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The Journal of Immunology, 2001, 167: 3765-3772.
Copyright © 2001 by The American Association of Immunologists

Cytotoxic Activity of Human Dendritic Cells Is Differentially Regulated by Double-Stranded RNA and CD40 Ligand1

Pierre-Olivier Vidalain*, Olga Azocar*, Hideo Yagita{dagger}, Chantal Rabourdin-Combe* and Christine Servet-Delprat2,*

* Laboratoire d’Immunobiologie Fondamentale et Clinique, Institut National de la Santé et de la Recherche Médicale Unité 503, Lyon, France; and {dagger} Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The main function of dendritic cells (DCs) is to induce adaptive immune response through Ag presentation and specific T lymphocyte activation. However, IFN-{alpha}- or IFN-{gamma}-stimulated CD11c+ blood DCs and IFN-{beta}-stimulated monocyte-derived DCs were recently reported to express functional TNF-related apoptosis-inducing ligand (TRAIL), suggesting that DCs may become cytotoxic effector cells of innate immunity upon appropriate stimulation. In this study, we investigate whether dsRNA and CD40 ligand (CD40L), that were characterized as potent inducers of DC maturation, could also stimulate or modulate DC cytotoxicity toward tumoral cells. We observed that dsRNA, but not CD40L, is a potent inducer of TRAIL expression in human monocyte-derived DCs. As revealed by cytotoxicity assays, DCs acquire the ability to kill tumoral cells via the TRAIL pathway when treated with dsRNA. More precisely, dsRNA is shown to induce IFN-{beta} synthesis that consecutively mediates TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expression in dsRNA- or IFN-{alpha}-treated DCs is potently inhibited after CD40L stimulation. Unexpectedly, CD40L-activated DCs still developed cytotoxicity toward tumoral cells. This latter appeared to be partly mediated by TNF-{alpha} induction and a yet unidentified pathway. Altogether, these results demonstrate that dsRNA and CD40L, that were originally characterized as maturation signals for DCs, also stimulate their cytotoxicity that is mediated through TRAIL-dependent or -independent mechanisms.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Dendritic cells (DCs)3 are considered as sentinels of the immune system (1). Immature DCs reside in peripheral tissues, where they survey incoming pathogens. The capacity of DCs to recognize pathogens and become activated therefore represents the first critical event in the initiation of the immune response. Because of the wide variety of pathogens, DCs are equipped with receptors to become activated when exposed to pathogen-associated molecular patterns (PAMPs) (2) such as LPS (3) or CpG motif in DNA from bacteria (4). Encounter with pathogen leads to DC maturation and migration to secondary lymphoid organs. Ag presentation by DCs activates specific naive T cells to express CD40 ligand (CD40L) (5), which, in turn, activates DCs, achieving the terminal differentiation required to develop adaptive immunity (6, 7). Indeed, signaling through CD40 leads to up-regulation of MHC I and II molecules, CD80/CD86 and cytokines such as IL-12 and IL-1{alpha}{beta}, which all participate in T cell stimulation (6, 8, 9).

DC effector function may not be restricted to Ag presentation. Indeed, recent reports demonstrate that human CD11c+ blood DCs, upon IFN -{alpha} or IFN-{gamma} stimulation (10), and monocyte-derived DCs, upon IFN-{beta} stimulation or measles virus infection (11, 12), acquire the ability to kill tumoral cells. In these cases, cytotoxic activity of DCs was TNF-related apoptosis inducing ligand (TRAIL) mediated. TRAIL is a type II membrane protein of the TNF family closely related to three death-inducing ligands: FasL, TNF-{alpha}, and TWEAK/Apo3L (13, 14). TRAIL induces apoptosis by cross-linking death domain-containing receptors TRAIL-R1 (also known as DR4) (15) or TRAIL-R2 (also called DR5 or KILLER/DR5 or TRICK2) (16, 17, 18, 19, 20). Apoptotic signaling occurs by recruitment of Fas-associated death domain adapter protein that later on induces caspase 8 activation (21, 22). Among the molecule known to induce apoptotic cell death, TRAIL has received great attention because of its potential therapeutic applications. Indeed, it was reported that TRAIL specifically induces apoptosis in virus-infected cells (23, 24) and tumoral cells (13, 14, 25, 26, 27) with minimal cytotoxicity toward normal tissues in vivo (28). These results suggest that TRAIL-expressing DCs may operate in vivo like innate effector cells that induce virus-infected and tumoral cell apoptosis. More recently, TRAIL was also described as a potent inhibitor of autoimmune arthritis and inflammation. Indeed, TRAIL inhibits activated T cell proliferation and cytokine production (29, 30). These last results demonstrate that not only TRAIL may be an innate immunity effector molecule involved in the elimination of virus-infected or tumoral cells, but also it may play an inhibitory role in adaptive immunity through limiting T cell activation. Consequently, the stimulatory capacity of TRAIL-expressing DCs is questionable as TRAIL might inhibit T cell activation.

