International Immunology

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International Immunology, Vol. 13, No. 5, 675-683, May 2001
© 2001 Japanese Society for Immunology

Effective antigen presentation by dendritic cells is NF-B dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines

Satomichi Yoshimura, Jan Bondeson, Brian M. J. Foxwell, Fionula M. Brennan and Marc Feldmann

Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK

Correspondence to: M. Feldmann

	Abstract

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Antigen presentation is a key rate-limiting step in the immune response. Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and co-stimulatory molecules, but little is known about the biochemical pathways that regulate this function. We here demonstrate that monocyte-derived mature DC can be infected with adenovirus at high efficiency (>95%) and that this procedure can be used to dissect out which pathways are essential for inducing DC antigen presentation to naive T cells. Using adenoviral transfer of the endogenous inhibitor of NF-B, IB, we show that DC antigen presentation is NF-B dependent. The mechanism for this is that NF-B is essential for three aspects of antigen-presenting function: blocking NF-B coordinately down-regulates HLA class II, co-stimulatory molecules like CD80, CD86 and CD40, and immuno-stimulatory cytokines like IL-12 and tumor necrosis factor-. In contrast adhesion molecules are up-regulated after infection with the adenovirus transferring IB, indicating that NF-B also regulates the duration of T cell–DC interaction. These results establish NF-B as an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this finding has potential implications for the development of therapeutic agents for use in allergy, autoimmunity and transplantation.

Keywords: adenovirus, antigen presentation, dendritic cell, NF-B

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Dendritic cells (DC) are the most effective cells for presentation of antigen to naive T cells in the primary immune response (1). They are bone marrow-derived cells which were first described in the early 1970s by Steinman and Cohn (2), and subsequently studied by many groups, e.g. (3–6). Studies on DC were initially hampered by the difficulty in isolating them in sufficient numbers from tissues or blood, but this problem was overcome in part by the realization that a subset of DC could be generated in vitro by culture of CD34⁺ cells or human monocytes with granulocyte macrophage colony stimulating factor (GM-CSF) and IL-4 (7–9). These cultured DC have the phenotype of immature DC, and can subsequently be matured into high MHC expressing, high CD80/86 expressing DC through incubation with tumor necrosis factor (TNF)- or lipopolysaccharide (LPS) (10).

The importance of antigen presentation in the generation of the immune response, so evident in vitro, has been confirmed in vivo by the demonstration that blocking antigen presentation down-regulates both humoral and cell-mediated immune responses, and has been shown to be useful in treating animal models of disease. Thus antibody to murine MHC class II has been used to treat experimental allergic encephalomyelitis (11) and blocking the CD80/86 co-stimulatory molecules with antibodies or CTLA-4–Ig fusion protein is beneficial in transplants (12) or animal models of autoimmunity such as arthritis or encephalomyelitis (13,14). This has led to a search of new ways of down-regulating antigen presentation which may be useful in human diseases or in transplantation. However, this work has been hampered by the lack of knowledge about the intracellular pathways that regulate antigen presentation.

Many, if not most, normal human cells transfect poorly with the techniques available today such as electroporation or lipofection (15), which work well with a restricted number of cell lines. Hence the powerful genetic approaches for analysing biochemical or cell signalling pathways, by introducing constructs expressing inhibitory or activating molecules cannot be used in normal cells (16). In order to overcome this difficulty, we have developed methods of augmenting the efficiency of adenoviral uptake into various normal cells, including human macrophages, which has enabled us to demonstrate, for example, that cytokine (TNF-) gene regulation is complex and stimulus dependent, even in a single cell type (17,18). Here we show that monocyte-derived mature DC can be infected with adenovirus at high efficiency (>95%) and that this procedure can be used to dissect out which pathways are essential for inducing dendritic antigen presentation to naive T cells. The results indicate that antigen presentation is dependent on NF-B activation and that all three aspects of antigen-presenting function, i.e. MHC expression, co-stimulatory molecule expression and cytokine production, are coordinately regulated.

