TY - JOUR
AU - Werdelin, O
AB - SUMMARY An attempt was made to identify the selection pressures put upon a growing tumour by CD8+ T cells. To this end tumours induced with 3-methylcholanthrene in T cell-deficient nude mice and in congenic T cell-competent nu/+ mice were transplanted to nu/+ recipients. The rejection rate of the sarcomas from nude mice was almost twice that of the sarcomas from nu/+ mice. Depletion of CD8+ T cells from nu/+ recipients prior to transplantation made them accept nude tumours that were consistently rejected by untreated nu/+ recipients. These findings suggest that a methylcholanthrene sarcoma during its growth in a T cell-competent host adapts to the T cell system through a selective elimination of highly immunogenic tumour cells that are susceptible to CD8+ T cell-mediated lysis. 3-methylcholanthrene sarcomas, immune surveillance, T cell responses to tumours, tumours in nude mice Introduction A growing tumour is subject to many selection pressures from the immune system of the host which may leave their imprint on the phenotype of the final tumour [1]. One of the major selection pressures is thought to be applied by the T cell system and in particular by CD8+ cytotoxic lymphocytes (CTL) [1–4] that are capable of killing tumour cells which express and present tumour antigens in association with MHC class I molecules on the tumour cell surface [5–8]. In a previous study of the selection pressures exerted on a growing tumour by the T cell system, sarcomas were induced with 3-methylcholanthrene (MCA) in T cell-deficient nude mice and in congenic T cell-competent mice [9]. When the fully developed tumours had been established as uncloned cell lines, they were transplanted to T cell-competent recipient mice. The tumours induced in the nude mice, henceforth the nude tumours, were found to be significantly more prone to rejection than the tumours induced in the congenic normal nu/+ mice [10]. We suggested that this was because the nude tumours had evolved in the absence of a functional T cell system and therefore had not adapted to growth in a host with an intact T cell system. However, since several types of cells may be involved in the rejection of transplanted tumours, the type of cell responsible remained to be identified. The purpose of the present experiments was to investigate if CD8+ T cells were essential for the observed rejection of the transplanted tumours. Three highly immunogenic tumours were chosen for the experiment. These were transplanted to congenic normal nu/+ recipients effectively depleted of CD8+ T cells, in a cell dose that was known to be invariably rejected by unmanipulated nu/+ recipients, and the acceptance ratio was observed. Materials and methods Mice Athymic BALB/c/A/Fib/Bom nu/nu mice (nude) and congenic, phenotypically normal littermates (nu/+) of 24th backcross and 11 intercross generation were used in the experiments. For ascites production Bom:NMRI-nu nude mice were used. All mice were supplied by M&B Ltd (Ry, Denmark). All mice were females, 6–8 weeks old at the start of the experiments. They were kept under specific pathogen-free conditions and were given autoclaved bedding, food and water. Tumours The tumours used for these experiments were the tumours previously used for transplantation experiments [10]. They were fibrosarcomas produced with either 0·5% (40 mg) or 0·1% (8 mg) MCA by subcutaneous implantation of filter discs [9], containing the MCA in paraffin, in female BALB/c mice, 6–8 weeks of age, either nu/+ or nude mice. Cell cultures The tumours were brought into culture and maintained as uncloned tumour cell lines in complete medium (RPMI 1640 with HEPES supplemented with 10% fetal calf serum (FCS), 4 m m l-glutamine, 5 × 10−5 m 2-mercaptoethanol (2-ME), 100 U penicillin/ml and 100 mg streptomycin/ml) in 25-cm2 tissue culture flasks, and further grown in 175-cm2 tissue culture flasks for less than 4 weeks until a total number of 150 × 106 cells per cell line was reached. The tumour cells were cultured at 37°C in an atmosphere of 5% CO2. Cells forming a confluent monolayer were harvested using 0·001% trypsin in 0·02% EDTA for