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IMMUNOBIOLOGY
From the Department of Immunohematology and Blood
Transfusion, Leiden University Medical Center, and the Department of
Medicinal Chemistry, Leiden University, Leiden/Amsterdam Center for
Drug Research, The Netherlands.
T-cell receptors (TCRs) of a series of minor histocompatibility
antigen (mHag) HA-1-specific cytotoxic T-cell (CTL) clones isolated
from 3 unrelated patients have been shown to use the same BV6S4A2
segment with conserved amino acids in the CDR3V T cells are activated by the interaction
between the T-cell receptor (TCR) and its specific ligand Subtle changes in the antigenic peptide can result in altered
recognition or no recognition by the T cell. Partial agonists cause
decreased activation of the T cell or induce a limited set of effector
functions by the T cells. TCR antagonists are nonstimulatory ligands
that compete with the agonist for the TCR.6-8 Hence, they
can prevent proliferation, cytokine production, and cytotoxicity by MHC
class II and class I restricted T-cell clones.9,10 Antagonists have been generated in vitro by single or double amino acid
substitution of the antigenic peptide.9-11 In addition,
naturally occurring variants of human immunodeficiency virus, hepatitis B virus, and malaria encoding mutated epitopes that could down-regulate the CTL response by TCR antagonism have been
described.12-14 TCR antagonists have been proposed as a
potential therapy for autoimmune diseases. Although TCR antagonists
have been developed and have been shown to decrease the severity of
autoimmune diseases, such as experimental allergic encephalomyelitis
(EAE) or adjuvant arthritis (AA),11,15-17 inhibition of
polyclonal responses may be difficult to establish. Each different TCR
apparently requires a different TCR antagonist.10,18
Numerous T-cell responses have been described that use a restricted set
of TCR V Human minor histocompatibility antigen (mHag) HA-1 is a nonameric
peptide VLHDDLLEA encoded by one allele of the KIAA0223 gene.25 HA-1 Five different CTL clones recognizing mHag HA-1 in the context of
HLA-A2 express the same V Our goal was to develop antagonist peptides for the immunodominant
HA-1-specific T cells. First, TCR contact residues in the HA-1 antigen
were determined for 2 different HA-1-specific CTL clones. These amino
acids and 2 adjacent amino acids were substituted with all 20 amino
acids and tested for agonistic and antagonistic activity in
cytotoxicity assays. To achieve physiologically relevant antagonistic
activity, the inhibition of lysis of an endogenously HA-1-expressing
EBV- BLCL by the HA-1-specific CTL was determined. Candidate
antagonistic peptides were tested for their effect on HA-1-specific
CTL clones, polyclonal CTL lines, and patient peripheral blood
mononuclear cells (PBMCs) derived at the time of active GvHD after
HA-1-mismatched SCT. The results show that it may be feasible to
develop general antagonistic peptides that can inhibit T-cell
recognition of the natural HLA-A2-HA-1 ligand.
Cell lines
Peptides
Peptide binding to HLA-A2 Binding of candidate peptides to HLA-A2 molecules was measured using recombinant HLA-A2 molecules in a cell-free competition-based assay as described previously.32 Relative binding affinities of the peptides are expressed as the IC50 values (concentration of the peptide that inhibits 50% of the binding of the reference peptide). HA-2 peptide (amino acid sequence, YIGEVLVSV) is used throughout as a negative control and binds effectively to HLA-A2 with IC50 value of 6.7 nM.32Cytotoxicity assay Chromium Cr 51-labeled target cells (2500 cells) in 25 µL RPMI 1640 medium with 3 mM L-glutamine and 15% human serum were incubated with 25 µL peptide solution for 30 minutes at 37°C. CTLs were then added, resulting in a final volume of 150 µL. After 4 hours at 37°C, 51Cr release in the supernatant was measured by standard methodology. HA-1 T2 or EBV-BLCL was used to
determine the agonistic activity of the substituted peptides.