	Methods

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Reagents
Human recombinant GM-CSF and TNF were kind gifts of Dr Glenn Larsen (GI) and Dr D. Tracey (BASF) respectively. Human recombinant IL-4 was purchased from R & D Systems (Minneapolis, MN). Phorbol myristate acetate (PMA) and LPS were obtained from Sigma (St Louis, MO). Soluble CD40 ligand–CD8 construct-producing cells J588L were generously provided by Dr P. Lane (Basel Institute for Immunology) and Dr A. Schimpl (Institute für Virologie und Immunbiologie). Supernatant from J588L was collected from confluent cultures and filtered (0.2 µm).

Dendritic cell maturation
Mononuclear cells were isolated from single-donor plateletphoresis residues as described (17). A total of 10⁷ monocytes were plated in 10 ml volumes in 100 mm Petri dishes and DC maturation was performed as described (19). On day 6, non-adherent cells were collected and analysed or transferred to new Petri dishes. The cultures were supplemented with monocyte conditioned medium (MCM) (20) and TNF- at final concentrations of 20% v/v and 10 ng/ml respectively. Fresh GM-CSF and IL-4 were present during all the culture period. In some experiments, cells were washed out of supplemental cytokines or MCM at day 6 or 9 before use in phenotypic or functional assays.

Adenoviral vectors
Recombinant, replication-deficient adenoviral vectors encoding Escherichia coli ß-galactosidase (AdvßGal) or having no insert (Adv0) were provided by Drs A. Byrnes and M. Wood (Oxford, UK). An adenovirus encoding porcine IB with a CMV promoter and a nuclear localization sequence (AdvIB) was provided by Dr R. de Martin (Vienna, Austria). Viruses were propagated and titred as previously described (21,22).

Analysis of infectibility
Mature DC were re-plated on 96-well flat-bottom plate at a density of 2x10⁵ cells/well and were either left uninfected, or infected for 2 h with a m.o.i. of from 40:1 to 500:1 of Adv0 or AdvßGal, in serum-free RPMI 1640. Cells were then incubated in RPMI 1640 supplemented as described above but without MCM. Cells were taken off the plates 48 h after infection, spun down, washed in FACS staining solution and incubated at 37°C for 10 min before 45 µl of a 2 mM solution of fluorescein-di-(ß-D)-galactopyranoside (Sigma) was added for 1 min (23). Addition of excess (10 times) ice-cold staining solution was used to stop the reaction and cell fluorescence was analysed by FACS as described below.

Western blotting and electrophoretic mobility shift assay
Batches of 10x10⁶ DC were either left uninfected, infected with 300:1 of Adv0 or infected with 300:1 of AdvIB. Two days after infection cells were either left unstimulated or stimulated with LPS (50 ng/ml) for 60 min. Cytosolic and nuclear extracts were prepared as described (24) and proteins separated by SDS–PAGE on a 10% (w/v) polyacrylamide gel, followed by electrotransfer onto nitrocellulose membranes. IB and the p42/p44 MAP kinases were detected using antibodies purchased from Santa Cruz Biotechnology (Santa Cruz, CA).

Protein (20 µg) from the nuclear extracts prepared as described above was analysed for NF-B activity by electrophoretic mobility shift assay as previously described (23). Competition analysis with excess cold NF-B probe and with an unrelated probe (AP-1) was performed.

Analysis of cytokines
In these experiments, mature DC were either left uninfected, or infected with a m.o.i. of 300:1 of Adv0 or AdvIB as described above. Cells were then incubated in RPMI 1640 supplemented as described above, but without MCM. Two days after infection, cells were replated at 2x10⁵ cells/well on a 96-well plate and either left unstimulated or stimulated with PMA (10 nM), LPS (50 ng/ml) or J588L conditioned medium which contained sCD40 ligand (50% v/v) for 24 h. Supernatants were taken off and analysed for TNF- (25), IL-6 and IL-8 (26), IL-12 (27), and IL-15 and IL-18 [using antibodies and recombinant cytokines purchased from R&D Systems (Minneapolis, MN)], and the p75 soluble TNF receptor (28) by ELISA.

