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Departments of
*
Pathology and
Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; and
Department of Hematology, Erasmus University, Rotterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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-matured monocytes-DC. Moreover,
expression of critical differentiation, maturation, and costimulatory
molecules, including CD1a and CD83, was reduced and their capacity to
induce Ag-specific T cell proliferative and IFN-
release responses
was impaired. These data point to a role for vaults in both DC survival
and functioning as APC. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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It was only recently that P-glycoprotein (Pgp), a molecule well known for its ability to transport a broad spectrum of xenobiotics out of cells and thereby induce multidrug resistance (MDR) (2), was identified as yet another molecule that might play a role in this migratory process (3). Since the putative contribution of Pgp and, possibly, other mechanisms defined earlier in drug resistance studies, to DC functioning is still unknown, we set out to further explore this issue. Notably, immune responsiveness might well benefit from such mechanisms. To preserve their sentinel function in immune responses, DC should not readily suffer untoward damage from exposure to potentially toxic materials, as often derived from microbial and environmental sources. Hence, the expression of Pgp and a newly discovered cell organelle, the vault, was studied during in vitro DC development from various peripheral blood-derived precursor cells (4, 5). Vaults are evolutionarily highly conserved, large ribonucleoprotein particles (6). The particles represent multimeric RNA-protein complexes with one predominant component, the major vault protein (MVP). Although the cellular role of vaults has remained elusive, several findings support the view that vaults have a transport function by acting as a carrier, mediating bi-directional nucleo-cytoplasmic exchange as well as vesicular transport of compounds, including cytostatic drugs (7, 8, 9, 10, 11, 12, 13, 14). The present results demonstrate that not only Pgp but also vaults are expressed and up-regulated during the differentiation and maturation of DC from various sources. Furthermore, endocytosis of anti-MVP Abs leads to reduced viabilities and interference with DC maturation and Ag-presenting capacity, thus pointing to a critical role of vaults in DC functioning.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Human peripheral blood mononuclear cells isolated by adherence
to plastic were (either upon cryopreservation or directly) cultured in
IMDM (10 x 106 cells/2.5 ml) containing 25
mM HEPES (BioWhittaker, Verviers, Belgium), 10% FCS (Integro, Zaandam,
The Netherlands), 2 mM L-glutamine (Life Technologies,
Paisley, U.K.), 50 IE/ml sodium-penicillin G, 50 µg/ml streptomycin
sulfate, and 50 µM 2-ME (Merck, Darmstadt, Germany) (complete medium)
supplemented with 100 ng/ml rGM-CSF (Leucomax, Sandoz, The Netherlands)
and 1000 U/ml rIL-4 (CLB, Amsterdam, The Netherlands). After 6 days of
culture, a semiadherent cell population was obtained which displayed a
veiled DC morphology. These immature DC were subsequently cultured for
1 day in the absence or presence of either LPS (25 ng/ml,
Escherichia coli; Difco, Detroit, MI) or rTNF- (50 ng/ml;
Eurocetus, Amsterdam, The Netherlands) to induce maturation before
harvesting. Loosely adherent cells were harvested with 0.5 mM
EDTA/PBS.
Cultures set up for studying vault functions were performed with anti-vault Abs added to the culture medium at the onset, day 4, and day 6 of MO-DC cultures. Each time the amount of administered Abs was set on 5 µg/ml. Polyclonal Abs used were rabbit anti-MVP pabW (15) and rabbit IgG (normal rabbit serum; DAKO, Glostrup, Denmark). mAb experiments were performed with mouse (LRP-56 and MVP-9) and rat (LMR5) mAbs against MVP, respectively, irrelevant control mouse and rat mAbs produced in our laboratory (16, 17). These Abs were dialyzed before use (Slide-Alyzer Cassette; Pierce, Rockford, IL).
CD34-derived DC culture
DC were generated from CD34+ cells
isolated from peripheral blood of G-CSF-mobilized patients. Cells
bearing CD34 Ag were isolated from mononuclear fractions through
positive selection by mini-MACS using the CD34+
progenitor cell isolation kit according to the manufacturer’s
recommendations (Miltenyi Biotec, Bergisch Gladbach, Germany).