dsRNA is a common by-product of RNA virus replication that signals to the immune system and activates antiviral immune response (31). In this study, DCs were stimulated with poly(I:C) that is a synthetic dsRNA often used in models of viral infection. Poly(I:C) was recently reported to induce maturation in DCs, suggesting that dsRNA behaves as a structural signature of viruses that can directly signal to DCs the presence of an infectious pathogen (32, 33, 34). In contrast to dsRNA, CD40L is a basic endogenous signal that ensures the initiation of adaptive immune responses through the induction of full DC maturation.

In this study, dsRNA and CD40L were tested for their ability to stimulate innate DC cytotoxicity toward tumoral cells. We demonstrate that human monocyte-derived DCs developed TRAIL-mediated cytotoxic activity toward tumoral cells after stimulation with dsRNA. TRAIL induction is shown to be dependent on the expression of IFN-{beta} by the DCs. Contrary to dsRNA, CD40L stimulation was shown to inhibit TRAIL expression in DCs. Unexpectedly, CD40L-activated DCs still developed cytotoxic activity toward tumoral cells. This latter did appear to be partly mediated by TNF-{alpha} induction and a yet unidentified pathway. Altogether, these results demonstrate that dsRNA and CD40L that were originally characterized as DC maturation signals, also stimulate DC cytotoxicity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents

dsRNA was poly(I:C) and ssRNA was poly(C) obtained from Amersham Pharmacia Biotech (Piscataway, NJ; recombinant human (rh) IFN-{alpha}A and rhIFN-{beta} were purchased from Calbiochem (La Jolla, CA); rhTNF-{alpha} was kindly provided by the Schering-Plough Laboratory for Immunological Research (Dardilly, France); sheep polyclonal anti-human IFN-{alpha} and sheep polyclonal anti-human IFN-{beta} Abs were purchased from BioSource International (Camarillo, CA); CD1a-PE, CD14-PE, HLA-DR-FITC, CD80-PE, CD83-PE, CD86-PE, and CD25-PE Abs were obtained from Immunotech (Marseille, France); anti-human CD40L (mAb LL2) was generously provided by the Schering-Plough Laboratory for Immunological Research.

Cells

Monocyte-derived DCs were generated in vitro as previously described (35). After 6 days of culture in the presence of 50 ng/ml rhGM-CSF (kindly provided by Schering-Plough) and 500 U/ml rhIL-4 (TEBU, Le Perray en-Yvelines, France), >95% of the cells were DCs as assessed by CD1a labeling. Cultures of DCs were performed in RPMI 1640 (Life Technologies, Paisley, U.K.) supplemented with 10 mM HEPES (Life Technologies), 2 mM L-glutamine (Life Technologies), 40 µg/ml gentamicin (Life Technologies), and 10% FCS (Boehringer Mannheim, Meylan, France). DCs were cultured at 106 cells/ml. In the murine fibroblast cocultures, 106 DCs/ml were cultured in the presence of 105/ml irradiated (7000 rad) fibroblastic CD40L- or CD32-transfected L cells (both kindly provided by Schering-Plough Laboratory for Immunological Research). Murine 2PK-3 lymphoma and human TRAIL-transfected 2PK-3 were previously characterized (36).