Flow cytometry analysis of DC infectibility and surface markers
All samples were analysed on a FACScan flow cytometer using the CellQuest software (Becton Dickinson, San Jose, CA). Analysis was carried out on a population of cells gated by forward and side scatter to exclude dead cells and debris. Dendritic cell surface markers were studied using mAb to: HLA-DR, CD86, CD11c, CD14 [phycoerythrin (PE)-conjugated; PharMingen, San Diego, CA), CD83 (PE-conjugated; Immunotech, Marseille, France), CD1b (PE-conjugated; Serotec, Oxford, UK), CD40 (FITC-conjugated; PharMingen) and CD25 (PE-conjugated; PharMingen), HLA-DQ (FITC-conjugated; PharMingen), CD80 (PE-conjugated; PharMingen), CD54 (PE-conjugated; Serotec), CD50 and CD11a (FITC-conjugated; Serotec). Secondary antibody, used when appropriate, was PE-conjugated F(ab')₂ goat anti-mouse Ig (Southern Biotechnology Associates, Oxford, UK).

Analysis of apoptosis
Mature DC were left uninfected, infected with 300:1 Adv0 or infected with 300:1 AdvIB as described above. Cells were then cultured in complete medium for 2 days prior to being transferred to a 50 µg/ml solution of propidium iodide (29) and kept on ice for 30 min before analysis by FACS scan to monitor DNA fragmentation.

Statistical methods
All statistical testing was performed using a paired comparison, one-sided Student's t-test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Infectivity of DC by adenovirus and reduction in cytokine production by adenovirus overexpressing inhibitor of NF-B
Several groups have previously demonstrated that DC can be infected by adenovirus (30–32), in order to help induce immune responses to a variety of genes. However, they have not described infection efficiencies that were high enough (>90%) to efficiently block pathways and permit assessment of the importance of these pathways in DC function. DC were derived from monocytes purified by centrifugal elutriation, by culture with GM-CSF and IL-4 for 6 days as described by Sallusto and Lanzavecchia (7). For maturation, TNF- and MCM were added for 3 days (19,20). Figure 1 documents the phenotype of the in vitro generated mature DC: high DR, CD83, CD1b, CD40, CD11c, CD86 and CD25; low CD14. The infectivity of mature DC was assessed using an adenovirus encoding ß-galactosidase (Advßgal) and was >95% at a m.o.i. of 300:1 (Fig. 2A), but not at lower virus titres. Infection of mature DC with 300:1 was routinely performed with an adenovirus encoding IB (AdvIB). This leads to abundant cytosolic overexpression of IB, while infection with an adenovirus with no insert had no effect (Fig. 2B). An electrophoretic mobility shift assay demonstrated that AdvIB infection inhibits LPS-induced NF-B activation (Fig. 2C); competition experiments using excess cold NF-B probe and using an unrelated probe were performed to ascertain that the shifted band seen was really active NF-B. To rule out that this IB overexpression caused DC apoptosis, a DNA fragmentation assay was performed as described in Methods. There was no increase in DC apoptosis caused either by adenovirus infection per se or by NF-B inhibition (Fig. 3).

View larger version (29K): [in this window] [in a new window]   Fig. 1. DC surface markers were studied using mAb to: HLA-DR, CD86, CD11c, CD14 (PE-conjugated; PharMingen, San Diego, CA), CD83 (PE-conjugated; Immunotech, Marseille, France), CD1b (PE-conjugated; Serotec, Oxford, UK), CD40 (FITC-conjugated; PharMingen) and CD25 (PE-conjugated; PharMingen). Secondary antibody was PE-conjugated F(ab')2 goat anti mouse Ig (Southern Biotechnology Associates). Cell populations cultured with (red line) or without (green line) DC maturation were phenotyped with the panel of mAb listed above and compared with isotype control (blue area) on a FACScan (Becton Dickinson).

 

View larger version (63K): [in this window] [in a new window]   Fig. 2. In excess of 90% of DC can be infected with adenovirus. (A) Mature DC infected with Adv0 or AdvßGal as described in Methods, and cell fluorescence from Adv0-infected (black area) and AdvßGal-infected (grey line) DC was analysed by FACS. (B and C) DC were either left uninfected, infected with 300:1 of Adv0 or infected with 300:1 of AdvIB. IB overexpression was determined by Western blotting, and the p42/p44 MAP kinases were used as a control (B) and nuclear extracts were analysed for NF-B activity by electrophoretic mobility shift assay (C).