Endogenously HA-1 expressing EBV-BLCL was used to determine the
antagonistic activity of the substituted peptides. Peptide
concentrations ranged from 5 µg/mL to 0.5 ng/mL during preincubation,
giving final concentrations of 1.67 µg/mL to 0.167 ng/mL. Percentage
inhibition was calculated as follows: 1  (% Lysis peptide-loaded
HA-1+ EBV-BLCL)/(% Lysis HA-1+ EBV-BLCL) × 100.
Interferon-  -coated ELISpot plates (Mabtech, Cincinnati, OH). After
culturing for another 20 hours, the IFN- spots were visualized using
the commercial ELISpot (Mabtech) kit according to the instructions of
the manufacturer. The number of IFN- spots in each well was
determined with the use of a fully automated inverted light microscope.
Molecular modeling All molecular modeling operations were performed on a Silicon Graphics O2 workstation (Mountain View, CA, USA). Quanta 4.0 molecular modeling suite (Molecular Simulations, San Diego, CA) was used as the software package. Several HLA-A2.1-peptide complexes were retrieved from the PDB, the Brookhaven Protein Databank,33 including reference codes 1hhg, 1hhh, 1hhi, 1hhj, and 1hhk. The crystal structure of the complex between HLA-A2, a TAX peptide, and its TCR (A6) was kindly provided by Dr P. Ghosh.1 This latter structure holds the same peptide (LLFGYPVYV) present in the 1hhk file, though in a slightly different conformation. The modeling procedure consisted of the following steps. First, the peptide in the 1hhj file (ILKEPVHGV) was used as a template for the generation of a VLHDDLLEV conformer, one of the relevant peptides in the current study, because they share the highest homology. The directionality of the side chains in VLHDDLLEV was based on the conformation of the peptide in the HLA-TCR complex. Second, the peptide backbone of VLHDDLLEV was superimposed on the backbone of the peptide in the HLA-TCR complex as closely as possible. Third, TCR clone 5W38 was compared with crystalline TCR by means of protein homology modeling. Large, mutually conserved sequence elements in both TCRs served as anchor points to define the borders of the hypervariable regions. The TCR chain was
most in contact with the peptides, with important sequence
differences between the 2 TCRs as indicated in Table
1.
Homology modeling of fragment N is most speculative. Fragments V and J both share significant homology among the 2 receptors, and an initial model for fragments V and J of clone 5W38 was easily obtained by the on-screen mutation of A6. For fragment N, the following procedure was used. A sequence analogy search in the PDB identified reference code 1aih with the element GARWSEA. Highest homology of all sequences available with the N fragment (GARGWEN) was in clone 5W38. Three-dimensional topology of GARWSEA (slightly alpha-helical in nature) was used as a template for the conformation of the GARGWEN element. The resultant GARGWEN conformer was patched onto the crystal structure of A6 after on-screen excision of the di-peptidic element VT. This procedure required energy minimization of the new fragment. For this purpose Quanta's CHARMm force field was used in a default operating mode. Fourth, the eventual VLHDDLLEV (peptide)-5W38 (TCR) complex was further
energetically optimized by keeping the peptide fixed and the variable
loops of 5W38 flexible. Similarly, the variable regions of the TCR
Determination of general TCR contact residues in HA-1 The interaction of 3 HA-1-specific HLA-A2-restricted CTL clones 3HA15, 5W38, and clone 15with the HA-1 peptide was studied by
analyzing the recognition of alanine-substituted peptides. All 3 clones
express different TCRs but share the same BV6S4A2 segment. T-cell
clones 3HA15 and clone 15 even share the same V- and  -chains but
are still different in J sequences and CDR3 regions (Table
2). Binding capacity of
alanine-substituted peptides to the HLA-A2 molecule was first
determined using a cell-free assay based on the inhibition of binding
of a fluorescence peptide. Except for the peptides with alanine at
positions 2 and 6, all alanine-substituted peptides were good HLA-A2
binders (data not shown). In addition, the alanine-substituted peptides
were titrated on the TAP-deficient and efficient exogenous
peptide-presenting T2 cell line and were evaluated for recognition by
the 3 CTL clones in a cytotoxicity assay (Figure
1). Substitution of both aspartic acids
at positions 4 and 5 and of the glutamic acid at position 8 prevented
recognition by all 3 clones. Substitution of leucine at position 7 inhibited the recognition of 2 of 3 clones, 3HA15 and clone 15. These
data suggested that positions 4, 5, and 8 are important for TCR
recognition of all 3 clones.