Phenotypic analysis

Immunostainings were performed in 1% BSA and 3% human serum-PBS. To perform cytoplasmic TRAIL and TNF-{alpha} immunostainings, 30-min permeabilization with 0.33% saponin was required. For TRAIL detection, cells were labeled by using a biotin-conjugated anti-TRAIL polyclonal Ab (2.5 µg/ml; R&D Systems, Minneapolis, MN) revealed by using PE-conjugated streptavidin (Caltag Laboratories, Burlingame, CA). For TNF-{alpha} detection, cells were labeled by using anti-TNF-{alpha} mAb (10 µg/ml; R&D Systems) revealed by using antimouse PE-conjugated Ab (Immunotech).

Type I IFN detection

At 24 h, supernatants were collected for type I IFN detection. The supernatants were serially diluted 2-fold in a 96-microwell plate and added to confluent vero monolayer cells in RPMI 1640 plus 5% FCS. After incubation for 24 h at 37°C, the cells were infected with vesicular stomatitis virus at 0.1 PFU/cell. Cytopathic effects were scored under the microscope 24 h later. Titration end point represents dilutions that gave destruction of 50% of the cells. IFN titers are expressed as International Units per milliliter with reference to a standard IFN curve. IFN-{alpha} and IFN-{beta} levels in the DC supernatants were determined by ELISA following the manufacturer’s specification (R&D Systems).

Cytotoxicity assay

To determine cytotoxic activity of DCs, TRAIL-sensitive MDA231 cells were labeled with 100 µCi of 51Cr for 1 h at 37°C, washed three times, and resuspended in complete medium. Then 51Cr-labeled MDA231 cells (104/well) were incubated with varying numbers of effector cells for 8 h. Anti-TNF-{alpha} mAb (10 µg/ml; R&D Systems), anti-TRAIL RIK-2 mAb (10 µg/ml; Ref. 36) or anti-TWEAK/Apo3L CARL-1 Ab (10 µg/ml; Ref. 37) were added to some assays.

RNase protection assays

RNA was extracted from 4 x 106 cells using RNA NOW-TC reagent (Biogentex, Seabrook, TX). The RNase protection was performed using 4 µg of RNA with the RiboQuant multiprobe RNase assay system (BD PharMingen, San Diego, CA) according to the manufacturer’s specification. In brief, RNA was hybridized overnight with the in vitro-translated 32P-labeled probe (hAPO-3c; BD PharMingen). Following hybridization, samples were treated with RNase A+T1 and proteinase K, phenol-chloroform extracted, and ethanol precipitated. The protected fragments were resolved by electrophoresis on a 5% acrylamide/urea gel and exposed on a Phosphor Screen (Molecular Dynamics, Sunnyvale, CA) for 12 h to quantify the intensity of the bands.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
dsRNA induces TRAIL production in monocyte-derived DCs

DCs were obtained from purified blood monocytes cultured for 6 days in the presence of GM-CSF and IL-4. These cells expressed high levels of CD1a and HLA-DR but did not express the monocyte marker CD14, indicating that they were fully differentiated DCs (Fig. 1GoA). Then DCs were cultured with a dose response of dsRNA (poly I:C) concentration for 12 h. As dsRNA was previously described to induce DC maturation (32, 33), expression of CD80 and CD86 costimulatory molecules and CD83 and CD25 maturation markers was quantified. As shown in Fig. 1GoB, initiation of DC maturation was observed following stimulation with 0.2 µg/ml dsRNA but higher concentration of 20 µg/ml was required to induce full phenotypic DC maturation. IFN-{alpha} and CD40L stimulation were used as a negative and positive control for DC maturation, respectively. Then TRAIL expression was quantified by flow cytometry analysis. Surface TRAIL expression was bright positive in dsRNA-treated monocytes (Fig. 2GoA). In the same culture conditions, surface TRAIL expression in DCs was very weak. However, intracellular stainings revealed a strong induction of cytoplasmic TRAIL in DCs treated with dsRNA (Fig. 2GoC), suggesting that most of TRAIL in DCs was cleaved by a specific protease when expressed on the cell surface. The specificity of this intracellular immunostaining was confirmed by using untransfected or human TRAIL-transfected 2PK-3 cells as negative and positive controls, respectively (Fig. 2GoB). In contrast to dsRNA, ssRNA poly(C) had no effect on TRAIL expression. Maximal TRAIL induction was observed following stimulation with low dsRNA concentration (0.2 µg/ml; Fig. 2GoD). Thus, DCs were hypersensitive to dsRNA as the concentration required to induce TRAIL is 100 times lower than the concentration required for full phenotypic DC maturation. Contrary to dsRNA, CD40L had no effect on TRAIL expression (Fig. 2Go, C and D). This observation demonstrates that DC maturation by itself does not induce TRAIL expression.