 

View larger version (32K): [in this window] [in a new window]   Fig. 3. Mature DC were either left uninfected or infected with a m.o.i. of 300:1 of Adv0 or AdvIB, before being analysed for DNA fragmentation as described in Methods.

 
This enabled us to ascertain the effect of blocking NF-B on DC function. First, we studied the production of some key proinflammatory DC cytokines, induced by various stimuli, PMA, LPS and CD40 ligand. TNF- induced by PMA, IL-6 induced by PMA or LPS and IL-12 (p70) induced by PMA or soluble CD40 ligand were significantly (P < 0.001) down-regulated by AdvIB (Fig. 4), indicating their dependence on NF-B. The production of other cytokines, including IL-8, IL-15, IL-18 and the p75 soluble TNF receptor, were either unchanged or less potently affected by NF-B inhibition (Table 1), indicating that these cytokines were chiefly regulated by other pathways. There was no detectable production of certain anti-inflammatory cytokines, e.g. IL-10 or the IL-1 receptor antagonist in these cultures (data not shown).

View larger version (14K): [in this window] [in a new window]   Fig. 4. Mature DC were either left uninfected (white bars), or infected with a m.o.i. of 300:1 of Adv0 (grey bars) or AdvIB (black bars) as described above. Supernatants were analysed for TNF- (a) IL-6 (b) and IL-12 (c) by ELISA.

 

View this table: [in this window] [in a new window]   Table 1. Effects of AdvIB infection on DC cytokines and surface markers

 
Reduction in antigen-presenting function by inhibiting NF-B
As the culture period for generating DC in vitro is relatively long and requires significant quantities of human blood, it was more feasible to initially study the antigen-presenting function of DC by using the mixed lymphocyte reaction. This uses allogeneic cells, from two different blood donors, rather than repeatedly employing the same donor, as is needed for antigen-specific T cell responses. DC have long been acknowledged to be the most potent antigen-presenting cells for the mixed lymphocyte (33). As few as 100 DC clearly induce a proliferative response, assayed by the uptake of non-radioactive BrdU or [³H]thymidine (Fig. 5). There was no effect of infecting DC with Adv0, but AdvIB infection dramatically reduced T cell proliferation, as was consistently observed in six experiments using BrdU or three with [³H]thymidine to assay proliferation (Fig. 5). The effect of AdvIB on peptide-specific antigen presentation was also assessed. Preliminary data indicate that antigen presentation to long-term tetanus toxoid T cell lines is also markedly inhibited by AdvIB infection (V. Calder et al., unpublished data).

View larger version (20K): [in this window] [in a new window]   Fig. 5. Abrogation of the MLR induced by DC by adenovirus IB infection. Mature DC were left uninfected (), infected with Adv0 (•) or infected with AdvIB () at a m.o.i. of 300:1. DC were then plated in graded doses for 105 purified, allogeneic T cells in triplicate in a 96-well round-bottom microtitre plate on day 1 after adenovirus infection. Proliferation was determined on day 6 using either a BrdU labeling and detection kit III (Boehringer Mannheim, UK) (a) or the [3H]thymidine uptake assay (b). Each point represents the mean ± SEM from either six (a) or three (b) separate experiments.

 
Mechanism of reduced antigen-presenting function
We have analysed the molecular mechanism by which AdvIB inhibits DC antigen-presenting function. The fact that AdvIB infection reduces the production of several proinflammatory cytokines made it relevant to investigate the role of these molecules in the reduced antigen-presenting capacity and experiments adding back IL-12, IL-15 or TNF- to IB-inhibited DC were performed. The AdvIB-inhibited response was augmented by <5% of the control Adv0 response by any of these cytokines at various doses (data not shown). However, neutralizing antibodies to IL-12 or TNF- moderately reduced the proliferative response induced by DC (Fig. 6) and so reduction in these stimulatory cytokines probably contributes in part towards the reduced antigen-presenting capacity after AdvIB infection.

