The peptide-specific alloreactive human T cell repertoire varies largely between individuals and is not extended in HLA-A*0205anti-HLA-A*0201 pairings
Arnaud Moris,1,
Dorothee Wernet,2,
Stefan Stevanovi
and
Hans-Georg Rammensee
Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany
2 Department of Transfusion Medicine, Otfried-Müller-Straße 4/1, 72076 Tübingen, Germany
Correspondence to:
H.-G. Rammensee
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Abstract
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Alloreactive T cells recognize framework or peptide-dependent determinants on foreign MHC molecules. Among the peptide-dependent alloreactive T cells a significant proportion is specific for one particular peptide presented by the allo-MHC molecule as antigen-specific T cells would do. Such alloreactive, peptide-specific T cells are referred to as `allorestricted'. High-avidity HLA-A*02 allorestricted cytotoxic T lymphocyte (CTL) clones specific for peptide libraries can be generated from HLA-A*02 donors. We made use of this technique to study the role of closely related self-HLA molecules on shaping of the alloreactive T cell repertoire. Peripheral blood lymphocytes from HLA-A*0205 individuals were stimulated by HLA-A*0201 targets pulsed with an HLA-A*0201 peptide library. We did not observe a bias towards peptide-specific CTL in the HLA-A*0201-directed alloreactive repertoire of HLA-A*0205 donors as compared to HLA-A*02 donors. Comparison of the alloreactive T cell response between two donors having similar HLA haplotypes demonstrated that the allorestricted T cell repertoire is largely different between individuals.
Keywords: alloreactivity, allorestriction, immunotherapy, positive selection, T cell repertoire
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Introduction
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Allograft rejection and graft versus host disease (GvHD) are the clinical manifestations of T cell reactivity to foreign MHC molecules (1). Although the molecular basis of allorecognition has been extensively studied in the past 20 years, it remains enigmatic. A puzzling observation is that the frequency of cytotoxic T lymphocytes (CTL) that recognize allogeneic MHC class I molecules is typically 10- to 100-fold higher than that of T cells recognizing viral antigen presented by self-MHC molecules (2).
One model to explain this paradox suggested that TCR directly recognize allelic polymorphisms on the MHC molecules (3). The expression of such epitopes at high density on the cell surface would result in stimulation of T cells bearing low- as well as high-affinity receptors for the allogeneic MHC molecule. The principal studies supporting this model described CTL clones that recognize the MHC molecule in the absence of bound peptide (4,5). An alternative model suggested that T cells recognize many different cellular antigens, i.e. peptides, together with the foreign molecule. The strong alloreactive response would then be explained by multiple binary interactions between alloreactive T cell clones and new peptides not presented by self-MHC (6). In the meantime, the existence of peptide-specific alloreactive T cells has been clearly demonstrated (711). These allorestricted CTL can recognize specific peptideMHC combinations just like nominal antigen-specific T cells do (1214). Furthermore, the mouse as well as the human allorestricted T cell repertoire is broad and diverse, as shown by the use of peptide libraries (12,14). In addition, several studies have indicated the existence of peptide-dependent CTL (8,15,16) that are not specific for a particular peptide. This fraction of alloreactive T cells might be sensitive to the conformation of the MHC that is adapted when particular, but unrelated, peptides are bound to the MHC molecule (2). The nature of determinants involved in the alloreactive T cell recognition appears therefore to be very diverse. Still, overall a dominance of peptide-dependent recognition among CTL has been reported in mice and humans (17,18).
The existence of high-avidity CTL in the diverse repertoire of allorestricted T cells (1214) raises the possibility of generating CTL reactive against low-copy-number peptides bound to non-self-MHC molecules. Many tumors overexpress normal proteins, thereby modifying the set of self-peptides associated with MHC class I molecules. This phenomenon allows triggering of tumor-specific CTL. However, CTL undergo negative selection and peripheral tolerance mechanisms that diminish the number of or eliminate self-peptide-specific CTL. Since tolerance to self-antigens is self-MHC restricted (19), allorestricted T cells can be raised against self-antigen including tumor-associated antigens (self as seen from the tumor's host) and presented by allogeneic MHC (foreign for the T cell) for adoptive immunotherapy (19,20). Indeed, it has been recently shown that allorestricted CTL specific for mdm-2 wild-type peptide were a successful reagent for immunotherapy (13), and that the CTL engrafted and retained specificity in the host without causing GvHD (21).