approximately 5 min at 22°C. All plastic ware used for tissue culture was from Nunc A/S (Roskilde, Denmark). Tumour transplantation All tumour cell lines were uncloned and all tumours had been passaged more than 15 times in vitro prior to the transplantation. The 16 tumours used in the present experiments were the same used by us in the preceding set of experiments [10]. Eight of the tumours had been induced in nude mice and eight had been induced in nu/+ mice. Tumour cells were grown to the desired number in 175-cm2 tissue culture flasks and harvested as described above. Cells were washed once in PBS (0·1369 m NaCl, 0·002 68 m KCl, 0·006 46 m Na2HPO4 + 2H2O and 0·00147 m KH2PO4 without Ca2+ and Mg2+), counted and resuspended in complete culture medium without FCS to the desired concentration of 150 × 106 cells/ml. The cells were injected subcutaneously in the flank of the recipients. Recipient mice were inspected twice weekly. Tumour acceptance was defined as the presence of a progressively growing tumour with a diameter of ≥ 7 mm. Monoclonal antibodies The rat anti-mouse CD8 hybridoma cell line (ATCC TIB 105, 53-6.72) was purchased from ATCC (Rockville, MD). The cells were cultured as described above and harvested when the desired cell density was reached. Exponentially growing cells (2·5 × 106) were injected intraperitoneally in nine NMRI nude mouse in order to produce ascites. This hybridoma produced ascites containing high titres of the anti-CD8 MoAb, anti-lyt 2. The concentration of antibody was determined by both bicinchoninic acid assay and indirect ELISA. Crude ascites contained approximately 50 mg/ml protein (bicinchoninic acid assay) of which 10–20 mg/ml were IgG protein (ELISA) (data not shown). Depletion of CD8+ cytotoxic T cells in vivo Pilot experiments were performed to determine the appropriate depletion dose. Mice were injected intraperitoneally once a week with 1 ml containing varying doses of the ascites and the effect was measured by FACS analysis on unseparated spleen cell population and on purified spleen T cell population from treated mice. PBS-diluted ascites (1 ml) was injected intraperitoneally into nu/+ mice for 3 consecutive days in the week before transplantation of tumour, and then once a week throughout the experiment. The ascites was diluted 1:10 and 1:50 in PBS. Each dose contained 1–2 mg (1:10) and 0·2–0·4 mg (1:50) antibody protein. Both doses depleted > 95% of CD8+ T cells. Control mice were injected with 1 ml 1 mg/ml and 1 ml 0·2 mg/ml technical grade rat IgG control antibody in PBS, batch no. I8015 (Sigma, St Louis, MO) also for 3 consecutive days 1 week before tumour transplantation, and then once a week throughout the experiment. The treatment was terminated 90 days after tumour acceptance in the nude mice, and the number of mice that had not developed a tumour was recorded. Flow cytometry All FACS analyses reported here were performed on spleen cells of T cell-depleted mice in order to check the efficacy of the depletion regime. Spleens were removed, minced into single-cell suspension using a metal sieve (US sieve series no. 100), and resuspended in Hanks' PBS medium. Erythrocytes were lysed by adding 5 ml of NH4Cl for 5 min. The spleen cells were counted, resuspended, and washed twice in FACS buffer (PBS supplemented with 2% FCS and 0·1% sodium azide). This FACS buffer was used throughout the experiment. Cells were incubated with the primary antibody in saturating concentration at 4°C for 30 min. The antibody used was a PE-conjugated anti-CD8b, lyt 3.2 0·2 mg/ml (cat. no. 01055A) from PharMingen (San Diego, CA). Flow cytometry was performed on a FACScan (Becton Dickinson, Heidelberg, Germany). The FACScan program was used to calculate the mean fluorescence intensities and the s.d. of the mean fluorescence of the sample. Each sample analysed contained a minimum of 104 cells. Statistical analysis In the large transplantation experiment the rejection/acceptance data are binomially distributed, and the null hypothesis statistically tested was that the rejection rate was the same in the two recipient groups receiving the same dose of tumour cells from either nude donors