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The Journal of Immunology, 2000, 165: 96-101.
Copyright © 2000 by The American Association of Immunologists

Anti-TCR-Specific DNA Vaccination Demonstrates a Role for a CD8+ T Cell Clone in the Induction of Allograft Tolerance by Donor-Specific Blood Transfusion1

Caroline Vignes2, Elise Chiffoleau2, Patrice Douillard, Régis Josien, Hélène Pêche, Jean-Marie Heslan, Claire Usal, Jean-Paul Soulillou and Maria Cristina Cuturi3

Institut National de la Santé et de la Recherche Médicale Unité 437 "Immunointervention dans les allo-et xeno-transplantations" and Institut de Transplantation et de Recherche en Transplantation, Nantes, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Donor-specific allograft tolerance can be induced in the adult rat by pregraft donor-specific blood transfusion (DST). This tolerance appeared to be mediated by regulatory cells and to the production of the suppressive cytokine TGF-ß1. A potential immunoregulatory CD8+ clone bearing a Vß18-Dß1-Jß2.7 TCR gene rearrangement was previously identified in DST-treated recipients. To assess the functional role of this T cell clone in the induction of tolerance by DST, we have vaccinated DST-treated recipients with a plasmid construct encoding for the Vß18-Dß1-Jß2.7 TCR ß-chain. DST-induced allograft tolerance was abolished by anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination in six of seven recipients, whereas vaccination with the vector alone, or with the construct encoding a TCR Vß13 ß-chain, had no effect. However, the transcript number of the Vß18-Dß1-Jß2.7 chain was unchanged in allografts from vaccinated DST-treated rats, suggesting that this clone was not depleted by vaccination, but rather was altered in its function. Moreover, TCR Vß18-Dß1-Jß2.7 DNA vaccination restored the anti-donor alloantibody production, partially restore the capacity of spleen cells from tolerized recipients to proliferate in vitro against donor cells, and decreased the inhibitory effect of TGF-ß1, seen in DST-treated recipients, in spleen cells from vaccinated DST-treated ones. This study strongly suggests that this CD8+ TCR Vß18-Dß1-Jß2.7 T cell clone has an effective immunoregulatory function in allograft tolerance induced by DST.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
A requirement for recipient T cells in the induction of allograft tolerance has been reported in several models (1, 2). Moreover, CD4+ suppressive T cells have been found in allograft tolerance induced by pregraft transfer of donor cells (3). We have previously reported that tolerance to LEW.1W cardiac allografts could be induced in adult LEW.1A rats by pregraft donor-specific blood transfusion (DST)4 (4). In recipients, DST elicited the expansion of a CD8+ clone bearing a Vß18-Dß1-Jß2.7 TCR gene rearrangement specific for donor MHC Ags (5). This clone arose in blood and spleen over the time course of transfusion, and it was detected in nonrejected allografts as soon as the first day after the transplantation, suggesting a regulatory role for this clone in the induction of tolerance.

Vaccination with naked DNA promotes a highly efficient protection against microbes and tumors (6) and also provides a means to suppress self-autoreactive T cells. Recently, protection from experimental autoimmune encephalomyelitis (EAE) in mice was observed following injection of DNA encoding the Vß region of an autoreactive TCR (7).

To investigate the functional role of the Vß18-Dß1-Jß2.7 clone in the induction of tolerance by DST, we have tested the effect of a specific vaccination with DNA encoding for the TCR ß-chain of this clone on tolerance induction.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Animals and transplantations

Eight- to 12-wk-old male LEW.1W (RT1.u) rats served as blood and heart donors, and LEW.1A (RT1.a) rats served as allograft recipients (Centre d’Elevage Janvier, Le Genest-Saint-Isle, France). For the induction of tolerance, allograft recipients were transfused with 1 ml of fresh donor blood 14 and 7 days before transplantation (4). Heterotopic heart grafts were performed using the Ono and Lindsey technique (8). The grafts were evaluated daily for function by palpation through the abdominal wall.

