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Adequate T helper cell activation is essential in the initiation of an immune reaction. The inability to control tumor outgrowth can be due to inadequate T helper responses underlying poor tumor-specific immunity. In the cellular immune response, specialized APCs process protein and present antigenic peptide fragments in MHC class II molecules to CD4+ T helper lymphocytes. These provide "help" to effector cells via the production of cytokines. Although tumor cells can directly present endogenously processed antigenic peptide in surface MHC class I molecules to CD8+ CTL precursors, initiation of tumor-specific CTL responses is likely to involve indirect presentation of tumor antigens by specialized APCs.
Evidence for a role of T helper cell–mediated immunity comes from studies with genetically modified tumor cells. CD4+ cells can be directly activated by transfection of MHC class II
A central role of CD4+ T cells emerged from studies of immunity against FMR (Friend, Moloney, Rauscher)1 murine leukemia virus (MuLV) type tumors by Greenberg (5). Transfer of purified polyclonal T cells from FBL (Friend MuLV-induced erythroleukemia cell line) vaccinated mice in naive animals can protect these mice against subsequent tumor challenge. Both purified CD4+ and CD8+ T cells transfer protection to FBL tumors (6). FBL cells do not express MHC class II molecules, but CD4+ T cells can protect mice even in the absence of CD8+ T cells. In this case, macrophages seem to play an important effector role. CD8+ T cells can only be effective if CD4+ T cells are present or if exogenous IL-2 is administered. Neither B cells nor NK cells seem to exert a significant role in the FBL sytem. These data suggest involvement of APCs, presenting tumor antigens, and a crucial regulatory role of Ths, which was strongly supported by experiments performed in Friend MuLV env-transgenic mice (7). These mice were rendered tolerant for env-specific Th responses and it was not possible to protect these mice against FBL tumors by vaccination.
Immune responsiveness to MuLV is classically regulated by the genes of the H-2 (MHC) complex (8). In particular, the H-2b haplotype confers resistance, and studies using H-2 recombinant and H-2 mutant mouse strains have mapped the protective effects to the class II I-Ab locus (9, 10). This MHC class II association indicates an important role of T helper cells influencing both CTL activity as well as class switching of antiviral antibodies from IgM to IgG. The H-2 I-Ab phenotype protects against early lymphomagenesis. The identification of two Friend MuLV env-derived epitopes, presented by MHC class II, I-Ab and I-Eb/d, respectively, indicated that tumor-directed T helper immunity is virus specific (11). The few lymphomas that arise in H-2b mice have abrogated viral antigen or (more rarely) MHC class I expression (12), indicating that CTLs also play a crucial role. CTLs have been proven to recognize viral antigens, both gag and env proteins encode CTL epitopes (13). We have identified a Kb-presented, env-derived Moloney and Rauscher CTL epitope that is subdominant in C57BL/6 mice making use of the Db mutant BM13 mouse strain (14). The Db-presented gag-leader (gag-L) derived immunodominant CTL epitope for the FMR type of MuLV has been identified only recently (15).
Vaccination with a synthetic peptide comprising a relevant T cell epitope is a powerful method to induce highly specific T cells. Protective vaccination using CTL peptide epitopes has been achieved in pathogenic viral models (16, 17) and tumor models (18–20). Peptide vaccination in IFA led to measurable specific CTL induction and protective immunity against virulent virus or tumor cells. Importantly, peptide vaccination can also be applied succesfully for therapy of established tumors by presenting the peptide in IFA, on RMA-S cells, or on activated dendritic cells (21, 22).
We now report the induction of tumor-protective immunity by a single vaccination with a tumor-specific MuLV env-encoded T helper peptide. Strong protection can be achieved against highly aggressive tumor cells that lack MHC class II expression. This indicates the requirement of cross-priming of tumor antigens by local APCs. We show that CD8+ T cells, recognizing the gag-L–encoded CTL epitope, are crucial effector cells that are efficiently activated with help from peptide-primed tumor-specific CD4+ T cells. Vaccination with a mixture of the T helper peptide and the immunodominant CTL epitope resulted in synergistic, long-term tumor protection.