Molecular modeling of the VLHDDLLEA-5W38 peptide-TCR complex Proposed interactions between the HA-1 peptide and the T-cell clones were further studied by a computer model of the HLA-A2 molecule with the HA-1 peptide in conjunction with 5W38. The model was based on the crystal structure of HLA-A2 with the tax peptide and its specific TCR, A6. In Figure 2 a close-up of the peptide binding site on the TCR clone 5W38 is represented. Aspartic acid side chains on positions 4 and 5 are in close contact with the N and J fragments of the clone. The first serine in J and an arginine
in the NDN region of CDR3V seem to be important for this
interaction. Interestingly, the histidine side chain on position 3 may
also interact with the TCR because of the large CDR3V chain. In the
model, the arginine residue in the CDR3 V fragment GARGWEN is
particularly close to position 3 of the peptide. Positions 7 and 8 of
the peptide with a leucine and a glutamic acid side chain,
respectively, appear to be close to the TCRV chain NDN region. In
fact, a hydrogen bond is feasible between the glutamic acid-NH group
in the peptide backbone and the C = O backbone moiety of the first
glycine residue in the chain NDN fragment. As a consequence, the
leucine side chain at position 7 in the peptide is oriented toward a
hydrophobic region, consisting of the tripeptide Val-Ala-Leu in the NDN
fragment. The orientation of the Glu8 side chain in the peptide is
arbitrary because there is no immediate TCR counterpart in its
vicinity. Overall, the binding between peptide and receptor is
compatible with the diagonal mode, as reported for the 2 crystal
structures available.1,5 Finally, positions 2, 6, and 9 of
the peptide are directed toward the HLA molecule and do not interfere
with TCR binding.
Selection of HA-1 TCR antagonists Peptides were synthesized with every possible amino acid substitution at the proposed TCR contact residues 4, 5, and 8 and at 2 adjacent residues, positions 3 and 7. These peptides were first tested for their agonistic and antagonistic activity against CTL clones 3HA15 and 5W38 in cytotoxicity assays. To test for agonistic activity, the peptides were incubated with an HA-1 EBV-BLCL for 30 minutes before the addition of CTL. To test for antagonistic activity,
the peptides were incubated with an HA-1+ EBV-BLCL. This
would enable the selection of antagonistic peptides capable of
inhibiting the recognition of naturally expressed HA-1 antigen.
Substitution of position 5 with every amino acid completely abolished
the recognition by the 2 clones because no agonistic or antagonist
activity could be detected (Table 3).
Position 4 substitution resulted in the loss of agonistic activity for both clones. Approximately half of the position 4 substitutions had
antagonizing activity on 3HA15 but not on 5W38. These results, together
with the modeling data, strongly suggest that DD at positions 4 and 5 are essential TCR contact sites for 3HA15 and 5W38 and that they may be
considered primary TCR contact residues. Substitution of positions 3, 7, and 8 led to peptides with different activities, including
antagonistic activity (Table 3). From the 100 different tested peptides
we could not detect strong (more than 50% inhibition) antagonizing
peptides for 5W38, though we could find strong antagonists for
3HA15.
Analysis of candidate antagonists Among the 7 peptides that showed moderate to strong antagonistic but no agonistic activity for the 3HA15 and the 5W38 clones, 2 peptides that contained substitutions at position 3 (G or S) were selected for further analysis on the basis of reproducibly antagonizing 3HA15 and 5W38. Additional substitution of position 9 (V instead of A) of these 2 peptides resulted in peptides with higher affinity for HLA-A2 (IC50 of 18 nM for 3G9V and 3S9V compared to IC50 of 82 and 66 nM for 3G and 3S, respectively). All 4 peptides (3G, 3S, 3G9V, 3S9V) were efficient antagonists of clone 3HA15 and completely abolished the lysis of an HA-1-presenting EBV-BLCL (Figure 3A), whereas CTL clone 5W38 could be inhibited 50% by the 4 peptide antagonists (Figure 3B). The latter 4 antagonist peptides were subsequently used to antagonize a third HA-1-specific CTL clone, clone 15. Like clone 3HA15, clone 15 is derived from the polyclonal CTL line (A2Bx), and it expresses the same TCR V (AV3S1) and V (BV6S4A2)
chains but different J and CDR3 regions. In spite of the highly
homologous TCRs, the 2 clones reacted differently to the 4 peptides.
