Published online before print August 14, 2007
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* Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Kreuzlingen, Switzerland;
Klinikum Konstanz, Konstanz, Germany; and Divisions of
Microbial Ecology and
Immunology, Department of Biology, University of Konstanz, Konstanz, Germany
1 Correspondence: Biotechnology Institute Thurgau (BITg) at the University of Konstanz, Unterseestrasse 47, CH-8280 Kreuzlingen, Switzerland. E-mail: daniel.legler{at}bitg.ch
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: cell proliferation • chemotaxis • vaccination
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The exclusive ability to stimulate primary and secondary immune responses prompted the use of antigen-loaded, human monocyte-derived DCs (MoDCs) in vaccinations against tumors in numerous clinical studies [6 7 8 ]. However, DC-based immunotherapy, as currently applied, has not yet proven to be clinically successful [9 ]. Nevertheless, the question is not whether immunotherapies using DCs work but how to refine the immunological and clinical parameters of vaccination with DCs to improve the efficacy [8 ]. One major problem was that antigen-loaded DCs failed to leave the injection site [10 ]. This drawback was solved by the discovery that addition of the proinflammatory mediator PGE2 to any classical maturation stimulus of MoDCs facilitates migration toward CCR7 ligands [11 12 13 14 ]. Indeed, PGE2 is a general and mandatory factor, as human immature and mature MoDCs as well as ex vivo DCs require PGE2 during maturation to migrate in response to chemokines and chemoattractants [14 ]. It is interesting that the PGE2 signal facilitating migration can be mediated by E-prostanoid 2 (EP2) or EP4 receptor triggering on human polyinosinic:polycytidylic acid [poly(I:C)]-matured MoDCs [14 ] but seems to be restricted to EP4 in mouse Langerhans cells [15 ]. Furthermore, PGE2 was also shown to enhance DC maturation and their stimulatory capacity to prime naïve T cells and to modulate chemokine and cytokine production of DCs through a yet-unknown mechanism [11 , 16 17 18 19 ].
A recent study by Braun et al. [20 ] challenges the use of PGE2 for DC maturation, describing that the addition of PGE2 to maturation stimuli strongly up-regulated IDO in MoDCs. IDO is an enzyme, which degrades tryptophan, and expressed by DCs, can suppress T cell proliferation and survival and may promote tolerance [21 , 22 ]. It is interesting that PGE2 was shown to induce IDO on mRNA and protein level via EP2 receptor activation, but a second signal through TNFRs or TLRs was crucial for the enzyme activity [20 ]. In their hands, induction of IDO depended strictly on PGE2, as DC maturation stimuli alone did not induce IDO expression [20 ].
As ex vivo-generated MoDCs are widely used in clinical trials, and a comprehensive study about IDO expression, cell migration, and T cell priming by MoDCs, which are generated under clinically approved conditions, is missing, we decided to investigate recent concerns about the use of PGE2 and its effects on MoDCs under clinically relevant, serum-free conditions. Thus, we used different stimuli in conjunction with PGE2 and specific PGE2 receptor agonists for MoDC maturation and investigated IDO expression, activity, and cell migration and examined the capacity of MoDCs to stimulate T cell proliferation in relation to IDO expression.
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, 10 ng/ml IL-1β, and 20 ng/ml IL-6, all purchased from PromoCell). Where indicated, 1 µg/ml PGE2 (Minprostin® E2, Pharmacia, Uppsala, Sweden), 1 µg/ml specific agonists for EP2 (butaprost, Cayman Chemicals, Ann Arbor, MI, USA), or EP4 (PGE1 alcohol, Cayman Chemicals; ONO-AE1-329, ONO Pharmaceutical Co., Ltd., Osaka, Japan) was added.
Cell migration assay
To measure chemotaxis, 1 x 105 DCs were placed on a polycarbonate filter with a pore size of 5 µm in a 24-well TranswellTM plate (Corning Costar, NY, USA). Cells were allowed to migrate toward 250 ng/ml CCL21 (PromoCell) for 3 h at 37°C/5% CO2. Migrated cells were counted by flow cytometry (LSRII, BD Biosciences, Erembodegen, Belgium), and specific migration was calculated as percentage of the number of input cells after subtraction of spontaneous migration toward AIM-V medium without chemokine.
