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* Protein Engineering and Research Department and
Département de Biologie Joliot-Curie, Commissariat à l’Energie Atomique-Saclay, Gif sur Yvette, France;
SEDAC Therapeutics, Lille, France;
Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; and
¶ Institut National de la Santé et de la Recherche Médicale Unité 567, Institut Cochin, Hopital Cochin, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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86 and
11, respectively. Both positions are almost dimorphic and thus
produce a limited number of pocket combinations. Taken together, our
results support the existence of three main binding supertypes among
HLA-DP molecules and should significantly contribute to the
identification of universal epitopes to be used in peptide-based
vaccines for cancer, as well as for allergic or infectious
diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and -chains, which assemble
into a very similar structure (1, 2). Assembly of
the N-terminal domain of both chains forms the peptide-binding site,
which is composed of two helices standing above an eight-stranded
sheet floor. Conserved residues present in the binding site compose
a hydrogen bond network with the peptide backbone. They impose on the
peptide an extended conformation and sustain the broad peptide-binding
specificity of the HLA II molecules. Nevertheless, these molecules
possess their own peptide-binding selectivity (3, 4). This
is due to the polymorphic residues, which mainly lie within the binding
site. They have been distributed into five specificity pockets, which
accommodate the peptide amino acids numbered P1, P4, P6, P7, and P9
(1). Analyses of a wide spectrum of naturally bound
peptides and of synthetic analogs have identified peptide-binding
motifs and amino acid preferences for multiple HLA II molecules
(3, 4). These motifs generally correlate with the content
of the specificity pockets, allowing a detailed documentation of HLA II
molecules. Mainly HLA-DR and HLA-DQ have been investigated and appear
to be drastically different from each other. HLA-DR molecules are well
known to accommodate aromatic and hydrophobic residues, especially in
the P1 pocket (4, 5, 6, 7), while HLA-DQ molecules generally
accept relatively short side chains (8). The differences
appear less important between molecules encoded by the same locus
(9). Comparison of the repertoire of binding peptides
shows that HLA-DR molecules share common binding properties and hence
can be assembled into HLA II supertypes (6, 7). This
degenerated specificity allows the discovery of promiscuous peptides,
which bind to multiple HLA II molecules, and greatly enhances the
potential for the use of epitope-based vaccines (10, 11, 12, 13, 14, 15).
Supertypes were initially described for the class I molecules
(16, 17, 18) and only attributed to HLA-DR molecules for the
class II molecules (6, 7), probably because they are the
most investigated molecules.
In fact, the HLA-DP molecules have scarcely been studied. Initially,
they appeared less important in the immune response than HLA-DR and
HLA-DQ molecules, because HLA-DP incompatibility did not seem to
contribute to the risk of graft-vs-host disease
(GVHD)3 (19, 20). However, a single mismatch is now known to suffice in
triggering a specific T cell response after bone marrow transfer,
confirming the whole functionality of these molecules
(21). Both the - and -chains of HLA-DP molecules are
polymorphic molecules allowing multiple combinations of the 17
HLA-DPA1 and 86 DPB1 allelic forms
(22). However, only a limited number of HLA-DP molecules
are abundant in the worldwide population, the molecule
DPA1*0103/DPB1*0401 (DP401) being overrepresented (22).