or nu/+ donors. Results Tumour rejection For the purpose of identifying the three most immunogenic MCA tumours, 16 tumours, eight having been induced in BALB/c nude mice and eight induced in congenic BALB/c nu/+ mice, were used as donor tumours in a large-scale transplantation experiment. Each tumour was transplanted in three different doses: 107, 106 and 105 cells, respectively. Each cell dose was given to 10 nu/+ and three nude recipients. Rejection or acceptance of the tumour transplants was monitored by inspection of the recipient mice twice weekly until the termination of the experiment. The experiment was terminated when all surviving recipients had remained tumour-free for at least 90 days after the tumour had been accepted by the three nude control recipients. The 16 tumours were accepted in all three cell doses by all of 144 nude control recipients except one (data not shown). Tumour acceptance or rejection in nu/+ recipients is shown in Fig. 1. Graft of 107 tumour cells was accepted by 105 out of the 160 nu/+ recipients. However, the acceptance rate of the tumours coming from nu/+ mice was higher than that of the tumours coming from nude mice. Sixty-nine recipients accepted the nu/+t umours, while only 36 recipients accepted the nude tumours. The difference in rejection rates of the two panels of tumours was statistically significant (P < 0·01). Eighty out of the 160 nu/+ recipients accepted 106 tumour cells. Here too, the recipients accepted the nu/+ tumours more readily than the nude tumours, 52 versus 28 (P < 0·01). Tumour cells (105) were accepted by 64 out of the 160 nu/+ recipients, and again the recipients accepted the nu/+ tumours more readily than the nude tumours, 41 versus 23 (P < 0·01). Thus, for all three doses of tumour cells the acceptance rate of the nu/+ tumours was almost twice as high as for the nude tumours. This outcome is virtually identical to the one obtained previously [10] with the same tumours in an intermediate cell dose. Fig. 1 Open in new tabDownload slide Acceptance or rejection of transplanted nu/+ and nude tumours by nu/+ recipients. Each tumour was transplanted to 10 normal recipients in the doses 107 (●), 106 (○), or 105 tumour cells (▾). Tumour acceptance for each of the cell doses in the nu/+ recipients is indicated by a solid line with a symbol. The abscissa shows the time in weeks and the ordinate indicates the number of mice accepting the tumour. Fig. 1 Open in new tabDownload slide Acceptance or rejection of transplanted nu/+ and nude tumours by nu/+ recipients. Each tumour was transplanted to 10 normal recipients in the doses 107 (●), 106 (○), or 105 tumour cells (▾). Tumour acceptance for each of the cell doses in the nu/+ recipients is indicated by a solid line with a symbol. The abscissa shows the time in weeks and the ordinate indicates the number of mice accepting the tumour. Depletion of CD8+ T cells and the effect on tumour acceptance The three most immunogenic tumours were the nude tumours, nu93-1, nu97-1 and nu90-1, as evidenced by their ability to be rejected by all BALB/c nu/+ recipients even when the highest dose, 107 cells, was used (Fig. 1). With the aim of studying whether the rejection of the transplanted tumours was caused by CD8+ T cells, the regional lymph nodes of mice that had rejected these three tumours were removed, and the T cells were isolated and boosted in vitro with irradiated tumour cells following the protocol recommended by Jicha et al. [11]. Tumour-specific CTL could not be detected in 51Cr-release assays in any of the recipients of these three tumours at different time intervals after rejection of the tumour (data not shown). This was not due to resistance of tumour cells to CTL lysis, because all three cell lines were lysed by LCM-specific CTL after pulsing with the immunodominant Ld-restricted LCM virus peptide [12] (data not shown). The reason why tumour-specific CTL were not detectable is not obvious, but it is a general experience that CTL against MCA tumours are difficult to demonstrate [13] and to elicit such CTL may require hyper-immunization with the tumour [14]. Since CD8+ tumour-specific CTL were not