View larger version (17K): [in this window] [in a new window]   Fig. 6. Effect of neutralizing antibodies on the immuno-stimulatory capacity of mature DC. Graded numbers of mature DC and 105 cells of allo-lymphocytes were plated in 96-well plates. Then neutralizing antibodies were added to each well: control Ig (µg/ml) (), anti-TNF- antibody (0.1 µg/ml) (•), anti-IL-12 antibody (0.5 µg/ml) (), anti-CD86 antibody (1 µg/ml) () and anti-CD86 antibody (0.1 µg/ml) (). Proliferation was determined at day 6 using the BrdU assay. Each point represents mean ± SEM from three separate experiments.

 
In the investigation of the mechanism of the dramatic effect of NF-B blockade on DC antigen presentation, changes in cell-surface antigens were also investigated. It was noteworthy that some cell surface markers, like ICAM-1, LFA-1 and especially ICAM-3, which are involved in adhesion of T lymphocytes to DC were up-regulated after AdvIB infection, while multiple others involved in antigen presentation, including HLA-DR, HLA-DQ, CD86, CD80 and CD40 were down-regulated (Fig. 7 and Table 1).

View larger version (38K): [in this window] [in a new window]   Fig. 7. The effect of AdvIB infection on DC surface markers was studied using mAb to some of the antigens listed in the legend to Fig. 1, and also HLA-DQ (FITC-conjugated; PharMingen), CD80 (PE-conjugated; PharMingen), CD54 (PE-conjugated; Serotec), CD50 and CD11a (FITC-conjugated; Serotec). On day 5 after infection, populations of uninfected (green line), 300:1 Adv0-infected (solid black line) and 300:1 AdvIB-infected (dotted black line) DC were phenotyped with the panel of mAb listed above and compared with isotype control (blue area) analysed on a FACS scan (Becton Dickinson).

 
It is likely that the largest single molecular mechanism contributing to the inhibited antigen-presenting cell function may be reduced co-stimulation, as judged by the profound inhibitory effect on the mixed lymphocyte reaction of anti-CD86 antibody (34), which mimicked that of AdvIB (Fig. 6). However, diluting the levels of anti CD86 antibody 10-fold reduced the inhibitory effect markedly (Fig. 6), making it likely that it is the combined reductions in multiple aspects of antigen presentation, i.e. antigen (DR, DQ) expression, co-stimulatory molecules and cytokines that leads to the observed marked inhibition of antigen presentation after AdvIB infection.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The data presented here demonstrates unequivocally that NF-B is a major regulator of the antigen-presenting function of mature DC. This possibility had been suggested previously by the presence of activated NF-B in the nucleus of mature DC (35), but this correlation did not constitute proof of the essential role of NF-B in this process nor did studies with RelB knockouts, which have no DC of myeloid type (36). Only with the development of an efficient and specific inhibitory method as described in this manuscript can the role of NF-B be established. We have substantiated the results obtained with AdvIB using an alternative inhibitor of NF-B, proteosome inhibitor I [Cbz-Ile-Glu(O-t-bu)-Ala-leucinal], which inhibits NF-B activation by preventing the degradation of IB by the proteosome (37,38): in a dose-dependent manner, this drug inhibited the antigen presentation of DC in the mixed lymphocyte reaction (39).

The variable effects of AdvIB on cell-surface molecules was of interest (Fig. 7). These results clearly demonstrate, as do more direct tests (Fig. 3), that the effect of AdvIB is not non-specifically `toxic' and does not induce apoptosis. NF-B inhibition has been shown to induce apoptosis in a variety of cell lines (40–42) but not in primary non-cycling macrophages (17). The diminution of CD86, CD80 and CD40 are all likely to be important in the reduction in antigen-presenting function, but the exact contribution of each of them is difficult to disentangle; the profound effect of antibodies to CD86 would indicate that this molecule is of considerable importance (Fig. 6).