Whereas all 4 peptides strongly antagonized 3HA15, the inhibition of
clone 15 was partial, with best inhibition levels of 50% to 60% by 3S
and 3S9V (Figure 3C).
The differential effect of antagonistic peptides on the 3 CTL clones could be a reflection of their different affinity to the HA-1 peptide. To verify this possibility, the CTL clones were assayed against target cells in HA-1 peptide titration assays. All 3 CTL clones reacted similarly to the HLA-A2-HA-1 peptide ligand (Figure 3D). Antagonist peptides were subsequently used to antagonize polyclonal
HA-1-specific CTL lines derived from 3 different patients. The CTL
line A2Bx, the original CTL line of the CTL clone 3HA15 and clone 15, was inhibited 50% with the peptides 3S, 3G9V, and 3S9V and was
inhibited 40% with peptide 3G (Figure
4). CTL lines P.1.1 and K.1.1 were also
effectively inhibited by the antagonistic peptides 3G and 3S, with
maximal inhibition levels of 50% to 70% with 5 µg/mL peptides.
These results show that at the clonal and at the polyclonal level, CTL
responses can be inhibited by antagonist peptides.
Finally, we performed ELISpot (Mabtech) assays to determine
whether the antagonist peptides can inhibit the HA-1-specific CTL
present in the PBMCs of a patient who acquired GvHD after HLA-matched-HA-1-mismatched SCT. Because the patient and donor have
multiple mHag disparities besides HA-1, the patient's post-SCT PBMCs
were stimulated with stem cell donor EBV-BLCLs pulsed with 0.1 µg/mL
HA-1 peptide. Subsequent addition of antagonist peptides specifically
reduced the number of IFN-
Four crystal structures of MHC-peptide-TCR complexes indicate
that the diagonal mode of interaction between TCR and HLA molecules is
a general feature of different TCRs.1-5 mHag
HA-1-specific CTL clones have been characterized by the presence of
the BV6S4A2 chain and conserved amino acids in the V Interaction of HA-1 with 3HA15 and 5W38 TCRs Three different HA-1-specific CTL clones, 3HA15, 5W38, and clone 15, were evaluated for their TCR contact residues in the HA-1 peptide. All clones used the BV6S4A2 segment, and 2 (3HA15 and clone15) used the same AV2S1 segment. Alanine substitution analysis revealed that positions 4, 5, and 8 were important for the TCR interaction with the 3 clones. Position 7 was essential for the 2 clones with the identical VV chains. Recently, we identified a fourth HA-1-specific T-cell
clone expressing BV6S4A2, but with a different TCR, it also was shown
to have positions 4, 5, 7, and 8 as TCR contact sites (data not shown).
Computer modeling of the HLA-A2-HA-1 complex with the TCR of clone
5W38 indicated that the side chains of the aspartic acids at positions 4 and 5 indeed pointed out from the groove and fit in the pocket formed
by the 5W38 CDR3V and V chains. Because other substitutions at
these positions are as detrimental for T-cell recognition as the
alanine substitution, it can be concluded that positions 4 and 5 are
the most essential TCR contact sites in the HA-1 peptide. Positions 7 and 8 are more distant, but there seems to be contact with the 2 glycines and with Val-Ala-Leu in the CDR3V region of 5W38. In the
model, the histidine at position 3 could interact with the arginine of
the CDR3V region ARWGE of 5W38. The absence of activity of most
substitutions at this position for 5W38 supports this hypothesis.