detectable, it was decided to make in vivo CD8+ cell depletion experiments and transplant the tumours to the depleted recipients, in order to see if they would be able to reject the tumours. The three most immunogenic tumours were used, and the 106 tumour cell dose was chosen. Rat anti-CD8 ascites or a control rat IgG were injected intraperitoneally into the prospective recipients for 3 consecutive days during the week before transplantation of the tumour and then once every week throughout the experiment. The efficacy of the depletion regimen was verified by FACS analysis of spleen cells from anti-CD8 ascites-treated mice.Fig. 2 shows that the anti-CD8 treatment removed > 95% of the CD8+ T cell population compared with control mice receiving rat IgG. The flow cytometry profile of the cell population in spleens of untreated immunocompetent mice was the same as that obtained in control mice receiving rat IgG (data not shown). Fig. 2 Open in new tabDownload slide Flow cytometry profile of the cell population in the spleen of a normal immunocompetent nu/+ control mouse receiving rat IgG (a) and a CD8+ T cell-depleted nu/+ mouse after 4 weeks of antibody treatment (b). The cells were stained with PE-conjugated anti-CD8b (Lyt 3.2) antibody. The abscissa indicates the fluorescence in arbitrary units and the ordinate the number of cells stained. Fluorescence between 100 and 101 is the background staining. Fluorescence in the interval between 102 and 103 indicates the population of CD8+ T cells. Fig. 2 Open in new tabDownload slide Flow cytometry profile of the cell population in the spleen of a normal immunocompetent nu/+ control mouse receiving rat IgG (a) and a CD8+ T cell-depleted nu/+ mouse after 4 weeks of antibody treatment (b). The cells were stained with PE-conjugated anti-CD8b (Lyt 3.2) antibody. The abscissa indicates the fluorescence in arbitrary units and the ordinate the number of cells stained. Fluorescence between 100 and 101 is the background staining. Fluorescence in the interval between 102 and 103 indicates the population of CD8+ T cells. Tumour cells were transplanted to nu/+ mice and to nude control mice as well, and the recipients were inspected twice weekly for acceptance of the tumour transplant. After 32 days all nude control mice had developed a tumour (data not shown). The experiment was terminated 90 days after the tumour was accepted by the nude recipients. Fig. 3 shows that 14 of 15 recipients T cell-depleted with ascites diluted 1:10 accepted tumour nu-93-1 (one mouse died during the antibody treatment) and that 15 of the 15 mice treated with ascites diluted 1:50 accepted it. In comparison, none of the 20 IgG-treated control nu/+ recipients or the five untreated control recipients accepted this tumour, regardless of IgG dose. Virtually identical results were obtained with the two other tumours, nu-97-1 and nu-90-1 (Fig. 3). This outcome strongly argues that the rejection by untreated nu/+ mice of the MCA tumours used here was caused by CD8+ cells. This is consistent with the results obtained by Wen et al. [15]. Using CD4, CD8 and CD4/CD8 double knockout mice they demonstrated that CD8+ T cells function as the dominant effector cells in the rejection of transplanted MCA sarcomas. In addition they found that, in the absence of CD8+ T cells, CD4+ T cells were sufficient to cause rejection of the transplanted MCA sarcomas. Fig. 3 Open in new tabDownload slide The outcome of transplantation of three highly immunogenic tumours to CD8+ T cell-depleted recipients. Fifteen normal nu/+ mice were depleted with ascites diluted 1:10 approx. 1–2 mg/ml antibody and 15 were depleted with ascites diluted 1:50 approx. 0·2–0·4 mg/ml antibody for each of the three cell lines. Ten nu/+ control mice received rat IgG 1 mg/ml and 10 were given rat IgG 0·2 mg/ml. The abscissa indicates the time measured in weeks and the ordinate indicates the number of mice with tumour acceptance. Fig. 3 Open in new tabDownload slide The outcome of transplantation of three highly immunogenic tumours to CD8+ T cell-depleted recipients. Fifteen normal nu/+ mice were depleted with ascites diluted 1:10 approx. 