Studying the influence of the self-MHC molecules on the shaping of the alloreactive T cell repertoire could therefore provide technical insights into the generation of allorestricted T cells in vitro but also into thymic positive selection of T lymphocytes. In a recent report on mouse experiments, our group has demonstrated that the closer the foreign MHC molecule is related to the T cell's MHC, the higher the proportion of allorestricted T cells versus peptide-independent T cells (22). In the present study, we analyzed this relation in human T cell populations. We compared the influence of closely related HLA alleles on the allorestricted human T cell repertoire by stimulating and testing PBL from HLA-A*0205+ and HLA-A*02 donors with the TAP-deficient T2 cell line pulsed with a HLA-A*0201 peptide library.
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Methods
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Cells
The human EpsteinBarr virus-transformed lymphoblastoid B cell line (LCL) 721 (HLA-A*0201, -A*0101, -B*5101, -B*0801, -Cw1) (23) and the TAP-deficient cell line T2 (HLA-A*0201low, -B*5101low, -Cw1low) (24) were used in 51Cr-release assays or for T cell stimulation. Cell lines were maintained in RPMI 1640 (Life Technology, Eggenstein, Germany), 10% FCS (Sigma, Deisenhofen, Germany), 2 mM glutamine (BioWhittaker, Verviers, Belgium) and 50 U/ml penicillin/50 µg/ml streptomycin solution (BioWhittaker).
Generation of CTL
Peripheral blood lymphocytes (PBL) from healthy donors registered in the Blood Bank (Tübingen, Germany) were isolated from buffy coats by Ficoll-Hypaque density-gradient centrifugation using Lymphoprep (Nycomed, Oslo, Norway). PBL were plated in limiting dilution in round-bottom 96-well plates (Costar, Bodenheim, Germany), starting with 105 cells/well and dilution steps of 1:2. In each well the effector cells were stimulated with 2 x 104 irradiated T2 cells (200 Gy) pulsed with the synthetic HLA-A*0201 peptide library. Pulsing was performed overnight at room temperature with 10 µM peptide library in serum-free medium (25). After 7 days of culture, the effector cells were re-stimulated with 2 x 104 irradiated T2 cells pulsed with peptide and 4 x 104 irradiated syngeneic PBL (30 Gy) as feeder cells in IL-2-containing medium (Proleukin; Chiron, Ratingen, Germany). The cultures were tested 57 days later in a split-well 51Cr-release assay against T2 and 721, as described (12,14). According to our experience, these conditions lead to preferential expansion of
ß CD8+ T cells and do not support proliferation of cytotoxic 
T cells. Wells containing CTL preferentially recognizing peptide-loaded targets were then expanded in six wells of 96-well plates with 4 x 104 irradiated syngeneic PBL and 2 x 104 irradiated T2 pulsed with the peptide library. All T cell cultures were performed in IMDM (Life Technologies), 10% human serum (Pel Freez; Mast-diagnostica, Hamburg, Germany), 20 U/ml IL-2, 2 mM glutamine (BioWhittaker) and 50 U/ml penicillin/ 50 µg/ml streptomycin solution (BioWhittaker).
Cytotoxicity assay
Targets were labeled with 1.85 MBq of Na251CrO4 for 1 h at 37°C, with or without preincubation with the peptide library (50 µM) for 3 h at room temperature in serum-free medium. Labeled targets were incubated for 4 h with the CTL in RPMI (Life Technology), 10% FCS (Sigma), 2 mM glutamine (BioWhittaker) and 50 U/ml penicillin/50 µg/ml streptomycin solution (BioWhittaker). Subsequently, 50 µl of the supernatant was harvested and radioactivity was measured in a microplate format scintillation counter (1450 Microbeta Plus; Turku, Finland), using solid-phase scintillation (Luma Plate-96; Packard, Dreieich, Germany). Percent specific lysis was calculated as (c.p.m. experimental counts c.p.m. media control)/(c.p.m. detergent c.p.m. media control) x 100%. Medium controls were between 10 and 15% of detergent samples.
Peptides and peptide library
The synthetic HLA-A*0201 peptide library was already described (14). In brief, the peptide library was produced by applying the Fmoc amino acids in 3-fold excess in the respective position, using a peptide synthesizer 432A (Applied Biosystems, Weiterstadt, Germany). The library was analyzed by reverse-phase HPLC (System Gold; Beckman Instruments, Munich, Germany) and mass spectrometry (G2025A; Hewlett-Packard, Waldbronn, Germany). The library contains 34,560 peptides. The peptide called p68 used as negative control in the experiments was derived from the RNA helicase p72 (YLLPAIVHI).
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Results
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Comparison of the peptide-specific versus peptide-independent alloreactive T cell repertoire between two unrelated donors.
