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a Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea;
b Division of Transplantation/Immunotherapy, National Cancer Center Hospital, Tokyo, Japan;
c Kirin Brewery Company, Tokyo, Japan;
d Pharmacology Division, Research Institute, National Cancer Center, Tokyo, Japan;
e Department of Pediatrics, Chonnam National University Medical School, Gwangju, Republic of Korea;
f National Cancer Center Hospital, Tokyo, Japan
Key Words. Blood • Dendritic Cells • Th1/Th2 • Cell trafficking
Yoichi Takaue, M.D., Hematopoietic Stem Cell Transplant Unit, National Cancer Center Hospital, 1-1 Tsukiji 5-Chome, Chuo-ku, Tokyo 104-0045, Japan. Telephone: 81-3-3542-2511; Fax: 81-3-3542-3815; e-mail: ytakaue{at}ncc.go.jp
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ABSTRACT |
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INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) to facilitate T-cell-mediated cytotoxicity [7–9]. In contrast, DCs that generate Th2 responses may be clinically used in conditions in which Th1 responses are disturbed, e.g., transplantation, contact allergy, or autoimmune disorders, by secreting cytokines, including IL-4, IL-5, IL-6, and IL-10, to help B cells secrete protective antibodies [8,10].
Prostaglandin E2 (PGE2) is produced by stromal cells and tissue-infiltrating mononuclear cells, and is an important inflammatory mediator that elevates intracellular cyclic AMP (cAMP). PGE2 inhibits IL-2 and IFN- production by Th1-type cells, but not the production of IL-4 by Th2-type cells [11–13], and thereby, regulates the differentiation of naïve CD4+ T cells into Th2-type CD4+ T cells in vivo [11–13]. However, somewhat contradictory results have been reported regarding T-cell polarization induced by DCs that are cultured in the presence of PGE2. Kalinski and coworkers [6,14–16] reported that immature and mature DCs, generated in the presence of PGE2, either initially or during terminal maturation, induced naïve T cells toward a Th2 response by impairing the production of IL-12. On the other hand, other investigators reported the induction of a Th1 response mediated by the greater production of IL-2 and IFN- with the addition of PGE2, which resulted in higher IL-12 production [17–19]. Thus, the definitive effect of PGE2 in the differentiation of DCs remains to be established.
Chemokines play an important role in trafficking DCs to lymphoid organs [20]. Immature DCs express various inflammatory chemokine receptors, such as CCR1, CCR4, CCR5, CCR6, and CXCR4. As maturation proceeds, DCs upregulate the constitutive expression of chemokine receptor CCR7 and downregulate inflammatory chemokine receptors, which permits DCs to be localized in lymphoid tissues where pulsed DCs stimulate effector T cells via the interaction with T-cell receptors [20–22]. In addition, previous reports have suggested that the conditions used to culture DCs affect the expression of chemokine receptors [23,24]. Thus, this field appears to be complex, and factors that affect DC function through the expression of chemokine receptors or interaction with their ligands need to be defined.
Hence, in this study, we investigated the roles of PGE2 in the regulation of DC function, particularly focusing on the polarization of T cells and the modification of the expression of chemokine receptors.
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MATERIALS AND METHODS |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), and IL-2 were purchased from R&D systems (Minneapolis, MN; http://www.rndsystems.com). PGE2 was purchased from ICN Biomedicals (Aurora, OH; http://www.icnbiomed.com) and rMIP-3ß/ELC was from Dako (Kyoto, Japan; http://www.dako.dk).