1–2 mg/ml antibody and 15 were depleted with ascites diluted 1:50 approx. 0·2–0·4 mg/ml antibody for each of the three cell lines. Ten nu/+ control mice received rat IgG 1 mg/ml and 10 were given rat IgG 0·2 mg/ml. The abscissa indicates the time measured in weeks and the ordinate indicates the number of mice with tumour acceptance. Discussion The present experiments represent a new contribution to the longstanding discussion on immune surveillance of tumours [16–19]. The results support the hypothesis that an MCA sarcoma during its growth in a T cell-competent host adapts to the T cell system of the host, and that it does so through a T cell-mediated selective elimination of those clones of tumour cells that are most immunogenic and susceptible to elimination by CD8+ CTL. Hence, the fully grown tumour will contain many ‘escape variants’ of tumour cells. Several mechanisms have been proposed to explain how a tumour cell may manage to escape detection by the T cell system. Most of these involve defects in the MHC class I-restricted pathway of antigen processing and presentation cascade such as low/suppressed MHC class I expression [20,21], defective TAP molecules resulting in inability to process antigens to MHC class I [22], defects in the proteasome complex [23,24], altered expression of heat shock proteins [25,26], reduced sensitivity to interferon-gamma (IFN-γ) [27] and reduced expression of or even mutated intercellular adhesion molecule-1 (ICAM-1) adhesion molecules [28]. Of these the best understood is the accumulation of defects in the TAP molecules in human cervical carcinoma cells [22]. A thorough investigation of the present panel of MCA sarcomas has not revealed low MHC expression, structural defects in the MHC class I molecules [29], or lack of sensitivity to IFN-γ[30]. The MCA tumours used here have also been investigated for structural defects in both the proteasome complex and the heat shock proteins, and for changes in ICAM-1 expression, but no defects were detected [29]. The function of TAP molecules in the tumour lines has been tested in an indirect manner, as empty class I molecules are known to be expressed on the cell surface in increased amounts when TAP-deficient cell lines are cultured at reduced temperature [31]. None of the tumour lines increased their MHC class I surface expression at low temperature [29]. We therefore conclude that there is no functional defect of TAP in our tumour cell lines. Thus, there is at present no molecular explanation to account for why MCA tumours developing in nude mice are more immunogenic than MCA tumours developing in nu/+ mice. Acknowledgments These studies were supported by grants from the Danish Cancer Society, Dagmar Marshall Fond, Fabricant Einar Willumsens mindelegat, Michaelsen Fonden, Direktør Michael Hermann Nielsens Mindelegat. We thank R. T. Prehn for valuable comments on the manuscript, and Pernille Albrectsen, Margit Bæksted, Per Nielsen, Jørgen Kristensen, Sussie Schreiber and Grethe Thørner Andersen for expert technical assistance. References 1 Nowell PC . The clonal evolution of tumor cell populations . Science 1976 ; 194 : 23 – 28 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Greenberg PD . Adoptive T cell therapy of tumors: mechanisms operative in the recognition and elimination of tumor cells. [Review] Adv Immunol 1991 ; 49 : 281 – 355 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Shimizu K & Shen FW. Role of different T cells sets in the rejection of syngenic chemically induced tumors . J Immunol 1979 ; 122 : 1162 – 5 . 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Google Scholar Crossref Search ADS PubMed WorldCat © 2000 Blackwell Science Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - CD8+ T cells are crucial for the ability of congenic normal mice to reject highly immunogenic sarcomas induced in nude mice with 3-methylcholanthrene
JF - Clinical & Experimental Immunology
DO - 10.1046/j.1365-2249.2000.01292.x
DA - 2008-10-09
UR - https://www.deepdyve.com/lp/oxford-university-press/cd8-t-cells-are-crucial-for-the-ability-of-congenic-normal-mice-to-vBitpEZzLc
SP - 210
EP - 215
VL - 121
IS - 2
DP - DeepDyve
ER -