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  		FIGURE 1. Phenotype of monocyte-derived DCs stimulated with dsRNA, IFN-{alpha}, or CD40L. A, CD1a, CD14, and HLA-DR expressions in day 6 monocyte-derived DCs were quantified by flow cytometry analysis. B, Monocyte-derived DCs were left unstimulated or cultured for 16 h in the presence of different doses of dsRNA or rhIFN-{alpha} (5000 U/ml) or CD40L+ L cells (L cells:DCs ratio, 1:7). CD80, CD86, CD83, and CD25 expression was quantified by flow cytometry. Data shown are from one representative experiment of three.

 


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  		FIGURE 2. TRAIL expression in DCs stimulated with dsRNA poly(I:C), ssRNA poly(C), IFN-{alpha}, IFN-{beta}, or CD40L. A, Monocytes or DCs were cultured for 16 h in the presence or absence of dsRNA (0.2 µg/ml) or IFN-{alpha} (5000 U/ml). Surface TRAIL expression was quantified by FACS. Cells were stained with an isotypic control (thin line) or an anti-TRAIL Ab (heavy line). Data shown are FACS histograms from one representative experiment of four. B, FACS histograms of TRAIL immunostainings performed on permeabilized human TRAIL-transfected or untransfected 2PK-3 cells. C and D, DCs were cultured for 16 h in the presence or absence of CD40L+ L cells (L cells:DCs ratio, 1:7), ssRNA poly(C) (0.2 µg/ml), dsRNA poly(I:C) (0.2 µg/ml if not precised), IFN-{alpha} (5000 U/ml), or IFN-{beta} (500 U/ml). Cytoplasmic TRAIL expression was quantified by flow cytometry. Cells were permeabilized and then stained with an isotypic control (thin line) or an anti-TRAIL Ab (heavy line). C, FACS histograms of TRAIL immunostaining on DCs. Data shown are from one representative experiment of five. D, Percentage of TRAIL-positive DCs. Data shown are means ± SD of five independent experiments.

 
dsRNA-induced TRAIL synthesis is dependent on IFN-{beta} production

Up-regulation of TRAIL was observed following rIFN-{alpha} or IFN-{beta} stimulation of DCs (Fig. 2GoC). Because dsRNA was reported to induce type I IFNs in DCs (32, 34), the question of their involvement in TRAIL induction was addressed. First, type I IFN induction by dsRNA was confirmed by using a biologic titration assay (Table IGo). Second, IFN-{alpha} and IFN-{beta} concentrations in DC supernatants were determined by ELISA. As shown in Table IGo, IFN-{beta} but not IFN-{alpha} was produced by dsRNA-stimulated DCs. This led us to demonstrate that IFN-{beta} was responsible for TRAIL induction by dsRNA. DCs were stimulated with 0.2 µg/ml dsRNA in the presence of anti-IFN-{alpha} or anti-IFN-{beta} or a combination of both Abs. As shown in Fig. 3Go, anti-IFN-{beta} or a combination of anti-IFN-{alpha} and anti-IFN-{beta} Abs abrogated TRAIL induction in DCs. In contrast, anti-IFN-{alpha} Ab alone had no effect on TRAIL expression by dsRNA-stimulated DCs. In conclusion, TRAIL induction in DCs following dsRNA stimulation is dependent on autocrine/paracrine IFN-{beta} synthesis.