Fluorescence-activated cell sorting (FACS) analysis was performed using mouse monoclonal antibodies (mAbs) against fluorescein isothiocyanate-labeled CD14 (CD14-FITC), HLA-DR-FITC, IFN--FITC, phycoerythrin-labeled CD80 (CD80-PE), CD54-PE, IL-4-PE, and CD4-Percp, which were purchased from Becton Dickinson (San Jose, CA; http://www.bd.com). CD40-FITC and CD86-FITC antibodies were from PharMingen (San Diego, CA; http://www.bdbiosciences.com/pharmingen), and mAbs against CD45RA-FITC, CD1a-PE, CD45RO-PE, and CD83-PE were from Coulter-Immunotech (Miami, FL; http://www.coulter.com). Biotinylated mAbs against CCR1, CXCR4, and CCR6 were purchased from Dako. Isotype controls were run in parallel. Cell debris was eliminated from the analysis by forward and side scatter gating. The samples were acquired on a FACS Caliber cell sorter (Becton Dickinson) and analyzed with CellQuest software (Becton Dickinson).
Generation of Immature DCs and Induction of Mature DCs
CD14+ cells isolated from leftover peripheral blood stem cell (PBSC) products, which were collected from healthy donors mobilized with G-CSF for allogeneic transplantation after obtaining a consent form, were used to generate DCs. In brief, the PBSC products produced 2-6 x5 108 cells after washing the material remaining in the apheresis bags. CD14+ cells were isolated from the PBSC products (>85% purity) using the magnetic activated cell sorter (MACS) according to the manufacturer’s instructions (Miltenyi Biotec; Auburn, CA; http://www.miltenyibiotec.com). To generate immature DCs, the CD14+ cells were cultured at a density of 1 x 106 cells per 1 ml of culture medium with one of the following combinations of cytokines: A) GM-CSF (50 ng/ml) and IL-4 (50 ng/ml) or B) GM-CSF (50 ng/ml), IL-4 (50 ng/ml), and PGE2 (10–7 M). Freshly prepared cytokines were added every other day. Maturation of DCs was induced by adding TNF- (50 ng/ml) with or without PGE2 (10–7 M) to each group of cultures on day 6. DCs were harvested as immature (day 6) or mature (day 9) cells for morphologic, phenotypic, or functional evaluations. Additionally, the culture supernatants were collected on the same days and frozen at –20°C until measurement of IL-10 and IL-12 levels using enzyme-linked immunosorbent assays (ELISA).
Immature or mature DCs (3 x 104 cells) were then prepared on cytospin slides with centrifugation at 400 revolutions per minute (rpm) for 5 minutes. These slides were dried, fixed with Carnoy’s solution (ethanol:acetic acid:chloroform = 6:1:3), stained with May-Grunwald-Giemsa stain, and visualized by light microscopy.
T-Cell Preparation
CD3+ cells for the mixed lymphocyte reaction (MLR) assay were obtained from the peripheral blood of a healthy donor using human T-cell enrichment columns (R&D Systems). Naive CD4+CD45RA+ T cells for the cytokine assay were isolated from the PBSC products by two-step positive selection using MACS. CD8+ cells for the cytotoxic assay were also isolated from autologous PBSC products by positive selection using MACS. The purity of isolated cells was >90% for CD3+ cells and >95% for naïve CD4+CD45RA+ T cells or CD8+ cells.
Endocytic Activity
Cells (1 x 105), suspended in 100 µl of culture medium, were incubated with FITC-dextran (20 µg/ml) for 1 hour at 37°C in a water bath or at 4°C on ice, and then washed thoroughly with cold buffer consisting of phosphate-buffered saline (PBS), 5 mM EDTA, and 2% FCS. The samples were acquired on a FACS Caliber cell sorter, with 104 gating events for each sample, and analyzed with CellQuest software. The results were expressed as a mean fluorescence intensity (MFI) index calculated as the ratio of the MFI of the sample to the MFI of an isotype-matched control.
Allogeneic MLR
Allogeneic CD3+ cells (5 x 104/well), obtained from healthy donor blood, were cocultured in 96-well, round-bottomed culture plates with graded doses (2 x 102 - 5 x 104) of irradiated (30 Gy) DCs that were harvested from each group on day 6 or 9 of culture. After 5 days, the cells were pulsed with 1 Ci [3H]-methylthymidine per well for 16 hours, harvested, and analyzed in a liquid scintillation counter. The results were expressed as the mean counts per minute (cpm) ± the standard error (SE) of results obtained with four different samples, each performed in triplicate.