This molecule differs by only three aa from the DPA1*0103/DPB1*0402
(DP402) molecule, which is also frequently encountered (Table I
). Together, both molecules have a gene
frequency of 50% in Europe, 60% in South America, 80% in North
America, 60% in India, 25% in Africa, and only 15% in Japan
(22). In the Caucasian population, they are carried by
76% of individuals and hence are as frequent as the well-known
HLA-A2 molecule. In comparison, approximately six molecules of HLA-DR
are required to cover the same percentage of people. Therefore, we
could expect that peptides that efficiently bind to DP401 and DP402
will have a large impact as epitope-based vaccines. However, although
multiple clones or T cell lines of various peptide specificities are
restricted to HLA-DP4 (23, 24, 25, 26, 27, 28, 29, 30), the binding specificity of
HLA-DP4 molecules remains unknown. To our knowledge, only the peptide
specificities of HLA-DP2 and HLA-DP9 molecules have been investigated
(31, 32), and only preliminary data of naturally processed
peptides eluted from a DP4 molecule have been reported
(33). Therefore, we used specific binding assays to
describe the peptide-binding motif of the HLA-DP4 molecules and to
demonstrate that they define a new peptide specificity supertype.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Peptides were synthesized as previously described (7) and were purified by reversed-phase HPLC on a C18 Vydac column (Interchim, Montluçon, France). Mutated peptides were used without purification, because they did not exhibit >10% contaminants in analytical HPLC. The NY-ESO-1-derived peptides (119–143 and 158–166) and MART-1/Melan-A peptides (1–20, 41–60, 51–73, 62–72, and 103–118) were synthesized using standard F-moc chemistry by the University of Pittsburgh Peptide Synthesis Facility (shared resource) as described previously (34). The biotinylated Oxy (bOxy) peptide 271–287 was biotinylated with biotinyl-6-aminocaproic acid (Fluka Chimie, St. Quentin Fallavier, France) on the N terminus before cleavage from the resin and HPLC purification. Quality of the peptides was assessed by electrospray mass spectroscopy. The peptides encompassing the sequence of the major bee venom are the following: 1–18, 5–22, 9–26, 13–30,17–34, 21–38, 25–42, 29–46, 33–50, 37–54, 41–58, 45–62, 49–66, 53–70, 57–74, 61–78, 65–82, 69–86, 73–90, 77–94, 81–98, 85–102, 89–106, 93–110, 97–114, 101–118, 105–122, 109–126, 113–130, and 117–134. Those covering the sequence of the Nef HIV-1/LAI protein are the following: 1–36, 25–39, 37–71, 66–94, 86–100, 100–114, 113–128, 117–132, 132–147, 137–168, 155–185, 175–190, and 182–198.
Cell cultures and purification
EBV homozygous cell lines PITOUT (DPA1*0103, DPB1*0401), HHKB (DPA1*0103, DPB1*0401), HOM2 (DPA1*0103, DPB1*0401), and SCHU (DPA1*0103, DPB1*0402) were used as sources of human HLA-DP4 molecules. They were cultured up to 5 x 109 cells in RPMI 1640 medium supplemented by 10% FCS, 2 mM glutamine, 1 mM sodium pyruvate, 500 µg/ml gentamicin, and 1% nonessential amino acids (Sigma-Aldrich, St. Quentin Fallavier, France). B7/21 hybridoma was a kind gift from Dr. Y. van de Wal (Department of Immunohematology and Blood Bank, Leiden University Medical Center, Leiden, The Netherlands). It was cultured in DMEM supplemented by 10% FCS, 2 mM glutamine, 1 mM sodium pyruvate, 500 µg/ml gentamicin, 1% nonessential amino acids, 10 mM HEPES, and 50 µM 2-ME (Sigma-Aldrich). Abs were purified by immunoaffinity on protein A-Sepharose as recommended by the manufacturer (Pharmacia, Orsay, France). HLA-DP4 molecules were purified by affinity chromatography using B7/21 mAb (35) coupled to protein A-Sepharose CL 4B gel (Pharmacia) as described previously for L243 mAb (7).