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  		Table I. Type I IFN expression in DCs with or without dsRNA1

 


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  		FIGURE 3. Involvement of type I IFNs in dsRNA-induced TRAIL expression by DCs. DCs stimulated with 0.2 µg/ml dsRNA were cultured for 16 h in the presence of neutralizing anti-IFN-{alpha} or anti-IFN-{beta} Abs or a combination of both (2000 neutralizing U/ml anti-IFN-{alpha} and 500 neutralizing U/ml anti-IFN-{beta}). Permeabilized DCs were stained with an isotypic control (thin lines) or an anti-TRAIL Ab (heavy lines). Data shown are from one representative experiment of three.

 
dsRNA-stimulated DCs exert TRAIL-mediated cytotoxicity

Cytotoxic activity of dsRNA-stimulated DCs was tested on TRAIL-sensitive human breast adenocarcinoma MDA231 (Fig. 4Go). Unstimulated DCs did not exhibit cytotoxic activity against MDA231 cells. When stimulated for 16 h with 0.2 µg/ml dsRNA, DCs induced MDA231 cell lysis (Fig. 4GoA). In our assay, cytotoxicity of dsRNA-stimulated DCs was comparable, in terms of intensity, to cytotoxicity of either IFN-{alpha}- or IFN-{beta}-stimulated DCs (Fig. 4GoA). As a positive control, human TRAIL-transfected 2PK-3 cells were shown to induce 30–40% MDA231-specific lysis (data not shown). We next examined the contribution of TRAIL in the cytotoxicity of dsRNA-stimulated DCs. As shown in Fig. 4GoB, target cell lysis was strongly inhibited by neutralizing anti-TRAIL Ab (RIK-2). In contrast, neither anti-TWEAK/Apo3L- nor anti-TNF-{alpha}-neutralizing Abs inhibited cytotoxicity of dsRNA-stimulated DCs. Thus, we conclude that TRAIL is responsible for cytotoxicity of dsRNA-stimulated DCs.



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  		FIGURE 4. dsRNA-induced TRAIL synthesis is responsible for DC cytotoxicity. A, DCs were stimulated or not with dsRNA (0.2 µg/ml) or IFN-{alpha} (5000 U/ml) or IFN-{beta} (500 U/ml) for 16 h. Cytotoxicity was then tested against MDA231 cells by an 8-h 51Cr release assay at different E:T ratios. B, DCs were stimulated with dsRNA (0.2 µg/ml). Neutralizing anti-TRAIL (RIK-2) or anti-TNF-{alpha} or anti-TWEAK/Apo3L (CARL-1) Abs was added or not in the assay to inhibit TRAIL- or TNF-{alpha}- or TWEAK/Apo3L-induced lysis. Data represent the mean of triplicate samples (SD below 5%). Data shown are from one representative experiment of five.

 
CD40 engagement inhibits TRAIL but induces TNF-{alpha} expression in DCs

TRAIL was recently described to prevent cell cycle progression of T lymphocyte and cytokine production (29, 30). Consequently, inhibition of TRAIL expression is essential in DCs as it might interfere with their APC function. To test whether CD40L inhibits TRAIL expression, DCs were stimulated with IFN-{alpha} or dsRNA (0.2 µg/ml) and cultured in the presence of control L cells or CD40L+ L cells. Addition of CD40L+ L cells in the culture inhibited TRAIL mRNA expression induced by IFN-{alpha} or dsRNA, whereas control L cells did not (Fig. 5GoA). FasL mRNA expression was never detected in any of the culture conditions tested. At the protein level, CD40L+ L cells also inhibited TRAIL expression in DCs. This effect was exclusively dependent on CD40L as TRAIL inhibition was blocked by neutralizing anti-CD40L Abs. Control L cells did not affect TRAIL expression (Fig. 5GoB). These results demonstrate that TRAIL expression is strongly inhibited in DCs after CD40 engagement. In contrast, TNF-{alpha} was strongly induced by CD40L but not IFN-{alpha} or dsRNA (Fig. 5GoC). This effect was exclusively dependent on CD40 engagement as neutralizing anti-CD40L Abs blocked TNF-{alpha} induction. Control L cells did not induce TNF-{alpha} expression. Thus, CD40L ensures a switch in TNF-related family members expressed in DCs since TRAIL is inhibited but TNF-{alpha} induced after CD40 engagement.