Intracellular Cytokine Staining
DCs (1.05 x 105 cells/500 µl) that were harvested on day 6 or 9 were primed with 50 ng/ml staphylococcal exotoxins (Toxin Technology Inc.; Sarasota, FL; http://www.toxintechnology.com), which contain an enterotoxin (SEA-SEE), exfoliative toxins (ETA and ETB), and toxic shock syndrome toxin (TSST-1), for 1 hour at 37°C and then irradiated (30 Gy). DCs were cocultured with naïve CD4+CD45RA+ T cells (5 x 105/well) in the culture medium at ratios of 1:5 (total volume of 600 µl) and 1:300 (total volume of 500 µl) in 24-well plates. On day 5, the cells were washed out completely and expanded with fresh medium containing 500 U/ml of IL-2. Two hundred fifty microliters of culture supernatant were then replaced with medium of the same concentration every 3 days. On day 14, the supernatant was collected and frozen at –20°C until ELISA assays for IFN- and IL-4 were performed. The intracellular cytokine concentrations of the harvested T cells were measured by FACS analysis, as described previously. Briefly, T cells (106) were stimulated with phorbol myristate acetate (PMA) (10 ng/ml) and ionomycin (1 µg/ml) for 4 hours in a 37°C water bath. Brefeldin A (10 µg/ml) was added during the last 2 hours of incubation to prevent cytokine secretion. Cells were collected, fixed with 1% paraformaldehyde (Becton Dickinson), permeabilized with a commercial solution (Becton Dickinson), and stained with FITC-labeled anti-IFN- (IgG2a) and PE-labeled anti-IL-4 (IgG1) mAbs. The samples were processed by a FACS Caliber cell sorter, with at least 104 gating events for each sample, and analyzed with CellQuest software.
Cytotoxic T-Lymphocyte (CTL) Assay
Mature DCs (5 x 105) cultured from HLA-A24+ donors were loaded with 10 µM Epstein-Barr virus (EBV)-derived peptide (TYGPVFMCL), which can bind to HLA-A2402 as reported by Lee et al. [25], for 2 hours at 37°C. In 24-well plates, autologous CD8+ T cells were cocultured as effector cells at a ratio of 2:1 with DCs in 2 ml of medium (RPMI 1640:AIM-V = 1:1) containing 10% FCS (Sigma; St. Louis, MO; http://www.sigmaaldrich.com), 1% penicillin-streptomycin (GIBCO-BRL), and 0.1 mM/l nonessential amino acids supplemented with 100 U/ml IL-2 for 10 days; half the medium was changed every 3 days. BEC-2 cell lines (HLA-A2402) and Bamb-2 cell lines (HLA-A1/A26) generated by EBV-transformed B-lymphoblastoid cell line from an EBV+ healthy donor were kindly provided by Dr. Itoh (Kurume University School of Medicine; Kurume, Japan). The BEC-2 cells and Bamb-2 cells, as target cells, were loaded at a concentration of 1 x 106 cells/ml with 10 µM EBV peptide and incubated for 2 hours at 37°C in 5% CO2. Effector cells were cocultured with target cells at effector-to-target ratios of 2:1, 5:1, and 10:1 in 96-well round-bottomed culture plates (total volume of 200 µl) in duplicate or triplicate. After overnight incubation at 37°C in 5% CO2, the human IFN- concentration of the supernatant was measured (pg/ml) using ELISA according to the manufacturer’s instructions (OptEIATM Human IFN- Set; PharMingen).
Cytokine Assay by ELISA
IL-10 (limit of sensitivity, 3.9 pg/ml) and IL-12 (limit of sensitivity, 0.5 pg/ml) were measured in the supernatant collected at day 6 or 9 of DC culture using Quantikine Immunoassay Kits (R&D Systems) according to the manufacturer’s instructions. IL-4 (limit of sensitivity, 0.13 pg/ml) and IFN- were measured in the supernatant of naïve CD4+CD45RA+ cells obtained at day 14. Cytokines were quantified using a microplate reader at 450-490 nM, plotted against a standard curve with the cytokines, and expressed in pg/ml.