CD34+ progenitors were cryopreserved or seeded
for expansion at 105 cells/ml in complete medium
in the presence of rGM-CSF (100 ng/ml) and rTNF- (2.5 ng/ml) for 14
days before harvesting. Adherent cells were recovered using 0.5 mM
EDTA/PBS.
Chronic myeloid leukemia (CML)-derived DC culture
PBMC from CML patients were (either upon cryopreservation or
directly) seeded in a 2 x 106 cells/ml
concentration and cultured in complete medium supplemented with rGM-CSF
(100 ng/ml), rTNF- (2.5 ng/ml), and rIL-4 (1000 U/ml) for 10 days.
These immature CML-derived DC were subsequently cultured for 3 days in
the absence or presence of LPS (25 ng/ml) to induce maturation. Loosely
adherent matured cells were harvested with 0.5 mM EDTA/PBS.
Tumor cell lines
The drug-sensitive non-small lung cancer cell SW-1573 and its Pgp overexpressing multidrug-resistant, doxorubicin-selected (160 nM) subline SW-1573/2R160 (18) and the drug-sensitive small lung cancer cell line GLC4 and its MVP/vault overexpressing multidrug-resistant, doxorubicin-selected (1152 nM) subline GLC4/ADR (19) were used as controls for the immunoreactivity of the specific anti-Pgp protein and anti-vault protein Abs. The drug-selected cell lines were cultured in the presence of doxorubicin every other week and propagated in DMEM (BioWhittaker) supplemented with 10% FCS, 50 U/ml penicillin G, and 50 µg/ml streptomycin.
Antibodies
Immunophenotypical analysis of blood precursor cells and DC was performed using unlabeled mAb and mAb directly conjugated to FITC or PE. These included anti-CD83/PE (Immunotech, Marseille, France), anti-HLA-DR/FITC, anti-CD80 and anti-CD80/PE, anti-CD14 and anti-CD14/FITC (BD Biosciences, San Jose, CA), anti-CD86/PE, anti-CD54PE, anti-CD1a/PE (BD PharMingen, San Diego, CA), anti-CD86 (Ancell, Bayport, MN), anti-CD1a and anti-HLA-DR (Monosan; Sanbio, Uden, The Netherlands).
For immunophenotypical evaluation of Pgp, MVP and p193 expression, next to the unlabeled MVP-specific mAbs mentioned above under MO-DC culturing, the anti-MVP specific mAb MVP-37 (17) was used, as well as the following mAbs: anti-p193 mAb p193-4 (15), respectively, anti-Pgp mouse mAbs JSB-1 (20) and C494 (21) (Centocor, Leiden, The Netherlands), both recognizing internal epitopes, and MRK16 (22), UIC2 (23), 4.17 (24), and 4E3 (25) directed against extracellular epitopes. Except for the latter five Pgp-specific mAbs, all other mAbs mentioned were produced in our laboratory. Negative isotype-matched control murine mAbs were included in every experiment.
Flow cytometric analysis
Cells were washed in PBS supplemented with 0.1% BSA and 0.02% NaN3 and either fixed and permeabilized with 2% formaldehyde in acetone for 10 s (intracellular epitope detection) or stained directly after harvesting (extracellular epitope detection). Cells were preincubated for 20 min with normal goat serum followed by incubation for 45 min with primary mAb. Binding of unlabeled mAb was revealed by FITC-conjugated goat anti-mouse Ig (CLB). Fluorescence analysis was performed on a FACScan flow cytometer after acquisition of 10,000 events (BD Biosciences). Results were expressed as mean fluorescence indices (MFI) calculated as the ratio between the mean fluorescence of the specific mAb and the mean fluorescence of the negative control Abs.
Immunocytochemistry
Cytocentrifuge preparations of cells were air dried, fixed at room temperature in acetone for 10 min, or, in the case of the mAbs MVP-9, MVP-37, and p193-4, in 3% (w/v) paraformaldehyde/0.4% (w/v) glucose in PBS for 10 min. Further immunocytochemical staining procedures were performed as described before (15). In addition, biotinylated swine anti-rabbit Ig and streptavidin-biotin-peroxidase complexes (DAKO) were used. Cytospins were scored by two independent observers.