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  		FIGURE 5. TRAIL inhibition and TNF-{alpha} induction after CD40 engagement in DCs. A, DCs were stimulated with dsRNA (0.2 µg/ml) or IFN-{alpha} (5000 U/ml) for 16 h. Untransfected L cells or CD40L+ L cells were added as precised. FasL and TRAIL mRNA expression was quantified by performing an RNase protection assay (RiboQuant hApo3c; BD PharMingen) on total RNA extracts. L32 mRNA, encoding a constitutively expressed ribosomal protein, was used as a control probe. B and C, DCs were stimulated with dsRNA (0.2 µg/ml) or IFN-{alpha} (5000 U/ml) for 16 h in the presence of control L cells or CD40L+ L cells. Neutralizing anti-CD40L Ab (LL2, 10 µg/ml) was eventually added to the coculture of CD40L+ L cells and DCs. TRAIL (B) and TNF-{alpha} (C) expression in DCs was determined by flow cytometry analysis. Results presented are one representative experiment of five.

 
CD40-activated DCs are cytotoxic via TNF-{alpha} and a yet unidentified pathway

To check whether CD40-activated DCs developed cytotoxic activity, DCs were cultured for 16 h in the presence of CD40L+ L cells, then cytotoxicity against TNF-{alpha}-sensitive MDA231 cells was tested. As shown in Fig. 6Go, CD40-activated DCs induced MDA231 cell lysis. Since CD40-activated DCs express neither TRAIL nor FasL but high levels of TNF-{alpha}, its contribution to DC cytotoxicity was examined. Anti-TWEAK/Apo3L-neutralizing Abs had no effect on MDA231 lysis. In contrast, anti-TNF-{alpha}-neutralizing Abs exhibited a weak but significant inhibitory effect on the cytotoxicity of CD40-stimulated DCs (Fig. 6Go). Remaining DC cytotoxicity could not be blocked even with the highest dose (20 µg/ml) of anti-TNF-{alpha} Ab. Yet, anti-TNF-{alpha} Ab at 10 µg/ml was sufficient to abrogate optimal MDA231 lysis induced by rTNF-{alpha} at 30 ng/ml (data not shown). Thus, CD40-activated DCs are cytotoxic via TNF-{alpha} but also a yet unidentified TRAIL/FasL/TWEAK-independent pathway.



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  		FIGURE 6. Cytotoxicity of CD40L-stimulated DCs. DCs were stimulated with CD40L+ L cells or control L cells for 16 h. Cytotoxicity was then tested against MDA231 cells by an 8-h 51Cr release assay at different E:T ratios. Neutralizing anti-TNF-{alpha} or anti-TWEAK/Apo3L (CARL-1) was added or not in the assay to inhibit TNF-{alpha}- or TWEAK/Apo3L-induced lysis. Data represent the mean of triplicate samples (SD below 5%). Results presented are one representative experiment of five.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
According to literature, the major function of DCs is to process and present Ags to activate specific T lymphocytes and trigger adaptative immune response. However, beside their APC function, DCs were described to exert a cytotoxic activity. In mice, DC cytotoxicity was reported in the two major DC subpopulations described as "myeloid-related" (CD11bhighCD8{alpha}-) and "lymphoid-related" (CD11blowCD8{alpha}+) DCs. A subset of lymphoid-related splenic DCs has been shown to mediate apoptosis of CD4+ T cells (38). Lu et al. (39) also found that murine bone marrow-derived DCs express FasL and could induce apoptosis in Jurkat T cells. In rat, cytolytic DCs were characterized by their CD4-OX41-CD5- phenotype and their capacity to induce tumor cell apoptosis by a FasL-, TRAIL-, and TNF-{alpha}-independent pathway (40, 41). Recently, a subset of myeloid-related human blood DCs was characterized by its cytotoxicity toward several tumor cell lines through the expression of TRAIL (10). However, this human DC subset needs to be activated by IFN-{gamma} or IFN-{alpha} to express TRAIL and acquire the ability to kill. Finally, IFN-{beta} and measles virus (MV) infection were reported to induce functional TRAIL expression in human monocyte-derived DCs (11, 12). In this report, we demonstrate that dsRNA poly(I:C) and CD40L, that were previously characterized as maturation signals, are also potent stimulators of DC cytotoxicity. dsRNA-induced cytotoxicity is shown to be mediated by TRAIL, this latter being induced in DCs by an autocrine IFN-{beta} loop. Contrary to dsRNA, we document that CD40L acts as an inhibitor of TRAIL expression but induces TNF-{alpha} synthesis and unidentified factor(s) that both mediate the presently reported cytotoxicity of CD40L-stimulated DCs.