Transmigration Assay
To evaluate the chemotactic effects of DCs stimulated with chemokines, a double-chamber system was used, with previously described modifications [26]. Briefly, polycarbonate membranes with 8-µm pore size filters (ChemotaxicellTM; Kurabo; Osaka, Japan; http://www.kurabo.co.jp) were placed on 24-well culture plates to separate the upper and lower chambers. Macrophage inflammatory protein (MIP)-3ß for mature DCs was seeded at concentrations of 1, 10, and 100 nM diluted with 500 µl of culture medium in the lower chambers. Next, 0.5-1 x 105/100 µl mature DCs were added to the upper chambers. After overnight incubation at 37°C in 5% CO2, the cells that migrated into the lower chambers were collected. Using a Coulter counter, only cells larger than 12 µm were counted, to eliminate lymphocyte contamination. The results were expressed as a net migration percentage calculated as: (number of cells that migrated into the lower chamber containing chemokines—number of cells that migrated in medium alone)/total number of cells loaded in the upper chamber x 100.
Calcium Flux Measurement
Mature DCs, at a concentration of 1 x 106 cells/ml, were loaded with 5 µg/ml Fluo-3AM (Calbiochem; San Diego, CA), incubated for 30 minutes in a 37°C water bath, and centrifuged for 10 minutes at 1,500 rpm. The DCs were then resuspended in RPMI with 5% FCS at 1 x 106 cells/ml. Calcium flux was measured at 450 nM as a function of time in response to 100 nM MIP-3ß for mature DCs, with 3 mM EGTA and as a negative control and ionomycin (10 ng/ml) as a positive control, using a FACS Caliber cell sorter, and analyzed using FlowJo software (Becton Dickinson).
Reverse Transcription-Polymerase Chain Reaction (RT-PCR) for CCR7
Total RNA was extracted from 1-2 x 106 mature DCs using an RNeasy Mini Kit (Qiagen; Hilden, Germany; http://www.qiagen.com). The cDNA synthesized from total RNA by Moloney murine leukemia virus reverse transcriptase (Stratagene; Austin, TX; http://www.stratagene.com) was subjected to RT-PCR using 30 cycles at 94°C for 0.5 minutes, 57.5°C for 1 minute, and 72°C for 1 minute for CCR7 (TaKaRa; Tokyo, Japan; http://www.takarabio.co.jp/english/index.htm). The sense and anti-sense oligonucleotide primers for CCR7 were 5'-CGCGTCCTTCTCATCAGCAA-3' and 5'-GTCCCGACAGGAAGACCACT-3', respectively. PCR products were identified by electrophoresis on 2% agarose gels that were photographed.
Statistical Analysis
Values are presented as the mean ± SE. The Mann-Whitney U test was used to compare values between subgroups using SPSS 10.0 software. p values <0.05 were considered statistically significant.
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RESULTS |
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With FACS analysis, the expression of CD1a, CD40, and CD83 in immature DCs treated with PGE2 was significantly lower than that in control cells without PGE2 (means 8%, 40%, and 2% versus 73%, 86%, and 11%, respectively; p = 0.001, p = 0.004, and p = 0.028, respectively) as shown in Table 1
. The expression of CD14 on immature DCs was retained in cells cultured with PGE2, while this was lost in control cells (mean 86% versus 12%, p = 0.001, Table 1). Other phenotypes, including HLA-DR, CD80, CD86, and CD54 were similarly highly expressed on both cells, regardless of the presence of PGE2.