Cell Lines, Viruses, and Antibodies.
Moloney murine sarcoma and leukemia virus complex (MoMSV) was prepared and injected in the left thigh intramuscularly for sarcoma induction as described (25). Moloney Abelson virus was used for infection of B6 LPS blasts as described (25).
Monoclonal antibodies used for immunofluorescence staining and FACScan® (Becton Dickinson, Mountain View, CA) analysis were: anti-Kb (B8.24.3), anti-Db (28.14.8S), anti–I-Ab (17.227 and Y3P), anti-CD4 (H129.19), anti-CD8 (53.6.7), and anti-CD3 (500A2).
Monoclonal antibodies used for in vivo depletion of the CD4+ and CD8+ T cell subsets were GK1.5 and 2.43, respectively. Purified antibodies were administered by intraperitoneal injection of 100 µg of antibody in 0.2 ml PBS, in schedules that are specified in the figure legends.
Peptides.
Peptide Vaccination and Tumor Challenge.
T Cell Culture.
T helper clone 3A12 (CD4+) and CTL clone 2H9 (CD8+) was isolated from a bulk spleen cell culture of tumor-protected mice immunized with 11-mer MuLV T helper peptide (H11.1) that were challenged with 103 live RMA tumor cells. Spleen cells were restimulated with mitomycin-C (50 µg/ml for 1 h at 37°C) -treated and irradiated (25 Gy) RMA tumor cells. After 1 wk, bulk cultures were seeded under limiting dilution conditions and clones were randomly isolated and tested for specific proliferative capacity and cytotoxicity against RMA tumor cells.
All cells were cultured in Iscove's modified Dulbecco's medium (GIBCO Biocult, Glasgow, UK) supplemented with 5% FCS (tumor cells) or 10% FCS (CTL), penicillin, (100 IU/ml) and 20 µM 2-mercaptoethanol. T cell clones were cultured in the presence of 20 IU/ml human recombinant IL-2.
Proliferation Assays.
Cytotoxicity Assays.
Cytokine Assays.
The presence of cytokine transcripts of IFN-
RMA-S MHC Class I Peptide-binding Assay.
and β chain genes in mouse tumor cells (1–4). These cells become immunogenic, lose their tumorigenicity, and even induce protection against wild-type MHC class II negative tumors, indicating that direct MHC class II presentation of tumor expressed antigens can induce efficient anti–tumor responses.
Materials and Methods
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Mice.
C57BL/6 (B6 Kh, H-2b) mice were bred under specific pathogen-free conditions at TNO-PG (Leiden, The Netherlands).
771 is an MCF1233-induced B cell lymphoma cell line from a C57BL/10 mouse neonatally inoculated with MCF1233 MuLV as described (23). RMA is a mutagenized derivative of RBL-5, a Rauscher MuLV-induced T lymphoma cell line of C57BL/6 origin (24). EL-4 is a chemically induced (non-MuLV–induced) T cell lymphoma of C57BL/6 origin. HeLaDb is a stable transfectant of the human cervix carcinoma cell line HeLa, expressing the murine MHC class I molecule Db.
Peptides were synthesized on multiple peptide synthesizer (442; ABIMED, Langenfeld, Germany) as previously described (26). Peptides were analyzed for purity by reverse phase HPLC and lyophilized. The T helper epitope peptide env-H19 EPLTSLTPRCNTAWNRLKL (11) (and its length variants) and the env-derived CTL epitope peptide env-Kb8 SSWDFITV (14) were dissolved in PBS. The dominant gag-L–derived CTL epitope peptide was used as a 10-mer (gag-L–Db10) or a 9-mer (gag-L–Db9) (L)CCLCLTVFL (15) was dissolved in DMSO (20 µl/mg peptide) and diluted in PBS. The Sendai virus nucleoprotein CTL epitope SV9 (FAPGNYPAL) was used as a control Kb-binding peptide (16). The ovalbumin T helper peptide OvaH (ISQAVHAAHAEINEAGR) (27) was used as a control I-Ab–binding peptide. This peptide induces strong CD4 responses in C57BL/6 mice. Stock solutions of 5 mg/ml were stored at –80°C.