Poly(I:C) is a synthetic dsRNA often used in models of viral infections. Indeed, dsRNA is considered as a structural signature of the viral replication cycle which plays a critical role in the induction of antiviral type I IFNs (31). It has been proposed that recognition of conserved molecular patterns (PAMPs) that are characteristic of pathogens is a property of the innate immune system (2). We clearly confirm that dsRNA behaves as a PAMP that can directly signal to DCs, inducing maturation as previously described (32, 33, 34). Furthermore, a newly documented function is attributed to dsRNA in the present report: the induction of TRAIL-mediated DC cytotoxicity. TRAIL is a TNF family member characterized as a potent and specific inducer of tumoral cell apoptosis (13, 14, 25, 26, 27). As reported here, poly(I:C)-treated DCs exhibit TRAIL-mediated tumoricidal activity in vitro. Interestingly, TRAIL induction by poly(I:C) is probably not restricted to DCs since a significant induction of TRAIL has been reported in T lymphocytes (42) and monocytes (Fig. 2GoA). Interestingly, our data show that TRAIL is highly expressed on the cell surface of monocytes, but is mainly cytoplasmic in DCs. This is in agreement with the Fanger et al. (10, 43) report where surface TRAIL expression is shown to be bright in IFN-{gamma}-stimulated monocytes but weak in IFN-{gamma}-stimulated blood-derived CD11c+ DCs. These results suggest that in DCs but not in monocytes, TRAIL is cleaved on the cell surface by a specific protease. Finally, TRAIL induction by poly(I:C) is shown to be dependent on IFN-{beta} production in DCs, in agreement with Liu et al. (11) who reported the induction of a TRAIL-mediated tumoricidal activity in monocyte-derived DCs treated with rIFN-{beta}. More than 20 years ago, poly(I:C) was reported to stimulate macrophage tumoricidal activity (44) and to induce tumor regression in vivo (45, 46) through unidentified mechanisms. Our data suggest that TRAIL induction by poly(I:C) may partly account for the antitumoral activity of this molecule.

Beside their potential antitumoral activity in vivo, TRAIL-expressing DCs could also participate in innate antiviral immunity. Indeed, TRAIL may have a pivotal function in antiviral immune responses since virus-infected cells are sensitized to TRAIL-induced apoptosis by as yet unidentified mechanisms (23, 24). On the basis of our results, dsRNA synthesized during the viral replication cycle might signal to DCs and induce TRAIL expression. In this context, TRAIL-expressing DCs could act in vivo as innate immunity effector cells inducing virus-infected cell lysis. Because DCs reside in peripheral tissues, they might constitute a first and essential barrier against incoming viruses. Several recent reports also suggest that TRAIL participates in the establishment of MV- and HIV-induced immunosuppression. We reported that MV-infected DCs express TRAIL and induce MV-uninfected T cell apoptosis (12, 35). Increased sensitivity of T cells from HIV patients to TRAIL-induced apoptosis has been reported (25, 47). In a PBL-nonobese diabetic-SCID mouse model, a large number of HIV-uninfected CD4+ T cells undergo TRAIL-mediated apoptosis in HIV-infected lymphoid organs (48). Since dsRNA is produced during MV and HIV replication cycles, this molecule could induce massive TRAIL expression in DCs during viral spreading. Such overexpression of TRAIL may participate in T cell deletion, lymphopenia, and establishment of virus-induced immunosuppression.