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alone as a maturating agent, were evaluated by FACS, the cells with added PGE2 showed a significantly lower expression of CD1a than control cells (88% versus 65%, p = 0.024, Table 2). TNF- also induced a similar maturation pattern in immature DCs that were initially cultured with PGE2. CD1a expression in these cells was almost completely recovered when PGE2 was removed compared with the continuous presence of PGE2 (78% versus 19%, p = 0.004, Table 2). However, the DCs from which PGE2 had been removed showed a lower expression of CD83 and CD86, compared with those in the continuous presence of PGE2 (means of 62% and 72% versus 88% and 92%, respectively, p = 0.016 and p = 0.01, Table 2).
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DC with Added PGE2 Showed a High MLR at a High DC/T-Cell Ratio
Immature DCs cultured with PGE2 had a higher capacity to stimulate allogeneic CD3+ T cells than control cells at a higher DC/T-cell ratio (p = 0.003 and p = 0.007 at ratios of 1:1 and 1:2, respectively, Fig. 1A). On the other hand, there were lower allostimulatory effects in the MLR at a lower cell ratio, although variations were noted among different samples (p < 0.001 and p = 0.0013 at ratios of 1:16 and 1:128, respectively, Fig. 1A). These findings suggest that PGE2 affected the allostimulatory capacity of DCs depending upon the DC/T-cell ratio. The allostimulatory capacity of mature DCs on CD3+ T cells was also higher when the cells were cultured with PGE2 than without PGE2 at a high cell-dose ratio (Fig. 1B).
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levels, minimal expression of IL-4 by intracellular cytokine staining, and ELISA assays, although a slightly lower excretion of IFN- than in controls was observed in the presence of PGE2 at high DC/T-cell ratios (1:5). Mature DCs also showed a higher level of IFN- and a lower level of IL-4, but there was no difference in cytokine levels between different culture conditions (Figs. 2 and 3). The addition of PGE2 resulted in a lower IFN- production by naïve T cells, and removal of PGE2 at maturation induced a complete recovery of IFN- secretion (Fig. 3). This suggests that, in the presence of PGE2, immature or mature DCs induce naïve T cells to differentiate toward a Th1 response and that PGE2 inhibits the Th1 polarization of naïve T cells. Additionally, T cells cocultured with immature or mature DCs at a low cell ratio (1:300) showed a greater production of IL-4 and a lower production of IFN- than those at a high cell ratio, regardless of the presence of PGE2. This finding suggests that naïve T cells are polarized toward both Th1 and Th2 responses at a low DC/T-cell ratio (Figs. 2 and 3).
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). In this study, IL-12 and IL-10 were measured in the basal state without any other stimulation. Therefore, this finding suggests that T-cell polarization by DCs in the basal state does not depend on IL-10 or IL-12.
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ELISA assay, than against Bamb-2 target cells. This stimulation depended on the effector-to-target ratio. However, the potency of CTL itself was not augmented in the presence of PGE2 (Fig. 5).
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Phenotypic analysis of immature DCs using flow cytometry showed a high expression of CCR1 and CXCR4, with no difference between cell cultures with and without PGE2, whereas CCR6 was not expressed at all in immature DCs (Fig. 6). In mature DCs, there was a high migration and a high calcium flux in response to MIP-3ß, the ligand for CCR7, regardless of whether DCs were treated with PGE2 or not (Fig. 7). Additionally, RT-PCR to examine the expression of CCR7 showed similar positive reactions in mature DCs cultured with or without PGE2 (Fig. 7).
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DISCUSSION |
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This confusion is likely the result of different culture conditions, i.e., various cytokine combinations and culture media. Without the standardization of culture conditions, the results cannot be directly compared. In this study, immature DCs cultured in the presence of PGE2 showed variable allostimulatory capacity that totally depended on the ratio of DC to T cells; a higher MLR response was seen at a higher ratio and a lower MLR response was seen at a lower ratio. In this study, DCs cultured with added PGE2 during maturation had an enhanced allostimulatory capacity for CD3+ T cells compared with controls without PGE2.