Vaccination with DNA

Plasmid construction. We have cloned the TCR ß-chain of the Vß18-Dß1-Jß2.7 clone (see Table IGo for sequence) and a Vß13 ß TCR chain into a Bluescript vector as previously described (5). A 1-kb HindIII-BamHI fragment was then cloned into the phCMV plasmid containing the enhancer/promoter region of the major IE gene of human CMV, as previously described (9).


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  		Table I. Sequences of the complementarity determining region 3 (CDR3) region of the Vß18-Dß1-Jß2.7 clone and of primers and probes used for real-time detection of PCR products

 
DNA preparation and injection. Large-scale preparation of plasmid DNA was conducted using Mega-prep (Qiagen, Hilden, Germany). Fifteen days before the first DST, 500 µl of 10 mM cardiotoxin in PBS (Latoxan Rosans, Valence, France) were injected into the quadriceps of male 5-wk-old LEW.1A rats. This was known to enhance the efficiency of DNA vaccination (10). Five days later, 300 µg of DNA (1.5 mg/ml in water) were injected into the quadriceps, and this injection was repeated 1 wk later.

Real-time quantitative PCR

Table IGo shows the oligonucleotides and specific dye-labeled DNA probes used in this study.

Standard construction. The target sequence was amplified by PCR from cardiac allograft-derived total cDNA, then electrophoresed and purified using a gel extraction kit (QIAquick; Qiagen). Subsequent dilutions of this standard DNA were performed to obtain 107, 106, 105, 104, 103, and 102 copies per well.

PCR amplification. Total RNAs from allografts were extracted and reverse-transcribed as previously described (5). A constant amount of cDNA corresponding to the reverse transcription of 100 ng of total RNA, or each dilution of the standard, was amplified in a volume of 25 µl containing 300 nM of each primer and either 300 nM of the specific labeled probe or SYBR Green PCR Core Reagent (Perkin-Elmer, Foster City, CA) in the Taq Man PCR Core Reagent (Perkin-Elmer). Amplifications were performed in an ABI Prism 7700-Perkin-Elmer Sequence Detection System. The reaction started with a step of 2 min at 55°C, followed by 10 min at 95°C, and then by 40 cycles consisting each of 15 s at 95°C and 1 min at 60°C (65°C for clonotype amplification).

Analysis. Direct detection of PCR products was monitored by measuring the increase in fluorescence. The exact number of copies was deduced from the comparison of the measured fluorescence with the standard curve.

Measurement of anti-donor IgG deposit on heart graft tissue sections

Measurement of anti-donor IgG deposits on heart allograft tissue sections was performed as previously described (11). Briefly, heart allograft samples were harvested 5 days after transplantation and immediately snap-frozen in liquid nitrogen. Cryostat sections (5 µm) were fixed in acetone and stored at -20°C until use. Sections were incubated at room temperature for 60 min with serial dilutions of biotinylated mouse anti-rat IgG mAb (H. Bazin, University of Louvain, Louvain, Belgium). Sections were then incubated for 30 min with HRP streptavidin (Vector Biosys, Compiegne, France) and developed with peroxidase substrate (Vector VIP). Control sections were incubated with purified normal mouse Ig. Serial sections were assessed using doubling dilutions of mouse Abs, from 1:2,000 to 1:32,000. For each section, 10 adjacent fields (x20) were evaluated. Results are expressed as the highest dilution of mouse anti-rat IgG Ab showing positive labeling (end-titer dilution).