HLA-DP4-specific binding assays
Binding assays were based on previously published protocols
(8, 32, 36). Briefly, they were performed in 10 mM
phosphate, 150 mM NaCl, 1 mM n-dodecyl
-D-maltoside, 10 mM citrate, and 0.003%
thimerosal (pH 5) buffer with 10 nM of
bOxy271–287, an appropriate dilution of HLA-DP4
molecules (0.1 µg/ml), and serial mid-dilutions of competitor
peptides. After 24-h incubation at 37°C, samples were neutralized and
applied to B7/21-coated plates for 2 h. Bound biotinylated peptide
was detected by means of streptavidin-alkaline phosphatase conjugate
(Amersham, Little Chalfont, U.K.), and 4-methylumbelliferyl phosphate
substrate (Sigma-Aldrich). Emitted fluorescence was measured at 450 nm
upon excitation at 365 nm in a Victor II spectrofluorometer
(PerkinElmer Instruments, Les Ulis, France). Data were expressed as the
peptide concentration that prevented binding of 50% of the labeled
peptide (IC50). IC50 values
of the Oxy271–287 peptides served as reference
in each experiment.
Computer modeling of the HLA-DP4/Oxy complex
HLA-DP4/Oxy complex was built by amino replacement from the
DR1-HA complex (Brookhaven Protein Data Bank accession code
1dlh), most (100) of the residues to be replaced being surface
residues. The water molecules buried in the DR1-HA complex were first
removed because of obvious clashes when left during residue
replacements. Great care was taken to minimize perturbation of residues
and backbone in the surroundings of the replaced residues. This was
done by gently and progressively propagating the perturbation using the
following procedure: 1) the replaced residue was accommodated by
alternating energy minimization and low temperature (10–50 K) dynamics
with the rest of the protein held fixed; 2) the neighboring residues in
contact with the replaced residue were subjected to the same treatment;
and 3) both the replaced residue and its neighbors were minimized again
with the rest of the protein held fixed. When all the required
replacements were completed, the whole DP4 protein obtained was
thoroughly minimized (1000 steps) to anneal the small remaining
strains. Except for the region where two residues were deleted
(deletion of residues 23–24 in the -chain), the DP4 structure was
found to be very similar to the original DR1 structure. The Sybyl
program (Tripos Associates, St. Louis, MO) was used for this
work.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After a round of screening of biotinylated peptides, we selected
the Oxy271–287 peptide to establish binding
conditions for both DP401 and DP402 molecules. This peptide has been
sequenced from naturally processed peptides eluted from
DPA1*0201/DPB1*0401 molecules (33) and presents 100%
identity with a fragment of the oxytocinase protein (GenPept accession
code U62769). As shown in Fig. 1, a
concentration range of the nonbiotinylated
Oxy271–287 peptide totally inhibits the binding
of its biotinylated form to both molecules, thus demonstrating the
peptide interaction specificity. The mid-inhibition occurred at 10
nM concentration. In this assay, the binding specificity for the
HLA-DP4 molecules was ensured by the known specificity of the B7/21 Ab
(35). It was used to immunopurify the HLA-DP4 molecules
and to trap them onto ELISA plates. Nevertheless, we also assessed that
other peptides known to bind HLA-DP4 molecules were equally good
binders in our assays. The HLA-DP4 eluted peptide
IL3R127–146 (33) and the T
cell epitopes MAGE3245–268
(28), HSV283–302 (29),
NSP2 (24), and tetanus toxoid (TT) peptide
947–963 (26) inhibited the binding at different levels of
efficiency. In sharp contrast, the HA306–318
peptide, which is known to bind efficiently to multiple HLA-DR
molecules (5, 37), and the peptides
HCI46–63 and
DQB43–57, which bind efficiently to
HLA-DQ molecules (38), were totally inactive.
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). Three 13-mer peptides (271–283,
272–284, 273–285) were as active as the native peptide on both
molecules, suggesting that the core region extended from K273 to L283.