In contrast there was up-regulation of ICAM-1, LFA-1 and ICAM-3 by IB. These proteins are involved in the clustering of T cells with antigen-presenting cells (43–45), and this result suggests that the physical interaction of T cells and DC and their attachment is also influenced by NF-B, but in the opposite way. The phenomenon that inhibition of NF-B can result in up-regulation of some molecules, while others are down-regulated, has earlier been observed in c-rel^–/– macrophages (46). It was of interest that certain cytokines produced by DC (e.g. TNF-, IL-6 and IL-12) were regulated by NF-B, but that others (e.g. IL-8, IL-15 and IL-18) were not. This suggests that other pathways are also involved in regulating this aspect of antigen presentation. In this context it would be interesting to evaluate the effects of NF-B inhibition on DC chemokines and their receptors (47), which would influence the selective migration of T cells and DC and their potential interaction.

The capacity of AdvIB to block antigen presentation by 99% (Fig. 5) suggests that the efficiency of adenoviral infection (Fig. 2) in these studies was very high. This is because of the sensitivity of the functional antigen presentation assay, which would detect as few as 100 functioning DC in 10,000, i.e. <1% (Fig. 5). However, that indirect functional calculation of adenoviral infection assumes that IB overexpressing DC are merely non-activating. We are currently evaluating whether these DC are also capable of inducing immunologic tolerance, i.e. inhibiting T cell responses induced by functional DC.

The question arises as to which subunits of NF-B may be of importance in antigen presentation and which are being blocked by the AdvIB. One possibility is the RelB component of the NF-B dimer, as mice deficient in RelB are immune suppressed, as they do not develop DC and hence have reduced antigen presentation (36,48,49). RelB as well as p50 and p65 has been demonstrated in the nucleus of activated DC (35) (and our unpublished data) and so all may be of importance for diverse antigen-presenting cell functions. The new technique described here has provided the first direct evidence that the pathways regulating antigen presentation can be analysed and that NF-B is essential for antigen presentation. The effects of blocking single subunits of NF-B can be addressed using adenoviruses. Whether other pathways and transcription factors also regulate DC function remains to be evaluated. There is now evidence for heterogeneity of DC in both mouse and human systems (50,51). Whether NF-B is also essential for the antigen-presenting function of the other subset in man or the three subsets in mouse remains to be established.

The coordinate regulation of multiple aspects of antigen-presenting function by NF-B is one of the striking observations of this study, with three major functions, i.e. MHC class II expression, co-stimulation and certain cytokines diminishing if NF-B is inhibited by AdvIB. In contrast, adherence molecules (LFA-1, ICAM-1 and ICAM-3) were augmented by AdvIB indicating that in the normal NF-B regulation of antigen-presenting function, limiting adhesion is probably also important, to permit antigen-presenting cells to detach and so be able to activate multiple T cells (52). Limiting T cell–DC contact may also be important in favoring immunity rather than immunological tolerance.

The work described here has multiple scientific and medical implications. Defining therapeutic targets is very important in the long process of developing new therapeutic agents, as it focuses future research and development into the areas most likely to be productive. NF-B appears to be such a target for blocking antigen presentation, whose inhibition would be useful in various medical conditions, such as in transplantation, allergy and autoimmunity. In terms of gene therapy, AdvIB or other viruses engineered to block antigen presentation are likely to inhibit the immune response to the adenovirus itself and so could prolong the expression of desired genes by the virus in vivo. In scientific terms, the results described here are also of importance. It has been proposed by Janeway and others (53,54) that activation of the innate immune system is a key component of immune induction. Graphically this has been termed the `danger signal' that activates the immune response (53,55). Our studies suggest that this `danger signal' operates via the activation of NF-B.

	Acknowledgments

 
This work was supported by the Arthritis Research Campaign and by Suntory Ltd. We thank Drs de Martin, Larsen, Tracey, Schimpl, Lane, Byrnes and Wood for their generous gift of reagents.

	Abbreviations

 

Adv0 adenovirus with no insert

AdvßGal adenovirus encoding E. coli ß-galactosidase

AdvIB adenovirus encoding porcine IB

BrdU bromodeoxyuridine

DC dendritic cells

GM-CSF granulocyte macrophage colony stimulating factor

LPS lipopolysaccharide

MCM monocyte conditioned medium

PE phycoerythrin

PMA phorbol myristate acetate

TNF tumor necrosis factor

	Notes

 
Transmitting editor: D. Tarlinton

Received 10 October 2000, accepted 8 February 2001.

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