Proliferation

A standard one-way MLC was performed. Cell suspensions from spleens were prepared, as described previously (11), from untreated recipients, and DST-treated recipients, vaccinated with the pCMV/Vß18 DNA and sacrificed 5 and 11 days after transplantation. Cells were resuspended in RPMI 1640 (Life Technologies, Grand Island, NY) supplemented with 2 mM L-glutamine, 5 x 10-5 M 2-ME, 1 mM sodium pyruvate (Life Technologies), and 10% FCS (Life Technologies). Irradiated dendritic cell-enriched cell populations from spleens of donor-type LEW.1W rats served as stimulator cells and were prepared as described previously (12). Responder (2.5 x 105) and stimulatory cells (2.5 x 104) were plated in 96-well round-bottom plates in triplicate in a volume of 200 µl and cultured for 3 days at 37°C in 5% CO2 with the last 8 h in the presence of 0.5 µCi [3H]TdR (Amersham, Les Ulis, France). The cells were then harvested on glass fiber filters, and [3H]TdR incorporation was measured using standard scintillation procedures (Packard Institute, Meriden, CT).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination abolishes DST-induced allograft tolerance

The Vß18-Dß1-Jß2.7 segment was cloned (5) and inserted into the phCMV plasmid (phCMV/Vß18 DNA). Because the Vß18-Dß1-Jß2.7 clone expansion is induced by DST, 300 µg of a plasmid construct containing this Vß18-Dß1-Jß2.7 TCR rearrangement were injected twice, at day 10 and day 3 before DST, into the quadriceps of LEW.1A recipients 5 days after a single i.m. injection of cardiotoxin. Instead of the phCMV/Vß18 DNA, control recipients received either the plasmid vector alone (phCMV DNA) or a plasmid vector encoding for a Vß13 ß-chain (phCMV/Vß13 DNA). Six of seven recipients vaccinated against the Vß18-Dß1-Jß2.7 clone rejected their allograft in 16.8 ± 5.1 days (Fig. 1Go). In contrast, recipients vaccinated with the control phCMV DNA or the phCMV/Vß13 DNA with the same cardiotoxin injection tolerated their allografts (Fig. 1Go). Moreover, nontransfused recipients vaccinated against the Vß18 chain before grafting normally rejected their allografts (6.4 ± 0.3 days). Thus the Vß18-Dß1-Jß2.7 clone plays a role in the induction of allograft tolerance by DST, but not in acute allograft rejection.



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  		FIGURE 1. Anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination abolishes allograft tolerance. Recipients were immunized before DST with the phCMV plasmid vector encoding the Vß18 ß-chain of the clone (DST+phCMV/Vß18-treated group). Control groups received the plasmid vector alone (DST+phCMV-treated group) or a plasmid vector encoding a Vß13 ß-chain (DST+phCMV/Vß13-treated group). As an additional control, allograft survival for untreated and DST-treated recipients are also represented. *, p < 0.001 vs DST-treated group, DST+phCMV-treated group, or DST+phCMV/Vß13-treated group.

 
DNA vaccination does not induce depletion of the Vß18-Dß1-Jß2.7 clone

We then analyzed the mechanisms underlying acute rejection induced by anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination. First, we investigated whether DNA vaccination depleted the Vß18-Dß1-Jß2.7 clone. For this purpose, we quantified clonotype transcripts using a method of real-time quantitative PCR in allografts harvested 5 days after transplantation. Quantification of Cß transcripts was also performed to give an index of the total T cell pool between the different experimental situations. Cß transcripts were unchanged in recipients vaccinated with the phCMV/Vß18 DNA compared with rats immunized with the plasmid vector alone (1.89 ± 0.1 vs 1.87 ± 0.23, respectively). This was confirmed by immunohistological analysis (data not shown). The expression of clonotype transcripts was 600-fold higher in allografts from DST-treated recipients than from untreated ones (Table IIGo). This pattern confirms our previous study using PCR and Immunoscope software analysis (C. Pannetier, Institut Pasteur, Paris, France), which had shown an early expansion of the Vß18-Dß1-Jß2.7 clone within allografts from DST-treated, but not from untreated, recipients (5). Clonotype transcripts were expressed at the same high level in allografts from DST-treated recipients immunized with phCMV/Vß18 DNA (Table IIGo). Therefore, in our experiments the DNA vaccination did not lead to the depletion of the Vß18-Dß1-Jß2.7 clone elicited by DST.