C57BL/6 mice, aged 7–10 wk, were vaccinated with a single dose of synthetic peptide (0.1–100 µg/mouse) in 50% (vol/vol) emulsion with IFA administered in a 0.2-ml depot subcutaneously. Control groups were similarly injected with a 50% (vol/vol) emulsion of PBS and IFA. After 14 d, the mice were challenged with 103 RMA tumor cells in 0.2 ml PBS, 0.1% (wt/vol) BSA, intraperitoneally. Weights of the mice were monitored every other day. Mice were killed if their weight increased for >25%. Statistical analysis on the survival data was performed using the log rank test. Significance was defined as probability values below 0.05.
CD4+ T cells were obtained from T helper peptide immunized mice by culturing spleen cells (3 x 106 cells/ well of 24-well plates) in the presence of 10 µg/ml T helper peptide in complete medium in the absence of exogenous IL-2. Bulk cultures after 1 wk were mainly (70–80%) CD4+ as determined by FACScan® analysis. The bulk culture was restimulated using irradiated B6 spleen cells in the presence of 10 µg/ml T helper peptide without IL-2. Clones were isolated by limiting dilution and tested for peptide specificity.
Proliferation assays were carried out in 96-well U-bottomed plates using CD4+ T cells as responder cells at 4 x 104, 2 x 104, 104, and 5 x 103 cells/well. Several stimulator cells were tested: irradiated (25 Gy) spleen cells (105 cells/well), with or without T helper peptide (5–10 µg/ml), with or without tumor cells (mitomycin-C–treated and irradiated RMA cells; 2 x 104 cells/well). All assays were performed in the absence of exogenous IL-2. After 3 d, the cultures were pulsed with [3H]thymidine (New England Nuclear, Boston, MA; 0.5 µCi/well) for 5 h. The results are expressed as mean cpm of triplicate cultures. Standard deviations were <10% of the mean.
CTL assays were performed as described (23). In short, 2 x 103 Na251CrO4-labeled target cells were incubated with effector cells for 5–6 h at 37°C. The culture supernatant was harvested and counted for released radioactivity. The percentage of specific 51Cr-release was calculated as a ratio of 100 x (cpm experimental release – cpm spontaneous release)/(cpm maximal release [1% Triton X-100] – cpm spontaneous release). All assays were carried out in triplicate. For target cell sensitization, 51Cr-labeled target cells were incubated with peptide 1 h before addition of the CTLs. Peptides remained present during the assay.
Bioactive IL-2 production was determined using the IL-2–dependent cell line CTLL2. 50 µl supernatant of specifically stimulated CD4+ T cell clones (3-d stimulation with irradiated [25 Gy] 771 [I-Ab+] cells with and without env-H19 peptide) was incubated with 5 x 103 CTLL2 cells in a total volume of 100 µl. As a standard, human recombinant IL-2 was used. After 24 h, the wells were pulsed with [3H]thymidine (New England Nuclear; 0.5 µCi/well) for 5 h. All determinations were performed in triplicate and standard deviations were <10% of the mean. 
, IL-2, IL-3, IL-4, IL-5, and IL-6 were tested by reverse transcriptase PCR using cytokine-specific primer sets as described (28). CD4+ T cell clones were specifically stimulated with env-H19 peptide-loaded 771 cells for 2 and 16 h and total RNA and cDNA was prepared as described (29). Controls were CD4+ T cells incubated with 771 cells without peptide, CD4+ T cell alone, and 771 cells with peptide without CD4+ T cells. Control reactions without reverse transcriptase were always negative for any primer set.
The RMA-S assay was performed as described previously (18). In short, RMA-S cells were cultured for 36 h at 26°C and were added to serial dilutions of peptide in serum-free medium. After a 4-h incubation at 37°C, cells were washed and incubated with the Db-specific mAb 28.14.8S for 30 min on ice. After washing, the cells were incubated with FITC-conjugated goat anti–mouse IgG F(ab')2 fragments for 30 min on ice and immunofluorescence was analyzed using a FACScan® flow cytometer.