Skewing of naïve T cells toward a Th1 or Th2 response is a crucial process in determining the ultimate outcome of the immune response, and this is affected by the culture environment of antigen-presenting DCs, as well as by the modulation of T-cell-receptor-mediated activation signals [29–31]. In this study, PGE2 caused DCs to induce naïve T cells, which secreted IFN- independent of IL-12 secretion in the basal state, with a Th1 response. Hence, some of our findings are consistent with recently published reports that PGE2 promoted a Th1 response [17,19]. However, the results from these reports suggested that IL-12 production by DCs was crucial for increasing the production of IL-2 and IFN- [17–19]. This discrepancy regarding IL-12 production between our study and others might be explained by differences in the supernatant sample used for the measurement; we measured the supernatant of DCs cultured in the presence of PGE2 without further stimulation, while others used supernatant after stimulating cells with various agents or supernatant of stimulated naïve T cells. A recent report supports our observation by finding only slight IL-12 secretion measured in samples in the basal state without further stimulation [32]. In addition, there is an interesting report that a high DC/T-cell ratio (1:4) resulted in a mixed Th1/Th2 response, while a low DC/T-cell ratio (1:300) induced T cells to become Th2 effectors, suggesting that the polarization of naïve T cells was influenced by their environment [33]. We showed that CD14+-cell-derived DCs induced naïve T-cell differentiation with a Th1/Th2 response at a lower DC/T-cell ratio (1:300), although we used different DC maturation agents and a different stimulation of T cells by DCs than the previous report [33].
In contrast, Kalinski and coworkers [6,14–16] reported that PGE2 induced type 2-polarized DCs, which promote the development of Th2 cells from naïve T cells via the inhibition of IL-12 production by DCs. Although Steinbrink et al. [19] argued that differences in the medium and cytokine combinations used for DC culture or a different ratio of T cells to DCs at stimulation produced contradictory results, we think that this discrepancy mainly resulted from the stimulating agents, such as cytokines or superantigen, used to produce DC maturation or to augment naïve T-cell stimulation, since we used a similar medium and ratio of T cells to DCs to those of Kalinski and coworkers. In that study, however, PGE2 inhibited Th1 polarization of naïve T cells by DCs in the basal state compared with controls. Based on this observation, it is still possible that the induction of a Th2 response of naïve T cells by DCs is promoted by strong stimulating agents.
We evaluated the CTL response to examine the possible clinical application of our culture system, since DCs in the presence of PGE2 induced a significant Th1 response. Unfortunately, the DCs cultured with PGE2 did not produce a stronger CTL response than control cells cultured without PGE2, thus excluding the possibility of clinical application. On the other hand, much attention has recently been focused on chemokine receptors as promising targets for clinical application. When immature DCs undergo maturation with various agents, CCR7, a constitutive chemokine receptor, is upregulated, and inflammatory chemokine receptors are downregulated, allowing the migration of DCs to lymphoid tissues [20–22]. In general, CCR6, a specific receptor for MIP-3ß/liver and activation-regulated chemokine, is highly expressed in immature DCs derived from CD34+ cord blood precursors, but not in CD14+ peripheral blood monocyte-derived DCs [20–22]. Recently, Yang et al. [24] reported that CCR6 was also expressed in monocyte-derived DCs cultured in the presence of transforming growth factor-1 and that this contributed to the regulation of the trafficking of DCs, suggesting that DC culture conditions significantly affect the expression of chemokine receptors. In our study, immature DCs cultured in the presence of PGE2 showed a high expression of CCR1 and CXCR4, but did not express CCR6 by a phenotype analysis. In addition, there was no difference in the expressions of CCR7 between mature DCs cultured with and without PGE2, which supports the notion that PGE2 does not directly influence the expression of chemokines.
In conclusion, our findings suggest that DCs cultured in the presence of PGE2 enhance the differentiation of naïve T cells toward the Th1 type, independent of IL-12 secretion in the basal state, and that PGE2 does not have any significant effect on chemokine receptor expression by DCs.
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ACKNOWLEDGMENT |
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REFERENCES |
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