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  		Table II. Anti-TCR Vß18-Dß1-Jß2.7 clone depletion1

 
These results on the effect of anti-TCR vaccination are consistent with a previous study of Waisman et al. in the EAE autoimmune disease model (7). EAE was elicited in mice immunized with one of the immunodominant peptides of the myelin basic protein and the majority of T cells responsible for the peptide recognition expressed the Vß8.2 segment (7). In this model, immunization with DNA encoding the Vß8.2 region protected mice from EAE for a subsequent challenge with the eliciting peptide (7). However, in this experiment, the protection was not due to the depletion of the Vß8.2 T cells, but to a modification of their function with a shift from a Th1 to a Th2 cytokine secretion profile.

Recipients vaccinated with the phCMV/Vß18 DNA exhibit an increased reactivity against donor Ags

Here, we have performed MLC using responder splenocytes from recipients sacrificed 5 and 11 days after grafting and stimulatory irradiated donor cells. We evaluated their proliferation after 3 days in culture. As shown in Fig. 2GoA, anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination partially restored the proliferative response of spleen cells from DST-treated recipients against donor cells. However, these cells remain mainly unresponsive to donor (Fig. 2GoA) as well as third party (Fig. 2GoB). This lack of specificity of unresponsiveness in vitro was previously demonstrated in DST-treated recipients (13). However, we previously shown that, in vivo, the DST effect was donor specific because third-party allografts are rejected in Lewis.1W blood- transfused Lewis.1A recipients (13) and because long-term tolerant animals accepted donor type but not third-party skin allografts (13).



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  		FIGURE 2. TCR Vß18-Dß1-Jß2.7 DNA vaccination partially restores the capacity of T cells from tolerized recipients to proliferate in vitro against donor cells. Splenocytes from recipients (four different animals in each group) sacrificed 5 and 11 days after grafting were stimulated with an irradiated donor (A) and third party (B) cell population of enriched dendritic cells, in a ratio of 10:1. Uptake of [3H]TdR was assessed after 3 days of culture. Each value represents the mean of proliferation index calculated from triplicates from four distinct recipients.

 
Role of TGF-ß1 in unresponsiveness of spleen cells from vaccinated recipients

Previously, we have shown that the nonspecific unresponsiveness of spleen cell from DST-treated allograft recipients was, in part, mediated by the immunosuppressive cytokine TGF-ß (13). Indeed, in vitro proliferative response was restored by an anti-TGF-ß mAb and exogenous IL-2. Therefore, we analyzed the mechanism of unresponsiveness of spleen cells from vaccinated recipients against donor cells. As shown in Fig. 3Go, this unresponsiveness was abolished by exogenous IL-2 alone, suggesting a state of anergy. In contrast, anti-TGF-ß mAb had no effect, suggesting that TGF-ß is not involved in the unresponsiveness of spleen from vaccinated and DST-treated recipients.



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  		FIGURE 3. Effects of rIL-2 and anti-TGF-ß mAb on anti-donor proliferative response of spleen cells from DST and DST-vaccinated rats. MLC were performed with spleen cells from untreated ({blacksquare}, n = 2), DST-treated (, n = 2), and DST-vaccinated ({square}, n = 2) allograft recipients sacrificed 5 days after the transplantation as responder cells and irradiated donor spleen cells as stimulator cells. [3H]TdR incorporation was assessed after 3 days of culture. Error bars represent mean ± SE between triplicate determination of two animals per group. When indicated, rIL-2 (50 U/ml) or a neutralizing anti-pan TGF-ß mAb (25 µg/ml), or both, were added at the beginning of culture. Experiment representative of two with similar results.