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Peptide Vaccination with T Helper Epitope Peptide Leads to Protective Immunity.
MuLV-encoded epitope peptides were tested for their capacity to induce tumor-protective immune responses in vivo. Synthetic peptide diluted in saline and emulsified in IFA was injected subcutaneously. The subdominant 8-mer CTL epitope env-Kb (SSWDFITV; reference 14) and the T helper 19-mer peptide env-H19 (EPLTSLTPRCNTAWNRLKL), originally described as a Friend MuLV T helper epitope (11) sharing identical sequences with Moloney and Rauscher MuLV but not with AKV/MCF type MuLV, were used to vaccinate immunocompetent C57BL/6 mice. After 14 d, the mice were challenged intraperitoneally with the Rauscher MuLV-induced tumor cell line RMA. RMA is an aggressively growing T cell lymphoma, lethal for mice within 4 wk when as few as 1000 cells are administered. RMA expresses MHC class I Kb and Db but is negative for MHC class II expression even after IFN- treatment, as monitored by staining with specific antibodies and Northern blotting analysis (data not shown). RMA cells isolated from the peritoneal cavity 3 wk after inoculation in C57BL/6 mice were tested for MHC expression and found to have retained their I-Ab negative phenotype in vivo (data not shown). Fig. 1 shows the weight increase of individual mice in time, reflecting ascites tumor growth. The subdominant CTL epitope env-Kb8, despite being expressed by RMA cells (14), did not induce a protective response (Fig. 1 B). In contrast, vaccination with the env-H19 T helper peptide (Fig. 1 C) led to inhibition of RMA tumor growth in a significant number of mice. Combined vaccination with the T helper and the subdominant env-Kb8 CTL epitopes (Fig. 1 D) did not significantly increase survival beyond that seen with the T helper peptide alone, within the first 40 d after tumor challenge. Fig. 2 shows 100-d survival of mice vaccinated with MuLV CTL and T helper peptides compared with an irrelevant ovalbumin T helper peptide (OvaH; reference 27). Vaccination with the OvaH peptide alone or in combination with the env-Kb8 CTL epitope did not induce detectable protection, whereas the MuLV T helper peptide induced long-term protection in 40% of the mice (Fig. 2 A). The combination vaccine (env-Kb8 and env-H19 mixture) induced long-term protection of 70% of the animals. This difference was not found to be statistically significant (P = 0.28). The nonrelated CTL and T helper epitopes Sendai virus SV-Kb9 and OvaH, respectively, did not induce measurable protective immunity. The recently described gag-L–derived, Db-presented dominant CTL epitope (L)CCLCLTVFL (15) was tested in a similar way (Fig. 2 B). The gag-L–Db peptide is able to induce protection in 20–40% of the mice either as a 9 or 10 mer. The mixture of the env T helper peptide and the gag-L CTL epitope peptide resulted in very efficient protection leading to long-term survival of 90% of the mice. The requirement for induction of tumor-specific T helper cells is shown in Fig. 2 C. Vaccination with a mixture of OvaH with the gag-L–Db9 peptide resulted in significantly less efficient protection than the combination vaccine of MuLV env-derived T helper peptide with the gag-L peptide. These results show that tumor-specific T helper peptide vaccination as such can induce efficient protective immunity against MHC class II negative tumor cells. This protective effect can be further enhanced by vaccination of T helper peptide in combination with CTL epitope-bearing peptides.