MoDC induced T cell proliferation
Human peripheral blood T cells were isolated from PBMCs of healthy donors using the pan T cell isolation kit (Miltenyi Biotec), according to the manufacturer’s protocol. Naïve T cells were negatively sorted using anti-CD45RO-conjugated magnetic microbeads (Miltenyi Biotec), resulting in a pure population of CD45RA+-expressing cells. Naïve T cells were separated further into CD4+ and CD8+ populations using anti-CD4-conjugated magnetic microbeads (Miltenyi Biotec). Naïve CD4+ and naïve CD8+ cells, respectively, were cocultured with mature 10,000 MoDCs in graded ratios in RPMI-1640 medium containing 10% FCS. Where indicated, 20 µM 1-methyltryptophan (1-MT; Sigma Chemical Co.) was added. T cell proliferation was measured after 5 days of coculture using a BrdU cell proliferation ELISA kit (Roche, Indianapolis, IN, USA), according to the manufacturer’s protocol.
IDO mRNA and protein expression
Total RNA of mature MoDCs was isolated using the RNeasy mini kit (Qiagen, Hilden, Germany) and transcribed into cDNA using the Taqman® RT reagent (Applied Biosystems, Rotkreuz, Switzerland) with random hexamer primers, according to the manufacturer’s instructions. For amplification of IDO mRNA, 1 µl cDNA was added to QuantiTect SYBR Green PCR Master Mix (Qiagen) containing 200 nM forward primer 5'-TGTCCGTAAGGTCTTGCCAAGA and 200 nM reverse primer 5'-CACCAATAGAGAGACCAGGAAGAATC. Real-time PCR was performed with an initial step of denaturation at 95°C for 15 min followed by 40 cycles of 15 s at 94°C, 30 s at 60°C, and 30 s at 72°C using the Taqman 7700 (Applied Biosystems). IDO mRNA expression was normalized to two housekeeping genes, β-2 microglobulin (β2M) and ubiquitin C (UBC), using the primers 5'-GCTATCCAGCGTACTCCAAAGATTC and 5'-CAACTTCAATGTCGGATGGATGA for β2M and 5'-ATTTGGGTCGCGGTTCTTG and 5'-TGCCTTGACATTCTCGATGGT for UBC, respectively, and SYBR Green PCR Master Mix (Applied Biosystems) containing 200 nM forward as well as reverse primer, according to the manufacturer’s instructions. Relative mRNA expression was calculated with the 
comparative threshold cycle method.
IDO protein expression was analyzed by Western blotting using an anti-IDO-specific antibody (Upstate, Charlottesville, VA, USA). The blot was reprobed with a β-actin antibody (Abcam, Cambridge, UK) to ensure equal protein loading.
Detection of active IDO protein in MoDCs
Mature MoDCs were harvested and washed three times in HBSS. Cells (2x106) were resuspended in 1 ml HBSS containing 100 µM L-tryptophan (Sigma Chemical Co.) and incubated for 4 h at 37°C/5% CO2. Supernatants were collected and subjected to HPLC analysis after addition of 200 mM H2SO4. Tryptophan and kynurenine were analyzed using a HPLC system consisting of two high-pressure pumps (Shimadzu LC-10ATvp), an autoinjector (Gilson 234), a C18 reversed-phase column (Grom-Sil 120 ODS-5ST, 5 µm, 150x4.6 mm, Grom, Herrenberg, Germany), and a UV-VIS diode array detector (SPD-M 10, Shimadzu, Japan). Analysis was performed at room temperature using a gradient program with a mobile phase comprising a mixture of 100 mM ammonium phosphate buffer, pH 2.6, and methanol at a flow rate of 1 ml/min with a detection wavelength of 227 nm. The solvent phase [5% (v/v) methanol] was held initially for 1 min, and then the concentration was increased to 45% over a period of 6 min, lowered to 5% within 0.5 min, and held for an additional 7 min. Amounts of tryptophan and kynurenine in MoDC supernatants were quantified with the CLASS-VP software (Shimadzu) on the basis of standard solutions of 20 µM, 50 µM, and 100 µM tryptophan and kynurenine (Sigma Chemical Co.), respectively.