 
Anti-TCR DNA vaccination modified the profile of cytokines mRNA expression within allografts

We have previously reported that tolerated allografts from DST-treated recipients were characterized by a dramatic inhibition of Th1 (IL-2, IFN-{gamma})- and Th2 (IL-4 and IL-10)-related cytokine expression (14, 15, 16) and an early and strong expression of TGF-ß1 (15, 17). This TGF-ß1 secretion has been shown to play a functional role in vivo because its neutralization after the transplantation abolished the tolerance in DST-treated recipients. Surprising, TGF-ß1 and IFN-{gamma} mRNA expressions were not modified within allografts of DST-treated recipients vaccinated with the phCMV/Vß18 DNA (Fig. 4Go). However, the acute rejection observed in rats treated with DST plus phCMV/Vß18 was associated with a restoration of TNF-{alpha} and IL-10 mRNA expression within allografts (Fig. 4Go). Therefore, this rejection occurring in recipients vaccinated with the phCMV/Vß18 DNA may depend on TNF-{alpha} and IL-10. However, this rejection would not implicate an overexpression of Th1 cytokine, which may explain the latency of its occurrence in comparison with untreated recipients.



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  		FIGURE 4. Anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination modified the expression of cytokine mRNA in allografts. Total RNA was extracted from heart allografts from DST-treated ({blacksquare}) and DST-vaccinated () rats at different time points after grafting. Quantitative RT-PCR analysis of TGF-ß1, TNF-{alpha}, IFN-{gamma}, IL-10, and hypoxanthine phosphoribosyltransferase (HPRT) mRNA accumulation was performed as described in Materials and Methods. Results are expressed as means ± SEM from the ratio between the number of cytokine and HPRT transcripts in allografts for four animals at each time point. *, p < 0.05.

 
Anti-TCR Vb18 DNA vaccination restores anti-donor IgG alloantibody production in DST-treated recipients

We have previously shown a role of anti-donor MHC class I alloantibodies in the mechanisms of allograft rejection in this model (11). Untreated recipients showed a strong anti-donor IgG alloantibody response (11). In contrast, in DST-treated recipients the level of anti-donor MHC class I IgG in the serum was similar to background levels. Moreover, passive transfer of sera from rejecting animals known to contain high levels of anti-donor alloantibodies promptly induced acute rejection in DST-treated recipients (11). The production of IgG directed against donor MHC in DST-Vß18-vaccinated recipients was thus analyzed. The IgG deposition was studied in heart allograft sections 5 and 11 days after the transplantation. As shown in Table IIIGo, anti-TCR Vß18 DNA vaccination completely restored the anti-donor IgG response in DST-treated recipients. DST-vaccinated rats produced 2- to 3-fold more IgG alloantibody than DST-treated recipients. IL-10 have been shown to be a potent growth and differentiation factor for activated B cells (18). The increased in IL-10 mRNA expression and protein production after Vß18 vaccination could be responsible for the recovery of alloantibody response.


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  		Table III. Anti-TCR Vß18-Dß1-Jß2.7 DNA vaccination restore the anti-donor alloantibody production in DST-treated recipients

 
The partial restoration of recipient cells DST-tolerized to proliferate in vitro (Fig. 2GoA) and to produce alloantibodies against donor cells following vaccination suggests that the Vß18-Dß1-Jß2.7 clone has a regulatory function in DST-induced allograft tolerance by suppressing alloreactive recipient cells. There is evidence that this CD8+ clone could exert its regulatory function by secreting or activating the immunosuppressive TGF-ß1 cytokine because the in vitro suppressive effect of TGF-ß1 in DST recipients (17) has been inhibited by the vaccination. Regulatory CD8+ T cells producing TGF-ß1 have been described in the protection against EAE induced by oral exposure to myelin basic protein (19). Regulatory T cells have also been described in the induction of transplantation tolerance (3) and, more frequently, in the maintenance phase of tolerance occurring in the 50- to 100-day period after transplantation (20, 21, 22). These latter suppressive T cells have been reported to belong to both CD4 and CD8 cell subtypes: either CD8+ only (20) or both CD4+ and CD8+ (21) or more often CD4+ solely (3, 21, 23). Donor-specific suppressive CD4+ T cells have been found in DST-treated rats (3), but our study suggests that CD8+ T cells could also exert a regulatory function in the induction of tolerance by DST. Whether these CD8+ T cells are responsible for the production or for the activation of TGF-ß1, as it has been previously described (24), is under investigation.