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treatment, could be observed that was expected as the cells lack MHC class II (data not shown). Five of these clones were tested for peptide-specific cytokine production profile. All clones produced IL-2 IFN-, but not IL-4, IL-3, IL-5, and IL-6 (data not shown), indicating a Th1 type of T helper response. In addition, we isolated tumor-specific T cell cultures from mice that were protected from tumor challenge. Spleen cells from env-H11.1 peptide-vaccinated mice that survived RMA tumor challenge after 6 wk were restimulated with RMA cells in vitro. From these T cell cultures we were able to isolate both CD4+ and CD8+ T cell clones. Fig. 5 A shows the peptide and tumor specificity of CD4+ clone 3A12. Although it is not able to recognize the MHC class II negative RMA cells directly, it specifically proliferates to the combination of RMA cells with APCs present in autologous spleen cells, indicating specific recognition of processed RMA-derived antigen. The peptide fine specificity of clone 3A12 is shown in Fig. 5 B. The recognition of shorter length variants of the peptide is in agreement with the observed protective ability of the shorter peptides (Table 1). Fig. 5 C shows the specific proliferative response of CD4+ clone 3A12 to endogenously processed viral antigen using Moloney MuLV-infected LPS blasts.
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MuLV env-gp70 T helper peptide vaccination resulted in long-term protection of 40–50% of the mice and a delay in tumor growth in 80–90% of the animals in contrast to irrelevant ovalbumin T helper peptide vaccination. Although protection is not complete, this indicates a significant specific immune response since RMA is an extremely aggressive tumor cell line in immunocompetent animals. Strikingly, a combination vaccine containing the immunodominant MuLV gag-L CTL epitope and the T helper peptide induces highly protective responses leading to long-term survival of 90% of the mice. Vaccination with the immunodominant CTL epitope by itself also induces protection, but is generally far less effective (
30% of the mice survive). Some bystander help was observed upon administration of the immunodominant CTL epitope in combination with the ovalbumin T helper peptide (Fig. 2 C), although the difference was not found to be statistically significant from vaccination with the CTL epitope alone. Bystander help can be beneficial for CTL induction as shown by others (32). This might be due to cytokines produced by Ova-specific T helper cells during the priming phase leading to increased numbers of CTL precursors. In the effector phase after tumor challenge the Ova-specific T helper cells will not be activated.
CTL induction in vivo has classically been reported to be T helper dependent (33), but synthetic peptide vaccination studies using the minimal CTL epitope sequence were either shown to be T helper independent (16) or dependent (34, 35) in different virus systems. Here, we report induction of protective CTL-mediated immunity by vaccination with a T helper epitope by itself or in combination with a CTL epitope indicating T helper dependence for optimal protection. The requirement for physical linkage between CTL and the T helper peptide as shown for HIV (36) is not essential since a single vaccination with a mixture of T helper and CTL epitopes in IFA induces efficient protective immunity.
Recent experiments by Bennett et al. (37) indicate that induction of CTL responses by cross-priming requires cognate T cell help, involving presentation of both CTL and helper epitopes on the same APC. We consider these findings in line with our study. Local specific help appears to be crucial for efficient CTL-mediated tumor control. This can only be expected when APCs present tumor-derived antigenic fragments to tumor-specific T helper cells. This explains why nonrelated bystander (OVA-specific) help is far less efficient. In conclusion, optimal virus or tumor vaccines should preferably contain both antigen-specific CTLs and T helper epitopes.
Vaccination with the MuLV-env–gp70 T helper peptide in IFA leads to activation of CD4+ T cells that exhibit a Th1 type cytokine production pattern as established in vitro at the clonal level. The Th1 type appears to be crucially related to the cellular (cytotoxic) response leading to tumor cell destruction. The essential rules for peptide vaccination inducing the required T helper type are presently not understood. In future experiments, we will purposely direct the T helper type response using specific antibodies and cytokines and monitor the effects on tumor protection.