To compare the influence of HLA-A*02 alleles on the repertoire of alloreactive T cells, PBL from an HLA-A*0205+ donor (HLA-A*0205/A*11, -B*07/*49, -Cw7) and an HLA-A*02 donor (HLA-A*01, -B*08/44, -Cw2/w7) were stimulated against T2 loaded with the HLA-A*0201 peptide library under limiting dilution conditions. The PBL were seeded at 105 cells/well as starting concentration and diluted in 1:2 steps down to 6 x 103 cells/well, a cell number giving rise to a high probability of clonal CD8+ T cells (14). After one round of re-stimulation, each individual well was tested in a split-well 51Cr-release assay on T2 cells loaded with p68 peptide (YLLPAIVHI) as a control and T2 cells loaded with the HLA-A*0201 peptide library (Fig. 1
). Each well's activity is represented as a dot. Dots close to the diagonal are considered to represent framework specific and not allorestricted or peptide-dependent CTL (Fig. 1
). At the lowest cell concentration of HLA-A*0205+ PBL, we never found a deviation from the diagonal, indicating that the great majority of the alloreactive CTL were framework specific (Fig. 1B
). At the highest cell concentration, only few CTL lines from the HLA-A*0205 donor showed signs of peptide specificity (Fig. 1A
). In contrast, several wells from the HLA-A*02 PBL showed lines or clones (Fig. 1C and D
) with potential peptide specificity.

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Fig. 1. Peptide specificity of the PBL stimulations. Individual limiting dilution wells from the HLA-A*0205+ responder (A and B) and the HLA-A*01+ (C and D) were assayed against T2 pulsed with a control peptide, called p68, from the RNA helicase p72 (YLLPAIVHI) and T2 pulsed with the HLA-A*0201 peptide library. PBL stimulations with the highest cells/well ratio (A and C) and with a high probability of clonality (BD) are presented. Wells containing peptide library-specific CTL were defined as those negative for lysis of T2 + p68 and positive for lysis of T2 + library, and are in the upper left region of the arbitrarily chosen quadrant. Arrows indicate peptide-specific wells that were expanded.
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The lines and clones from both donors exhibiting at least some peptide specificity were expanded and tested in a 51Cr-release assay at different E:T ratios (Fig. 2
). Two lines (2-35 and 2-59) out of four (Fig. 2B
) and one potential clone (10-63) out of four (Fig. 2C
) of the HLA-A*02 donor showed specificity for the HLA-A*0201 peptide library loaded on T2. However, out of the two lines expanded from the HLA-A*0205+ donor only one showed a very weak peptide specificity, if any. The results presented in Figs 1 and 2
are representative of the highest and lowest number of PBL seeded per well. The experiment was performed in duplicates and for each dilution the complete split-assay was performed. Furthermore, lines or clones were expanded and tested again in a 51Cr-release assay. All these data are summarized in Table 1
. Overall, the HLA-A*0205+ donor did not give rise to a higher number of peptide-specific or peptide-dependent alloreactive CTL than the HLA-A*02 donor, as we would have expected from our previous mouse data. In a different experiment using a second HLA-A*0205 donor and another HLA-A*02 donor (HLA-A*03/24,-B*07/50, -Cw2/w7), significant differences were not observed either (data not shown). These results suggested that the HLA-A*0205+ PBL repertoire is not more prone to react in a peptide-dependent manner towards HLA-A*0201 than the HLA-A*02 PBL repertoire.

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Fig. 2. Alloreactive CTL expanded from the PBL stimulations. Cell lines expanded from the 105 cells/well plates (A and B) and potential clones from the 6 x 103 cells/well plates (C) were tested for peptide specificity in a killer assay using different E:T ratios. (A) HLA-A*0205+ CTL and (B and C) HLA-A*01+ CTL. p68 control peptide corresponds to RNA helicase p72 (YLLPAIVHI).