Quantification of tryptophanyl-tRNA-synthetase (TTS)
MoDCs, matured in the presence or absence of PGE2, were cocultured with naïve, allogeneic CD4+ T cells as described above. After 4 days, T cells from the coculture were positively selected using an anti-CD3 antibody and magnetic nanoparticles (StemCell Technologies, Vancouver, BC, Canada). RNA was extracted and transcribed into cDNA. TTS mRNA was quantified by real-time PCR as described previously [23
]. TTS expression was normalized to two housekeeping genes (β2M and UBC) and calculated relative to unstimulated CD4+ T cells from the same donor.
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, together with PGE2 as maturation stimuli, was recently shown to induce the expression of IDO [20
], an enzyme involved in the degradation of tryptophan and thought to induce immune tolerance (reviewed in refs. [21
, 22
]). To test whether IDO mRNA is expressed on human MoDCs generated under serum-free conditions compatible for clinical trials, we isolated human monocytes from peripheral blood of healthy donors by positive selection using CD14 microbeads. Monocytes were differentiated into immature MoDCs by incubation for 5–6 days in serum-free medium containing IL-4 and GM-CSF. Immature MoDCs were then matured for 2 days with poly(I:C) or trimeric sCD40L in the absence or presence of PGE2, which is essential to generate a general migratory DC phenotype [14
]. IDO mRNA from mature MoDCs was quantified by real-time RT-PCR. As shown in Figure 1A
, PGE2 provoked a dramatic increase of IDO mRNA in MoDCs matured with sCD40L, similar to MoDCs matured with TNF- in combination with PGE2 [20
]. In striking contrast, MoDCs matured by poly(I:C) constitutively expressed high levels of IDO mRNA, independently of PGE2 (Fig. 1A)
. The induction of IDO mRNA on sCD40L-matured MoDCs by PGE2 was on average 113-fold, ranging from 17- to 270-fold, depending on the donor (n=7), whereas PGE2 had virtually no effect (less than 1.5-fold, n=6) on IDO expression in poly(I:C)-matured MoDCs (Fig. 1B)
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Figure 1. PGE2 enhances IDO mRNA expression in human MoDCs matured with sCD40L but not with poly(I:C). MoDCs, generated under serum-free, clinically relevant conditions, were matured for 48 h with trimeric sCD40L or poly(I:C) in the presence or absence of PGE2. Expression of IDO mRNA was analyzed by real-time RT-PCR. (A) Amplification plots of IDO mRNA expression in MoDCs of a representative donor in duplicates matured with sCD40L (black lines) and poly(I:C) (gray lines), respectively, are shown. Dashed lines represent MoDCs matured in the absence of PGE2, whereas solid lines correspond to MoDCs matured in the presence of PGE2. Rn, normalized reporter signal minus baseline signal. (B) Induction of IDO mRNA expression by PGE2 in mature MoDCs of multiple donors was quantified by real-time RT-PCR and expressed as fold increase induced by PGE2. (•) The mean of a duplicate analysis of a single donor [n=7 for sCD40L; n=6 for poly(I:C)].
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, IL-1β, and IL-6 in the presence or absence of PGE2. Under these conditions, IDO expression was restricted to MoDCs matured in the presence of PGE2 (Fig. 2A)
. These data clearly suggest that PGE2 is responsible for the induction of IDO on MoDCs matured with sCD40L, LPS, or cytokine cocktail, whereas TLR3 triggering alone was sufficient for a high expression of the tryptophan-degrading enzyme. We have demonstrated recently that the addition of PGE2 to DC maturation cocktail has to occur at the beginning of the maturation period to induce a migratory phenotype but can be omitted at later time-points [14
]. Thus, we investigated whether IDO up-regulation in maturing MoDCs also happens at early time-points and whether short-term incubation of DCs with PGE2 may prevent IDO expression. Therefore, we coincubated MoDCs, which were matured with sCD40L for 48 h, with PGE2 during the initial 4, 16, or 30 h and for the entire 48 h of maturation, respectively (Fig. 2B)
. In fact, IDO protein levels increased the longer PGE2 was present during MoDC maturation but were already detectable when maturing DCs were treated with PGE2 exclusively for the initial 4 h of maturation, followed by a further incubation of 36 h in the presence of sCD40L alone (Fig. 2B)
.