We did not observe any evidence for interactions with the CDR1 of
the 5W38 V Determination of general HA-1 antagonists One hundred peptides were assayed for their antagonistic activity on HA-1-specific 3HA15 and 5W38 CTL clones. To determine the level of antagonizing activity, peptides were loaded on EBV-BLCL that endogenously expressed mHag HA-1. In our opinion, this is a more physiological test system than a prepulse assay.9 In a prepulse assay a target cell is loaded with suboptimal amounts of antigen. Nonbound antigen is washed away, and the antagonistic peptide is added. The antigen gradually dissociates from the MHC molecules, and its abundance decreases in time. In contrast, HA-1 expressing EBV-BLCL continuously expresses a similar amount of HA-1 antigen sufficient to efficiently activate T cells. Although prepulsed targets are loaded with suboptimal amounts of antigen, generally resulting in low lysis, the HA-1 expressing EBV-BLCL are lysed to 60%. Only peptides that can antagonize this lysis may be effective for in vivo protocols.From the 100 peptides evaluated, only 2 peptides with a substitution on position 3 (3G and 3S) showed clear antagonizing activity toward the 3HA15 and the 5W38 clones in cytotoxicity assays. The potency of these antagonist peptides were additionally verified in the prepulse assay mentioned above. Figure 3A shows that when HA-1 peptide-pulsed target cells were used, efficient inhibition of target cell lysis by clone 3HA15 could be achieved by the addition of 5- to 50-fold 3G and 3S antagonist peptides. Although several good antagonists were found for 3HA15, only a few
moderate antagonists could be identified for 5W38. Possibly the longer
CDR3 chains of 5W38 have fewer contact sites with HLA-A2-HA-1, allowing less variation. Similar to the inhibition patterns of clone
5W38, the third HA-1-specific clone, clone 15, was also less
significantly inhibited than clone 3HA15, but the V Of interest is that the antagonists significantly inhibit the response
of polyclonal HA-1-specific CTL lines from different patients by 50%
or more. Moreover, the antagonistic peptides also reduced 30% of the
IFN- Clinical relevance The possible clinical relevance of these in vitro immunomodulation studies lies in the possibility of reducing the HA-1-induced GvHD in HA-1 disparate SCT donor-patient combinations. Three types of observations support the relevance of the latter proposition. First, HA-1 disparity is associated with the development of acute GvHD.28,29 Second, HA-1-specific CTLs have been isolated from different cohorts of patients with GvHD.26,27,30,35 Third, the apparent exceptional restricted use of the TCR repertoire for HA-1 recognition makes the general TCR antagonists applicable in the HA-1-mismatched combinations.24 Especially early after SCT, immunomodulation of the HA-1 response may be important. This supposition is based on recent work by Schlomchik et al,36 who described an MHC-identical, mHag-mismatched murine model of allo-SCT with bone marrow chimeric mice without class I on their antigen-presenting cells (APCs) but with class I on GvHD target tissues. This model was used to investigate the mechanism of GvHD activation. Several important conclusions have been drawn from these studies. They are that depleting host APCs before conditioning abrogates GvHD, replacing host with donor APCs abrogates T-cell activation, and cross-presenting host antigens by donor APCs does not cause GvHD; thus the target antigens for CD8 T cells in GvHD are restricted to proteins expressed by host APCs. In concordance with the results of the latter model system, we ascribe the association between HA-1 mismatch and the development of GvHD to the significant expression of HA-1 on the patients' professional APCs. We argue that through adequate presentation of HA-1 on the remaining patient's dendritic cells early after SCT, strong donor antihost allo-immune T cells are induced. This may give rise to the production of cytokines, subsequently leading to the activation of bystander allo-immune T cells such as CTL against mHag H-Y, a ubiquitously expressed mHag. It is expected that most recipient hematopoietic cells will be replaced by donor cells by day 50 to 60 after SCT. Thus, early modulation of the HA-1 immune response would benefit the patient.
We thank Dr G. Vriend (EMBL, Heidelberg, Germany) for the sequence analogy search and Dr A. Geluk for productive discussions.
Submitted May 7, 2001; accepted October 1, 2001.
Supported by grants from the Dutch Organization for Scientific Research (NWO 901-09-201) (J.d.H.) and the J. A. Cohen Institute for Radiopathology and Radiation Protection (E.A.J.M.G.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: E. A. J. M. Goulmy, Dept of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; e.a.j.m.goulmy{at}lumc.nl.
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© 2002 by The American Society of Hematology.
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Abstract
Introduction