Greenberg (5), in adoptive transfer experiments of FBL-specific CD4+ T cells, found macrophages to be a main effector population next to CTLs. We have performed adoptive transfer experiments with our specific CTL and Th clones in RMA tumor-bearing nude mice (our unpublished observations). We were able to control RMA tumor growth by intravenous infusion of the gag-L–specific CTL clone in combination with subcutaneous IL-2 or in combination with the T helper clone. In contrast, the T helper clone by itself could only partially control tumor outgrowth in these T cell–deficient mice, possibly by activating macrophages into tumoricidal effector cells (5). Therefore, we conclude that CTLs are important effector cells in this system, but we do not exclude other effector mechanisms operating in vivo. Macrophages and/or other professional APCs of the dendritic cell lineage are likely to play an important role in the cross-presentation of tumor antigens. Vaccination studies using vaccinia virus containing a chimeric Friend MuLV env gene resulted in CD4- and CD8-dependent protection against Friend virus–induced erythroid proliferation (38). Miyazawa et al. (39) showed protective effects of env-gp70 T helper peptide vaccination against Friend virus, especially by a I-Eb/k–binding peptide. Here, the mechanism was reported to be control of infection by induction of virus-neutralizing antibodies or direct effects of the CD4+ T cells. In our study, using an established tumor cell line, peptide vaccination and CD8 depletion studies strongly indicate a dominant role for Rauscher MuLV-specific CTL.
We have explored the possibility of using the helper and CTL epitope-containing synthetic peptides for therapeutic use in mice bearing RMA tumors or when tumor cells were administered at the same day of vaccination. Thus far, using the IFA protocol, we were not able to control this extremely aggressive tumor cell line in a therapeutic set up. Apparently, the naive immune system cannot control this rapidly dividing, established tumor cell line. Other ways of efficient activation of the immune system, i.e., using peptide-loaded dendritic cells (22), will be investigated in this model.
Peptide vaccines are generally extremely potent in vivo, but peptide administration can lead to either induction of protective responses or (unwanted) induction of specific T cell tolerance. This has been found for CTL epitopes in both virus (40) and tumor models (41, 42). Peptide vaccination with the LCMV CTL epitope can lead to induction of immunity, but is dose and route dependent. For immunization rather than tolerance induction, only a single dose of peptide in a quite narrow window is required (40). In the adenovirus tumor model, peptide-induced tolerization is dose independent (41, 42). In the MuLV system in which we use an identical peptide administration protocol, both T helper and CTL peptide vaccination appear to lead to activation rather than functional deletion of specific T cells. Our study with an intraperitoneally growing tumor shows that T helper peptide administration in IFA is protective across a wide dose of peptides of varying lengths. However, T helper peptides can induce tolerance as shown by the ovalbumin peptide (43), dependent on the mode of peptide delivery. Our findings indicate that T helper peptide vaccination with a single subcutaneous dose in IFA leads to immunization rather than tolerization.
The use of T helper epitopes in vaccines can have potential advantages. First, T helper cells might play an important role not only for optimal induction of CTL responses as reported in this paper, but also for maintainance of CTL memory as reported for LCMV (44, 45) and -herpesvirus (46). Secondly, the regulatory role of T helper cells allows recruitment of several effector systems next to CTLs that one can make use of to specifically attack tumor cells. Utilization of specific cytokines, antibodies, or adjuvants allows one to selectively tilt the response towards cells of the Th1 or Th2 type. And thirdly, T helper peptides are usually more promiscuous in binding to MHC class II molecules than CTL epitopes are for MHC class I. This opens the possibility that T helper–based vaccines are less allele dependent and thereby widely applicable. Inclusion of CTL epitopes next to T helper epitopes in vaccines nevertheless seems unavoidable for optimal action. Finally, these findings illustrate the importance of identification of tumor-specific T helper epitopes, even if tumor cells lack MHC class II expression.
Submitted: 1 August 1997
This study was financed by the Netherlands Cancer Foundation grants 93-560 and 97-1451.
Address correspondence to F. Ossendorp, Department of Immunohematology and Bloodbank, University Hospital Leiden, Bldg. 1, E3-Q, PO Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31-71-5263800; Fax: 31-71-5216751; E-mail: ossendorp{at}rullf2.medfac.leidenuniv.nl
1 Abbreviations used in this paper: FMR, Friend, Moloney, Rauscher; gag-L, gag-leader; gp, glycoprotein; MoMSV, Moloney murine sarcoma and leukemia virus complex; MuLV, murine leukemia virus; n.s., not significant.
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