Moreover, removal of F275 was associated with a large decrease in the
binding, suggesting that this position played a major role in the
interaction. Accordingly, alanine (Oxy F275A) and lysine (Oxy F275K)
substitution of this position altered the peptide’s ability to bind to
DP401 (Table III). The same dramatic
effect was seen toward DP402 with F5K but not with F5A. Interestingly,
substitutions by either alanine or lysine of a second phenylalanine
(F280) strongly affected the binding for both molecules. This residue
appeared as the main anchoring residue. Finally, substitution of L283
by a lysine diminished the binding to both DP401 and DP402, while
substitution of T278 by a lysine only slightly altered the binding to
DP401. Three residues, F275, F280 (I + 5), and L283 (I + 8), therefore
appeared as anchor residues and this pattern suggested strongly that
they were accommodated by both HLA-DP4 molecules in the P1, P6, and P9
pockets, respectively (1). This was in agreement with the
molecular modeling of the peptide Oxy273–285
bound to DP401 and DP402 (Fig. 2 and see
below). We thus synthesized a novel set of peptides substituted at
these positions to investigate the amino acids preferences of each
pocket (Table IV). In the P1 and P6
pockets, conservative substitutions were well tolerated in sharp
contrast to substitutions by E, N, and T. In the P4 pocket, only small
effects were observed, while significant but moderate binding loss was
found in the P9 pocket. Slight differences were observed between DP401
and DP402 as exemplified by substitutions with basic residues in the P4
pockets, N in the P1 and Y in the P9. However, as summarized in Table V, DP401 and DP402 exhibit a similar
binding motif mainly characterized by the existence of two main anchor
residues in the P1 and P6 pockets.
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We then modeled the complexes of the peptide
Oxy273–285 with DP401 and DP402 on the basis of
HLA-DR1/HA306–318 crystallographic data
(1) (Brookhaven Protein Data Bank accession code
1dlh). As illustrated in Fig. 2
, HLA-DP4 seems to possess a large
aromatic cavity in the N-terminal part of the bound peptide. There are
only two major replacements between HLA-DR1 and HLA-DP4, which are in
the exterior lateral side of the pocket:
DR1-Ala52 to DP4-F52 and
DR1-Phe89 to
DP4-Met89. These mutations do not modify the
size or hydrophobic character of this pocket, but the
Oxy-Phe275 seems to be more deeply buried in
HLA-DP4 than the longer HA-Tyr308 in HLA-DR1. In
sharp contrast, the P6 pocket looks very different in the two models
HLA-DP401 and DP402/Oxy as compared with the complex HLA-DR1/HA. This
pocket is quite shallow in HLA-DR1 because of the large side-chain
floor residue L11, while it is deep in the models of DP401 and DP402
because of the small floor residue G11. The sole difference between
DP401 and DP402 resides in the P9 and stays principally in the
mutations DP401-A38 to DP402-V38 and DP401-A57 to DP402-D57, the
position 58 being outside the binding groove. The mutation DP401-A57 to
DP402-D57 seems to create a similar hydrogen bond network to that found
in the P9 pocket of HLA-DR1. In these models, we also observed the
presence of buried water molecules and a lower number of hydrogen bonds
with the peptide as compared with the HLA-DR1 molecule (data not
shown). As a result, the HLA-DP4/Oxy model strongly suggests the
existence of two large aromatic pockets (P1 and P6), which may account
for our binding observations that aromatic/hydrophobic amino acids at
these positions serve as anchor residues.
DP4-specific motif is present in most of the peptides that bind to DP401 and DP402
We then assessed the relevance of the HLA-DP4 motifs in peptides
different from the Oxy peptides in relation with their capacity to bind
to HLA-DP4 molecules. We first aligned the sequences of the good DP4
binders that we described in Fig. 1: IL3R127–146
(33), MAGE3245–268
(28), HSV283–302 (29),
NSP2 (24), and TT947–963
(26) (Table VI). Only the
NSP2 peptide did not exhibit the HLA-DP4 motif although it bound
efficiently to HLA-DP4 molecules. The motif was also found in the
active peptide NY-ESO-1158–180, which we also
retained for this study, because it stimulated a HLA-DP4-restricted T
cell clone (30). We then looked for the presence of the
binding motif in unselected sets of peptides. In the 30 peptides that
encompassed the whole sequence of the major bee venom allergen, 4
peptides (API m1 73–90, 77–94, 81–98, and 117–134) had the motif.