Vaccination with plasmid DNA encoding for a pathogenic Ag has been used in numerous experimental models to induce protection against viral, bacterial, or parasitic infections (25, 26, 27, 28). Proteins encoded by the naked DNA injected into muscle are expressed by myocytes and then presented by professional APC such as dendritic cells (29, 30). This elicits long-lasting cellular and humoral Ag-specific responses, including the efficient generation of CD4+ Th1 and CD8+ CTL cells (26, 27, 31, 32). These mechanisms are reinforced by a nonspecific response evoked by the adjuvant properties of the DNA itself (33). Indeed, CpG immunostimulatory sequences from DNA directly activate B cells and APC (34). Production of IFN-{gamma} and IL-12 cytokines elicited by these sequences also stimulates Th1 helper activity (35). In contrast to vaccination against a foreign pathogen, anti-TCR vaccination consists in immunizing the animal against a self-molecule. DNA vaccination disrupts the established tolerance to the self-TCR, possibly by inducing the presentation of this molecule by class II MHC molecules of professional APC. Moreover, this presentation could occur in an inflammatory context when the efficiency of APC is increased and cells of the immune system are activated. The specific immune response elicited by this presentation in DST recipients would disrupt the function of the Vß18-Dß1-Jß2.7 clone. Waisman et al. have reported an immune deviation for the Vß8.2+ T cells in mice after injection of DNA encoding this Vß segment (7). In our study, we did not find a difference in the mRNA expression of IFN-{gamma} and IL-4 (Th1- and Th2-related cytokines) (Fig. 4Go and data not shown). In contrast, we found a significant increase in mRNA expression of TNF-{alpha} and IL-10 (Fig. 4Go) in allograft from DST-Vß18-vaccinated compared with DST-treated recipients. This difference was seen as soon as day 1 after transplantation. TNF-{alpha} and IL-10 are produced by several cell subsets (T cells, monocytes, macrophages). TNF-{alpha} has been previously reported to play a role in the mechanisms of allograft rejection (36, 37), and blocking TNF-{alpha} has been shown to prolong allograft survival (38). The role of IL-10 in allograft survival is less clear. In some models, it has been related to allograft rejection (39, 40), whereas in others it might play a role in allograft tolerance (40, 41).

The use of DNA vaccination has allowed us to investigate the role of a Vß18-Dß1-Jß2.7 clone in the induction of tolerance by circumventing the unavailability of anti-Vß18 mAb in rats. This study underlines that, in addition to its major application in protecting against pathogens, DNA vaccination may also provide an efficient method to manipulate specifically a T cell response in vivo for the investigation of an immune mechanism.


   Acknowledgments
 
We thank Valia Proust and Helga Smit for their excellent technical assistance in grafting and treating rats. We thank Joanna Ashton for the reading of the manuscript.


   Footnotes
 
1 This work was supported by a grant from the "Etablissement Français des greffes." C.V. and P.D. were supported by a fellowship from the "Ministère de l’Enseignement Superieur et de la Recherche." Back

2 C.V. and E.C. contributed equally to this work. Back

3 Address correspondence and reprint requests to Dr. Maria Cristina Cuturi, Institut National de la Santé et de la Recherche Médicale Unité 437, immeuble Jean Monnet, 30 boulevard Jean Monnet, 44093 Nantes Cedex 1, France. Back

4 Abbreviations used in this paper: DST, donor-specific blood transfusion; EAE, experimental autoimmune encephalomyelitis; HPRT, hypoxanthine phosphoribosyltransferase. Back

Received for publication June 7, 1999. Accepted for publication April 13, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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