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Comparison of the peptide-specific versus peptide-independent alloreactive T cell repertoire between two donors with similar HLA haplotypes
T cells are selected in the thymus for their ability to bind self-MHC molecules and are negatively selected in order to be tolerant to self-MHC molecules associated with self-antigens. For this negative selection mechanism the up to six classical HLA class I allele products in heterogeneous individuals all contribute in shaping the T cell repertoire. Thus, we speculated that the lack of dramatic differences in the alloreactive T cell repertoire in the previous experiment could be due to the heterogeneous HLA context of the donors masking a potential influence of HLA-A*0205. To test this hypothesis, we repeated the PBL stimulations, as described before, but with two donors expressing a similar HLA haplotype, with the exception of one HLA-C and one HLA-A allele. One donor was HLA-A*0205 and the other HLA-A*24 (see Table 2
). The results of the split-well 51Cr-release assay on T2 cells loaded with control peptide or the HLA-A*0201 peptide library are shown in Fig. 3
. As we observed before, the majority of the CTL lines from both donors showed specificity for a structure on T2 independent of the peptides added. Furthermore, for the HLA-A*0205 PBL there was no well displaying significant peptide specificity neither at high (Fig. 3A
) nor low (Fig. 3B
) cell number per well. PBL of the HLA-A*02 donor showed only borderline peptide-specific lysis at 105 cells/well (Fig. 3C
). In contrast, at lower cell numbers per well some CTL showed peptide specificity (Fig. 3D
). Still, for all dilutions, we decided to expand CTL that lysed T2 pulsed with the HLA-A*0201 peptide library at least 10% more than they lysed T2 pulsed with control peptide (Fig. 3
). The CTL 1-66, for example, that lysed T2 pulsed with the library with 69% specific lysis and T2 pulsed with control peptide with 47% specific lysis was selected, expanded and tested in a killer assay at different E:T ratios (Fig. 4
). Out of the five lines of the HLA-A*02 donor tested, only one (2-12) showed a significant specificity for the HLA-A*0201 peptide library loaded on T2 (Fig. 4C and D
). However, out of the six lines expanded from the HLA-A*0205+, none was clearly peptide specific.

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Fig. 3. Peptide specificity of the PBL stimulations from two similar HLA haplotypes. Individual limiting dilution wells from the HLA-A*0205+ responder (A and B) and the HLA-A*24+ (C and D) were assayed against T2 pulsed with a control peptide from RNA helicase p72 (YLLPAIVHI) and T2 pulsed with the HLA-A*0201 peptide library. PBL stimulations with the highest (A and C) and a lower (B and D) cells/well ratio are presented. Data presented are representative of the limiting dilution panel. Wells containing peptide library-specific CTL were defined as those negative for lysis of T2 + p68 and positive for lysis of T2 + library, and are defined in the upper left region of the arbitrarily chosen quadrant. However, as in the majority of the stimulations (AC and data not shown) no culture with significant peptide specificity was observed, we considered expanding lines that showed at least 10% more lysis against T2 pulsed with the library (located above the grey line). We assumed that those lines were a mix of peptide-specific and structure-specific cells. Arrows indicate peptide-specific wells that were expanded.
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Fig. 4. Alloreactive CTL expanded from the PBL stimulations of two similar haplotypes. Cell lines expanded from the 105 cells/well plates (A and C) and lines from the 2.5 x 104 cells/well (B and D) were tested for peptide specificity in a killer assay using different E:T ratios against T2 pulsed with the peptide library () and pulsed with a control peptide from RNA helicase p72 (YLLPAIVHI) ( ). (A and B) HLA-A*0205+ CTL and (C and D) HLA-A*24+ CTL.
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These results suggested again that even when the HLA background of the two donors is largely overlapping, the HLA-A*0205+ PBL repertoire seems not to be more prone to react in a peptide-dependent manner towards HLA-A*0201 as compared to the HLA-A*02 PBL repertoire.
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Discussion
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Our group has previously shown that high-avidity HLA-A*02 CTL clones specific for peptide libraries could be generated from HLA-A*02 donors (14). In the present report, we made use of this technique to study the role of closely related HLA molecules on the shaping of the alloreactive T cell repertoire. Although we could generate allorestricted CTL, we did not find a bias towards peptide specificity in the alloreactive T cell repertoire of three HLA-A*0205 donors, in comparison with HLA-A*02 donors, when stimulated by T2 cells loaded with an HLA-A*0201 peptide library. In the human system an alloresponse against a related HLA molecule seems not to contain more peptide-specific T cells than a response against an unrelated one. This appears to be in contrast to our previous observations with the mouse alloreactive T cell repertoire (12).