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Figure 2. PGE2 is not generally required for IDO protein expression in human MoDCs. IDO protein expression was analyzed by Western blotting using an IDO-specific antibody in total cell lysates of MoDCs matured with sCD40L, poly(I:C), LPS, or a combination of IL-1β, IL-6, and TNF- in the presence or absence of PGE2 (A). The blot was reprobed with β-actin antibody to ensure equal protein loading. (B) Expression of IDO protein was analyzed in immature DCs (iDC) or sCD40L-matured MoDCs, which were cultured in the absence or presence of PGE2 for the initial 4, 16, or 30 h of maturation or for the full maturation period (48 h).
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Figure 3. PGE2 induces active IDO protein, primarily through EP4 receptor signaling, but is not essential for IDO activity during maturation via TLR3. IDO activity was assessed by quantification of tryptophan degradation to kynurenine using HPLC analysis (A). MoDCs were matured for 48 h by poly(I:C) (B) or sCD40L (C and D) in the presence or absence of PGE2, EP2 (butaprost)- or EP4 (ONO-AE1-329, PGE1 alcohol)-specific agonists. Cells were washed and incubated in HBSS in the presence of 100 µM tryptophan for 4 h. Supernatants were subjected to HPLC analysis to assess IDO-mediated degradation of tryptophan (open bars) to kynurenine (solid bars). Mean values and SEM of seven independent experiments (B and C) of individual donors are shown.
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Figure 4. PGE2 induces IDO protein expression primarily via EP4. IDO protein expression (A) and migratory behavior (B) of MoDCs matured with sCD40L in the absence or presence of PGE2, EP2 (butaprost), or EP4 (PGE1 alcohol) receptor agonist was analyzed. (A) IDO protein expression was analyzed by Western blotting using an anti-IDO-specific antibody. The blot was reprobed with a β-actin antibody to ensure equal protein loading. One representative experiment out of eight is shown. (B) To prove functionality of EP receptor agonists, migratory capacity of MoDCs was analyzed in TranswellTM chemotaxis assay in response to CCL21. Mean values of two independent experiments with different donors are shown.
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Figure 5. PGE2 enhances the stimulatory capacity of MoDCs. MoDCs were matured with sCD40L in the presence (solid lines) or absence (dashed lines) of PGE2 and cocultured with alloreactive, naïve CD4+ (A) or CD8+ (B) T cells. After 5 days of stimulation, T cell proliferation was assessed by BrdU cell proliferation ELISA. Mean values and SEM of a representative experiment out of six are shown.
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Figure 6. PGE2-induced IDO activity does not limit the enhanced stimulatory capacity of PGE2-matured DCs. MoDCs were matured with sCD40L in the presence (black, solid lines) or absence (gray, solid lines) of PGE2 and cocultured with alloreactive, naïve CD4+ or CD8+ T cells for 5 days. To inhibit IDO activity, 1-MT (black, dashed lines) was added for the entire coculture. To ensure specificity, HCl, the solvent of 1-MT, was added at the same concentration (gray, dotted line). Mean values and SEM of four to six independent experiments with different donors are shown.
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Figure 7. Elevated expression of TTS in T cells cocultured with PGE2-matured MoDCs. MoDCs matured with sCD40L in the presence or absence of PGE2 were cocultured with naïve, allogeneic CD4+ T cells. After 4 days, TTS mRNA of sorted T cells from the coculture was quantified by real-time RT PCR. Relative TTS expression was normalized to TTS mRNA in unstimulated T cells from the same donor. (•) The mean of a duplicate analysis of a single donor (n=8).
