw4 but that the interaction with KIR cl42 is influenced by the composition
of the peptide in the groove. This contrasts the situation
with Ly-49 on mouse NK cells where any peptide that stabilized class I cell surface expression induced protection from
NK-mediated lysis. mAb blocking studies suggest that Ly-49A
interacts with the amino-terminal portion of the 2 domain of H-2Dd, away from the peptide-binding groove (4).
In contrast, the site of interaction between KIR and class I
includes the carboxy-terminal half of the
1 domain such
that side chains P7 and P8 in the bound peptide could influence KIR binding.
RMA-S-Cw4 cells loaded with peptide were tested in parallel for cl42-Ig binding and for inhibition of lysis by HLACw4-specific NK clones. There was a good correlation between cl42-Ig binding and the ability to induce protection
from lysis by a representative peptide-sensitive HLA-Cw4-
specific NK clone (Fig. 3). This peptide-dependent recognition of HLA-Cw4 by NK clones was reversible with the
KIR cl42-reactive mAb HP3E4 (Fig. 4). In contrast with
this reversion using anti-KIR mAb, anti-CD94 mAb
DX22 had no effect, indicating that the CD94 complex in
these cells did not contribute to the inhibitory effect. Thus,
we show that HLA-Cw4-specific NK clones that are inhibited through the HP3E4-reactive KIR do exhibit peptide selectivity. This does not preclude the existence of
other peptide-insensitive HLA-Cw4-specific NK clones
that might express either singly or in combination with
KIR other inhibitory receptors with potentially diverse and
as yet unknown modes of interaction with class I. Indeed,
such clones may have been used in previous studies in which HLA-C molecules on TAP-deficient cells provided
protection from NK-mediated lysis (22).
This study has identified a role for peptide in the specific interaction between HLA-Cw4 and the p58 inhibitory receptor cl42. The strength of this work is that recognition was determined by a direct binding assay with soluble KIR, thereby excluding any contribution by other NK receptors in the peptide-sensitive recognition of HLA-Cw4. Binding of a soluble form of KIR cl42 to HLA-Cw4 was not only dependent on the presence of a peptide, but it was also sensitive to the nature of the side chains at positions P7 and P8 of the nonamer peptide. This type of peptide-sensitive recognition of HLA class I by NK receptors was previously observed with HLA-B*2705-specific NK clones (18, 19). However, it is not known whether nonprotective B*2705bound peptides prevent the binding of p70 KIR. Both positively and negatively charged residues at P8 interfered with recognition of HLA-B*2705. In the case of HLA-Cw4, negatively charged residues at P8 were incompatible with binding of the p58 KIR cl42. These data establish that the sensitivity to peptide side chains P7 and P8 is a general feature shared by p58 and p70 KIR in their interaction with HLA class I.
Address correspondence to Eric O. Long, LIG NIAID NIH Twinbrook II, 12441 Parklawn Drive, Rockville, MD 20852-1727.
Received for publication 17 January 1997 and in revised form 14 February 1997.
We thank C. Winter for KIR-Ig fusion proteins; M. Weston for technical assistance; L. Lanier, M. LopezBotet, and S.Y. Yang for antibodies; P. Cresswell for transfected cells; R. Biassoni for plasmids; J. Coligan for peptides, and Hoffmann-La Roche for rIL-2.
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