Two of them (77–94 and 81–98) were found active but with different
level of activity (Table VI). In the 13 peptides that entirely covered
the HIV Nef protein, only the peptide Nef66–94
possessed the motif and bound to the HLA-DP4 molecules. However, a
second peptide (Nef132–147) also bound to
HLA-DP4 molecules but harbored a partial binding motif only. None of
the 4 peptides from MART-1/Melan-A exhibited the motif and only 1
peptide (MART-151–73) displayed a weak activity.
Finally, the motif was also found in the peptide
NY-ESO-1119–143 (34). It exhibited
a good binding activity. As a result, from the 13 binders we identify,
10 contain the motif in their sequence. Reciprocally, 2 peptides
contain the binding motif but did not bind to HLA-DP4 molecules. Forty
peptides have no binding motif and no activity. We also found few
discrepancies between DP401 and DP402, strongly suggesting that both
molecules share very similar anchor residues in the P1, P6, and P9
positions.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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11 as numbered by
alignment with DRB1. It also accepts large aromatic and aliphatic
residues. As compared with HLA-DR molecules, this pocket might be more
hydrophobic as a result of the replacement of D66 and E11 in
DRB1*0101 by L66 and A11 residues. This is probably why a glycine
at position 11 does not favor aromatic or hydrophobic residues in
HLA-DR molecules as illustrated by the P6 specificity of DRB1*0701
(4). Therefore, structural characteristics of the P1 and
P6 pockets appear to account for amino acid preferences observed in the
binding assays specific for HLA-DP4. Moreover, HLA-DP401 and -DP402
molecules differ by only three substitutions, which reside in the P9
pocket and which do not provoke major changes in the amino acid
preferences of this pocket. Therefore, it is not surprising that they
share very similar binding motifs. Based on the computer model of
HLA-DP4 molecules, the P1 and P6 pockets contain only two polymorphic
positions, 86 and 11, respectively. Both positions are almost
dimorphic: 86 is either a glycine or an aspartate while 11 is
either a glycine or a leucine. Therefore, amino acid preferences in the
P1 and P6 pockets are expected to be controlled by a limited number of
key amino acid combinations. Thus, we propose a supertype subdivision
of the HLA-DP molecules based on the 11 and 86 positions.
DPB1*0402 differs from DPB1*0201 by only one aa at position 71 as
numbered by alignment with DRB1 in the peptide-binding groove. As this
position resides in the P4 pocket, it does not modify the amino
preferences in the P1 and P6 pockets. Accordingly, the motif HLA-DP2
exhibits exactly the same amino acid preferences in these pockets as
HLA-DP4 (32). It differs only slightly from HLA-DP4 by the
residues accommodated by the P4 pocket. More precisely, a sequence
alignment suggests that the amino acids preferred in this pocket act as
hydrogen bond donors in HLA-DP2 (32), as agreed by
the modeling of HLA-DP/Oxy complex (data not shown). Moreover, the same
substitution at the position 71 exists between the molecules
DRB1*0401 and DRB1*0402 and has been shown to account for most of the
few binding discrepancies between these two HLA-DR4 allotypes
(39). Thus, as the major binding effects result from P1
and P6 substitutions in both HLA-DP2 and HLA-DP4, these molecules are
expected to share a common repertoire of peptides and hence to form a
supertype of HLA II molecules. In sharp contrast, the HLA-DP9 molecule
seems to belong to another supertype (31). This molecule
exhibits a totally different motif as a positively charged residue and
a short/hydrophobic residue serve as primary anchor in the P1 and P6
pockets, respectively (31). This motif is nicely
associated with the presence of a negatively charged aspartate at
position 86 in the P1 pocket and with the reduced size of the P6
pocket, in which is buried a leucine at position 11. Therefore,
based on these observations, we could speculate that HLA-DP molecules
are distributed into three main binding supertypes defined by the
following combinations of key amino acids: G11 G86, G11
D86, and L11 D86. We can outline that 86 in HLA-DR
molecules is also dimorphic and is occupied by a valine or a glycine.