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. These matured MoDCs, when loaded with antigens, are capable of propagating antigen-specific T cells in vitro and show cytotoxic activity for antigen-bearing target cells in the case of CD8+ T cells. However, despite a robust activation of the adaptive immune response against the targeted tumor antigen, DC-based immunotherapies often showed only a marginal clinical anti-tumor activity [9
, 30
]. This drawback is explained easily by the fact that in vitro-generated, antigen-loaded, radioactively labeled, mature DCs could not be detected in lymph nodes of the patients [10
]. Migration of mature DCs to the T cell zone of secondary lymphoid organs is guided by the homing chemokines CCL19 and CCL21 [3
, 31
]. We and others [11
12
13
14
] have realized that CCR7 expression, the chemokine receptor for CCL19 and CCL21, alone is not sufficient to facilitate migration of clinical-grade MoDCs. In fact, whatever stimuli may be used to mature clinical-grade MoDCs, supplementation of the maturation cocktail with the proinflammatory mediator PGE2 is fundamental for the development of a migratory MoDC phenotype [11
12
13
14
, 32
]. Moreover, also ex vivo peripheral blood DCs rely on PGE2 addition for efficient migration [14
]. The crucial role of PGE2 for DC migration has been substantiated further by the finding that skin-derived Langerhans cells derived from ptger4 null mice, which lack the PGE2 receptor EP4, showed impaired homing to draining lymph nodes, whereas EP2–/– animals had no such phenotype [15
]. In contrast, in humans, PGE2 triggering can be mediated through EP2 or EP4 to give rise to migratory DCs (Fig. 4B
and ref. [14
]).
A recent study by Braun and co-workers [20
] now challenged the use of PGE2 supplementation for MoDC maturation, as they found that PGE2 was responsible for the induction of IDO, which is the initial and rate-limiting enzyme converting tryptophan to kynurenine; and tryptophan is an essential amino acid important for protein synthesis, cell survival, and proliferation [33
, 34
]. Hallmark studies by Munn et al. [35
] and Mellor et al. [36
] discovered that IDO was able to prevent rejection of the fetus during pregnancy. IDO expression in DCs depends on IFN-
stimulation and correlates with the inhibition of T cell proliferation, which can be prevented with the IDO inhibitor 1-MT [37
38
39
]. Moreover, the tryptophan-derived catabolites kynurenine, 3-hydroxykynurenine and 3-hydroxyanthranilic acid can induce activation-induced T cell death [40
, 41
]. Braun and collaborators [20
] now described that the presence of PGE2 during TNF-- or LPS-induced maturation of human MoDCs induces active IDO protein. In the absence of PGE2, however, they found no IDO protein. The authors therefore suggested reconsidering the use of PGE2 in DC-based immunotherapy protocols. Using human MoDCs compatible for clinical trials, we now describe that the addition of PGE2 to LPS, sCD40L, or a cocktail of cytokines for MoDC maturation provoked up-regulation of IDO on mRNA and protein level (Figs. 1
and 2A)
, confirming and extending the observations by Braun et al. [20
]. However, we demonstrated that TLR3-mediated MoDC maturation using poly(I:C) induced IDO expression, independently of PGE2 (Figs. 1
and 2A)
, and poly(I:C)-induced IDO protein was fully active (Fig. 3B)
. In our hands, IDO protein expression strictly correlated with the enzyme’s activity. Thus, PGE2 is not a general prerequisite for IDO expression in mature MoDCs, as implied previously [20
].
In humans, the PGE2-promoted, enhanced migratory capacity of MoDCs is mediated through the PGE2 receptors EP2 and EP4 [14
], in contrast to mice, where the effect is accredited to EP4 alone [15
]. Braun and colleagues [20
] demonstrated that PGE2-induced, active IDO in human MoDCs is mediated exclusively through EP2 triggering. As a consequence, they suggested replacing PGE2 with a specific EP4 agonist in maturation protocols for DC-based immunotherapies to induce a migratory phenotype but to prevent expression of active IDO. In striking contrast, using two independent, specific agonists, we clearly demonstrate that under serum-free, clinically relevant conditions, PGE2-induced IDO protein expression and activity are mediated primarily by the PGE2 receptor EP4 (Figs. 3C
and 4A)
. EP2 triggering also induced IDO activity but to a much lower level (Fig. 3D)
, which correlated with lower IDO protein induction (Fig. 4A)
. The addition of PGE2, EP2, or EP4 agonists during MoDC maturation is not only essential for the development of a migratory phenotype but also induces active IDO protein. It is interesting that IDO may even be critical for DC activation and chemotaxis, as incubation of maturing DCs with the IDO inhibitor 1-MT impaired maturation-induced regulation of chemokine receptor expression [42