The T cell repertoire is reactive to gross as well as subtle changes in MHCpeptide complexes. T cells can react against self-peptide when presented in a new context, i.e. amino acid substitutions in the
-helices at positions that point towards the TCR can stimulate T cells (26,27). T cells can be raised in a peptide-specific way against completely allogeneic MHC molecules, having allelic differences in the peptide-binding groove as well as in the helices (1214). Furthermore, mutations in the peptide-binding groove that change only the spectrum of bound peptides can elicit an alloreactive response (22,28). We speculated that this latter constellation should allow an easier generation of allorestricted CTL against self-, viral or tumor-associated antigens. Indeed, in the mouse model our group found that alloreactions against MHC molecules carrying groove mutations only were clearly dominated by peptide-specific CTL (22). In contrast, alloresponses directed against molecules with both groove mutation and
-helices substitutions were more prone to give rise to structure-specific T cells (22). In the present study, we made use of the natural HLA-A*02 polymorphism to test this hypothesis with human T cells. The HLA-A*0201 molecule is found in all populations studied and shows a strong predominance in the Caucasian population (>95% of HLA-A*02 individuals). The majority of the amino acid substitutions that discriminate the HLA-A*02 alleles cluster around the peptide-binding groove of the MHC class I molecule. The HLA-A*0205 allele that was used in this study has 4 amino acid substitutions: Tyr9 (Y) and Trp156 (W) affect the pocket B/C and D/E respectively of the peptide-binding groove, and therefore modify the array of peptides presented by the molecule (2931); Arg43 (R) and Leu95 (L) do not interfere with the peptide (31). None of these amino acids was identified as a potential binding site for the TCR on the class I molecule (for review, see 32). The HLA-A*0205 allele was therefore the perfect candidate to study the T cell alloreactive repertoire against HLA-A*0201. However, we could not see a domination of the allorestricted towards structure-specific T cell response compared to an unrelated donor expressing HLA-A*01 (Fig. 1
), which has multiple amino acid substitutions affecting the peptide-binding groove, the helices and the TCR contacts (31,32). In our previous report we used Kb mutants having amino acid substitutions on the Kb molecule but having otherwise strictly the same class I (Db), class II and non-MHC (22) molecules. We therefore performed the stimulation by HLA-A*0201 molecules with PBL of an HLA-A*0205+ and HLA-A*24+ donor having almost an identical set of remaining HLA class I allelic products (Table 2
). Although we could generate allorestricted CTL, no significant difference in the alloreactive repertoire of the two donors was observed either.
We concluded earlier from our mouse experiments that the allorecognition is readily influenced by the selecting MHC molecule, and might mirror the resemblance between self and foreign. The T cell repertoire is indeed shaped by positive and negative selection on self-MHC molecules, in the thymus and by peripheral mechanisms (for review, see 33). Our present data do not exclude an influence of the selecting MHC on the alloreactive T cell repertoire. A single peptideMHC complex can select a large panel of CD8+ T cells (33); however, the overall contribution of the up to six different class I molecules in the selection of one CD8+ T cell is not clear so far. One possible explanation for our data could be that we did not find a donor having a permissive HLA context that would allow us to study the influence of the selecting HLA-A*0205 molecule alone on the shaping of the alloreactive repertoire directed against HLA-A*0201. The other HLA molecules could have shaded the influence of the HLA-A*0205 molecule by negatively selecting potential peptide-specific alloreactive T cells on HLA-A*0201. Furthermore, we focused on the classical MHC molecules, but other polymorphic HLA molecules (HLA-E, G) or MHC-like molecule (MICA/B) (34) and also non-MHC molecules could also play a role in the selection mechanisms. Moreover, the history of infection with immunogenic viruses might also have influenced the alloreactive repertoire of the donors (35). One might also speculate that the HLA-A*0201 molecule is special since it has the capacity to bind TAP-independent peptides from leader-related sequences. HLA-A*0205 CTL might cross-react on these leader peptides, leading to a higher killing background in our cultures. This might mask some of the allorestricted responses. An alternative explanation for the discrepancy to our mouse experiments might be that in the human system allorecognition is not influenced by the selecting HLA molecules. This, however, we consider as being unlikely.
Allogeneic bone marrow transplantation as treatment of leukemia patients is often associated with GvHD which is detrimental for the patient, but also graft versus leukemia (GvL) which is positively correlated with the prognosis (36). Both activities are attributed to alloreactive donor T cells. The transfer of donor allorestricted CTL specific for a leukemia tumor antigen at the same time as stem cell transplantation could be of particular interest to enhance the GvL without causing GvHD (37). A better understanding of the mechanism shaping the repertoire of alloreactive T cells is therefore of great interest to establish new protocols for the generation of allorestricted CTL against tumor or viral epitope to be used in immunotherapy.
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Acknowledgments
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We thank Dr D. J. Schendel for providing cells, and Drs R. Obst, C. Gouttefangeas and S. Pascolo for helpful discussions. This project was supported by the University of Tübingen, `fortüne program' no. 406-0-0 and by EU grant BIO4-98-0214.
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Abbreviations
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CTL cytotoxic T lymphocytes |
GvHD graft versus host disease |
GvL graft versus leukemia |
PBL peripheral blood lymphocyte |
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Notes
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1 Present address: Retrovirus and Gene Transfer, Pasteur Institute, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France 
Transmitting editor: T. Sasazuki
Received 7 December 2000,
accepted 28 March 2001.
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