It is known to control the P1 anchor residue (3, 4, 40)
and to contribute to the dimer stability of HLA II molecules
(41). It has also been identified as a key position that
segregates the preponderant alleles upon different binding modes
(4, 5, 7).
Moreover, as an unexpected consequence, our data may provide new
insights into the allogenic reactivity of HLA-DP and their debated role
in GVHD. It is known that HLA-DP incompatibility only leads to low
mixed lymphocyte reaction. Accordingly, the HLA-DPB1
disparity was not initially found to influence the risk of acute GVHD
(19, 20). Recent studies performed on HLA-A, -B, -DR, and
-DQ identical pairs demonstrated its role in the graft outcomes
(34, 42) as agreed by isolation of allogenic T cell clones
(21). However, the authors concluded that not all HLA-DP
incompatibilities elicit a measurable MLR response (42).
Therefore, HLA-DP appears to be of less importance in comparison with
other HLA II molecules. It is tempting to discuss these observations in
the light of our binding data. We suggest that the repertoire of
natural peptides that bind to HLA-DP molecules is preferentially
circumscribed by the amino acid combination at positions 11 and
86. Although HLA-DP2 and HLA-DP4 did not exhibit evident common
peptides (32, 33) and differ by the 71 which appeared
to be involved in allorecognition (42), subsets of HLA-DP
molecules from the same supertype may have in common a large number of
naturally presented peptides. In this context, precursors of allogeneic
T cells might be low in number as a result of negative thymic selection
and hence rarely give rise to graft rejection. In contrast, HLA-DP from
different supertypes would be fully allogeneic.
The binding assays presented in this paper constitute a promising way
of selecting peptides for vaccination. Peptide-based strategies of
vaccination generally use HLA-DR-restricted peptides as
TT830–843 (43) or PADRE
peptide (13) to trigger a specific immune response. Such
peptides have been primarily selected, because they are able to bind
multiple HLA-DR molecules and hence are expected to be active in most
individuals. Therefore, much effort has been devoted to finding such
peptides in pathogens (11, 15, 44, 45), allergens
(7, 46), and tumor Ags (34, 47). As outlined
previously (28, 30), HLA-DP4 are present in 75% of
Caucasians. Their frequency is equivalent to that of the well-known
class I molecule HLA-A2 (22). Therefore,
HLA-DP4-restricted peptides have a similar impact in the Caucasian
population to HLA-DR peptides that bind approximately six different
HLA-DR molecules. We can also notice that all the immunodominant
HLA-DP4-restricted peptides that have been delineated by others using T
cell lines or clones are included in the best peptide binders found by
our assays (24, 26, 28, 29, 30). Among them,
NY-ESO-1158–180 seems to promote a T cell
response that supports the humoral response against NY-ESO-1
(30). Therefore, HLA-DP4-restricted T cells appear as
active as HLA-DR-restricted T cells to provide a helper activity.
Together, these observations support the use of HLA-DP4-specific
binding assays to delineate new sequences for vaccination. As the
HLA-DP4-specific motifs clearly differ from that of HLA-DR molecules,
these peptides could nicely complement the HLA-DR-restricted peptides
in a multiepitopic strategy and hence diminish the risk of pathogen
evasion. In particular, in this study, we propose new sequences from
the major bee venom allergen, which could be used in specific
immunotherapy of patients allergic to bee venom (7), from
the HIV Nef protein and the melanoma Ag NY-ESO-1, which could be
included in a peptide vaccine (34, 48). However, as
compared with investigations of HLA-DR molecules, we identified fewer
active peptides (7, 34, 49). This might result from the
two constraints imposed on the P1 and P6 pockets and may suggest that
HLA-DP4 epitopes are rarer than HLA-DR epitopes. Therefore, considering
their frequency in the worldwide population, these epitopes are of
great value for vaccination and constitute an alternative to the
preparation of universal T cell epitopes.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bernard Maillère, Protein Engineering and Research Department, bat 152, Commissariat à l’Energie Atomique-Saclay, 91191 Gif sur Yvette, France. E-mail address: bernard.maillere{at}cea.fr
3 Abbreviations used in this paper: GVHD, graft-vs-host disease; DP401, DPA1*0103/DPB1*0401; DP402, DPA1*0103/DPB1*0402; bOxy, biotinylated Oxy; TT, tetanus toxoid.