]. With respect to DC-based immunotherapy, antigen-loaded DCs must acquire a migratory phenotype to reach the draining lymph node to initiate an efficient immune response. Initial studies using MoDCs, which were matured in the absence of PGE2, showed a clear deficit in migration [10
]. These data clearly argue for the use of PGE2 (or receptor agonists) for the generation of clinical-grade DCs. The induction of IDO, which may inhibit antigen-specific T cell proliferation within the lymph node, now challenges the use of PGE2. It is unexpected that despite active IDO expression, PGE2-matured MoDCs showed an enhanced capacity to induce allogeneic CD4+ and CD8+ (Figs. 5
and 6)
, as well as antigen-specific [19
] T cell proliferation compared with MoDCs matured in the absence of PGE2. To test whether the augmented capacity of PGE2-matured MoDCs was nevertheless limited by active IDO expression, we inhibited IDO activity with 1-MT. It is striking that we were unable to increase the number of proliferating T cells by PGE2-matured MoDCs when IDO activity was blocked (Fig. 6)
. The robust T cell activation of Th as well as cytotoxic T cell subpopulations induced by PGE2-matured MoDCs seems not to be restrained by IDO expression. However, we cannot rule out that IDO-expressing MoDCs may lose functional IDO expression during the coculture with T cells. The fact that efficient T cell proliferation can be induced by IDO-positive DCs was discovered recently. Terness and colleagues [39
] found that the proliferation of neither OKT3-stimulated human T cells of healthy donors nor myelin basic protein-specific T cells of patients with multiple sclerosis was impaired by autologous MoDCs expressing IDO. Moreover, resistance of synovial T cells of rheumatoid arthritis patients to IDO-mediated tryptophan deprivation was shown to be associated with enhanced expression of the enzyme TTS [23
], which protects T cells from IDO activity in two ways [23
, 43
]: One includes the formation of TTS complexes, which act as reservoirs of tryptophan for protein synthesis, thus overcoming the tryptophan-deprivation effect of IDO. The other way is the reduction of tryptophan catabolites, which can induce cell death. We discovered that T cells, which are cocultured with MoDCs, expressed a substantial amount of TTS. Interestingly, we found even higher amounts of TTS in proliferating T cells, which were engaged by MoDCs, matured in the presence of PGE2 (Fig. 7)
. This novel finding can explain easily why MoDCs matured with PGE2 can still prime T cells, despite IDO expression. Alternatively, we cannot exclude that the presence of T cells mediated a down-modulation/inactivation of IDO in MoDCs. It is interesting enough that IDO as well as TTS are induced by IFN- [24
]. Thus, it is conceivable that under pathological conditions, where IFN- is produced, TTS activity of T cells, which are recruited along with IDO-positive DCs to the lymph node at an early phase, is capable of silencing the tolerogenic potential of IDO. However, to regulate the immune response, T cell proliferation within the lymph node needs to be stopped at later time-points, e.g., when IFN- is no longer produced to induce TTS, whereas the homed DC may still express functional IDO.
In summary, we demonstrate that PGE2 induces active IDO expression in DCs generated under clinically relevant conditions early during maturation. However, PGE2 is not fundamental for IDO induction, as functional IDO expression is observed in TLR3-mediated MoDC maturation in the absence of PGE2. As under serum-free conditions, IDO expression by PGE2 is mediated primarily through the EP4 receptor, the proposed replacement of PGE2 by a specific EP4 agonist [20 ] for generation of migratory and IDO-negative MoDCs can no longer be recommended. Although PGE2 induces functional IDO in MoDCs, the T cell-stimulating capacity is enhanced. In addition, we demonstrate that T cells, activated by PGE2-matured MoDCs, express high levels of TTS, which protect them from tryptophan deprivation by IDO-expressing DCs. Overall, PGE2 is not only fundamental for the development of a migratory phenotype but enhances T cell stimulatory capacities of mature MoDCs.
Received September 15, 2005; revised July 17, 2007; accepted July 17, 2007.
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cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production J. Exp. Med. 186,1603-1608 J. Exp. Med. 179,1109-1118, indoleamine 2,3-dioxygenase, and tryptophan catabolism FASEB J. 5,2516-2522[Abstract]This article has been cited by other articles:
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