Recently, TRAIL was also characterized in mice as a negative regulator of adaptative immune response through the inhibition of T cell proliferation and cytokine production (29, 30). Moreover, TRAIL was described as a weak inducer of normal T cell apoptosis (49). In this work, we newly report the inhibition of TRAIL in DCs after CD40 engagement. Inhibition of TRAIL mRNA after CD40 ligation was reported in follicular lymphoma and normal B cells (50). Interestingly, among CD40L-induced factors in DCs is osteoprotegerin that is a soluble decoy receptor for TRAIL (51). Thus, CD40L-mediated inhibition of the TRAIL pathway in DCs could be mediated, not only through TRAIL down-regulation, but also by osteoprotegerin induction. Contrary to TRAIL, TNF-{alpha} is induced in DCs by CD40L and was reported to promote resting T cell proliferation through TNFR2 engagement (52). Altogether, these results suggest that CD40 engagement ensures optimal Ag presentation by DCs, not only through the induction of MHC molecules and costimulatory factors for T cells such as TNF-{alpha}, but also through the inhibition of the TRAIL pathway. In addition, CD40 ligation was recently described to ablate the tolerogenic potential of CD8+ DCs in mice (53). This could be explained by CD40-mediated inhibition of TRAIL or any other TRAIL-related factor as CD8+ DCs were reported to exert a cytotoxic activity toward CD4+ T cells (38).

Finally, we demonstrate for the first time that CD40-activated DCs can develop cytotoxic activity. It is unlikely that FasL or TRAIL mediate cytotoxicity since they are not expressed in CD40-activated DCs. Cytotoxic activity of CD40-activated DCs is also shown to be TWEAK/Apo3L independent. In contrast, we demonstrate that the TNF-{alpha} contribution to cytotoxicity is weak but significant. Thus, cytotoxicity of CD40-activated DCs is partly dependent on TNF-{alpha} but mainly mediated via a yet unidentified pathway. Whatever the contribution of TNF-{alpha}, these results document the fact that even fully mature CD40L-activated DCs can develop cytotoxic activity.

In vivo function of cytotoxic DCs is not yet defined, but several hypothesis have been formulated. They could be tolerogenic cells that induce apoptosis of autoreactive lymphocytes. They could act as regulators of immune responses that limit specific lymphocyte expansion. They could be also considered as innate immunity effector cells with a NK-like activity. In this report, we demonstrate that dsRNA- and CD40L-treated DCs develop tumoricidal activity that is mediated through two different pathways. In vivo relevance of such tumoricidal activity has to be demonstrated. Moreover, it would be of great interest to test whether the killing of target cells by DCs is followed by phagocytosis of their victims and efficient cross-presentation of target cell-derived Ags to T cells (54, 55). Cytotoxic DCs would therefore create an immediate link between innate and adaptive immunity that should not be ignored for DC-based immunotherapy.


   Acknowledgments
 
We thank Dr. Fabian Wild and Adrienne Anginot for their helpful technical participation in this work.


   Footnotes
 
1 This work was supported by Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer (Cancer Research Campaign Grant 5753), Région-Rhône-Alpes Emergence HMCO3F, and Agence Nationale de Recherches sur le SIDA (FF049G). Back

2 Address correspondence and reprint requests to Dr. Christine Servet-Delprat, Laboratoire d’Immunobiologie Fondamentale et Clinique, Institut National de la Santé et de la Recherche Médicale Unité 503, 21 Avenue Tony Garnier, 69365 Lyon, Cedex 07, France. E-mail address: servet{at}cervi-lyon.inserm.fr Back

3 Abbreviations used in this paper: DC, dendritic cell; CD40L, CD40 ligand; FasL, Fas ligand; PAMP, pathogen-associated molecular pattern; TRAIL, TNF-related apoptosis-inducing ligand; rh, recombinant human; MV, measles virus. Back

Received for publication April 27, 2001. Accepted for publication July 31, 2001.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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