Received for publication June 21, 2002. Accepted for publication October 10, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and -chain polymorphisms determine the specificity of the disease-associated HLA-DQ2 molecules, with -chain residues being most influential. Immunogenetics 45:142.[Medline]
-chain. Proc. Natl. Acad. Sci. USA 92:6567.-chain residue 86 controls DR dimer stability. Eur. J. Immunol. 23:1346.[Medline]
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 M. Perreau and E. J. Kremer Frequency, Proliferation, and Activation of Human Memory T Cells Induced by a Nonhuman Adenovirus J. Virol., December 1, 2005; 79(23): 14595 - 14605. [Abstract] [Full Text] [PDF]
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A. Immonen, S. Farci, A. Taivainen, J. Partanen, S. Pouvelle-Moratille, A. Narvanen, T. Kinnunen, S. Saarelainen, M. Rytkonen-Nissinen, B. Maillere, et al. T Cell Epitope-Containing Peptides of the Major Dog Allergen Can f 1 as Candidates for Allergen Immunotherapy J. Immunol., September 15, 2005; 175(6): 3614 - 3620. [Abstract] [Full Text] [PDF]
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I. A. Doytchinova and D. R. Flower In Silico Identification of Supertypes for Class II MHCs J. Immunol., June 1, 2005; 174(11): 7085 - 7095. [Abstract] [Full Text] [PDF]
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M. Mandic, F. Castelli, B. Janjic, C. Almunia, P. Andrade, D. Gillet, V. Brusic, J. M. Kirkwood, B. Maillere, and H. M. Zarour One NY-ESO-1-Derived Epitope That Promiscuously Binds to Multiple HLA-DR and HLA-DP4 Molecules and Stimulates Autologous CD4+ T Cells from Patients with NY-ESO-1-Expressing Melanoma J. Immunol., February 1, 2005; 174(3): 1751 - 1759. [Abstract] [Full Text] [PDF]
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M. Ayyoub, C. S. Hesdorffer, G. Metthez, S. Stevanovic, G. Ritter, Y.-T. Chen, L. J. Old, D. Speiser, J.-C. Cerottini, and D. Valmori Identification of an SSX-2 Epitope Presented by Dendritic Cells to Circulating Autologous CD4+ T Cells J. Immunol., June 1, 2004; 172(11): 7206 - 7211. [Abstract] [Full Text] [PDF]
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M. S. Lillicrap, R. C. Duggleby, J. C. Goodall, and J. S. H. Gaston T cell recognition of a highly conserved epitope in heat shock protein 60: self-tolerance maintained by TCR distinguishing between asparagine and aspartic acid Int. Immunol., March 1, 2004; 16(3): 405 - 414. [Abstract] [Full Text] [PDF]
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L. de Waal, S. Yuksel, A. H. Brandenburg, J. P. M. Langedijk, K. Sintnicolaas, G. M. G. M. Verjans, A. D. M. E. Osterhaus, and R. L. de Swart Identification of a Common HLA-DP4-Restricted T-Cell Epitope in the Conserved Region of the Respiratory Syncytial Virus G Protein J. Virol., February 15, 2004; 78(4): 1775 - 1781. [Abstract] [Full Text] [PDF]
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