Immunoblots
Postnuclear supernatants from MO-derived mature DC and control cells lines SW-1573/2R160 and GLC4/ADR were prepared and analyzed by immunoblotting following procedures as described previously (15).
Dye efflux studies
Cells were incubated in culture medium containing 2 µM daunorubicin (DNR; Sigma-Aldrich, St. Louis, MO) for 60 min at 37°C, washed in ice-cold medium, and resuspended in medium without or with 2 µM PSC833 (Novartis, Basel, Switzerland) or 10 µM verapamil (VER; Sigma-Aldrich). After 60 min of incubation at 37°C, cells were washed and immediately placed on ice for analysis by flow cytometry. Results were calculated as the ratios between the mean fluorescence of DNR retention in the presence of Pgp inhibitors and the mean fluorescence of DNR retention in the absence of Pgp inhibitors (dye fluorescence index (DFI)).
Double-labeling immunofluorescence
For double-labeling experiments, cytospin preparations of immature and mature MO-DC were fixed for 2–4 min in methanol (-20°C) or 10 min in acetone at room temperature. After a blocking step with normal goat serum (DAKO) for 20 min at room temperature, the cells were incubated simultaneously with anti-MVP (mAb MVP-9 on methanol-fixed spins or LRP-56 on acetone-fixed spins) and rabbit polyclonal Abs against TGN-46 for labeling the trans-Golgi network, CD63 for labeling lysosomes, MHCI or MHCII diluted in PBS/0.5% BSA for 60 min at room temperature. All rabbit polyclonal Abs were kindly provided by J. Neefjes and M. Fernandes Borja from the Dutch Cancer Institute (Amsterdam, The Netherlands). Subsequently, anti-MVP mouse mAb binding was detected using FITC-labeled goat anti-mouse Ig (DAKO), and the binding of rabbit polyclonal Abs was detected with Texas Red-labeled goat anti-rabbit Ig (Molecular Probes, Eugene, OR) (simultaneous incubation for 30 min at room temperature). Cells were mounted with Vectashield (Vector Laboratories, Burlingame, CA). Cells were examined with a MRC-600 confocal microscope (Bio-Rad, Herfordshire, U.K.), coupled to a Nikon microscope (Melville, NY). Negative controls consisted of simultaneously processed slides replacing either the mouse mAb LRP-56 and MVP-9 with isotype-matched control mAb (mouse IgG2b, anti-chromogranin A; DAKO) or replacing the rabbit polyclonal Abs with control polyclonal (anti-calcitonin; DAKO). For each condition, at least 50 immature and mature DC were evaluated for resulting staining patterns.
In vitro stimulation of specific T cell proliferation and IFN-
release
After 7 days of culture, viable LPS-matured MO-DC were seeded as
stimulator cells in round-bottom 96-well culture plates (Nunclon
International, Roskilde, Denmark) at 104 viable
(trypan blue exclusion) DC per well and pulsed for 2 h with 1
µg/ml influenza viral Ag preparation containing three major
hemagglutinins as outlined elsewhere (26). After
discarding the supernatant, 250 µl of fresh medium and 50 µl with
105 autologous PBL were added per well. Cells were cultured
for 6 days, after which 50 µl of supernatant was collected for
IFN- assays by ELISA, and [3H]thymidine was
added (0.4 µCi/well; Amersham, Aylesbury, U.K.), after which the
cells were harvested onto fiberglass filters and
[3H]thymidine incorporation was determined
using a flatbed liquid scintillation counter (Wallac, Turku,
Finland).
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Immature and LPS- and TNF--matured DC were differentiated in
vitro from peripheral blood MO. Using this model, first Pgp and MVP
expression were analyzed by flow cytometry. Development of MO-DC was
monitored by phenotyping the cells at the different stages in culture.
Characteristically, expression of the MO marker CD14 expression was
lost, whereas the DC differentiation marker CD1a was up-regulated (Fig. 1
A). Expression of other DC
differentiation markers (CD80, CD86, and HLA-DR) was also up-regulated
(data not shown), and there was de novo expression of the DC maturation
marker CD83 (Fig. 1A). Immunolabeling of permeabilized cells
with mAb directed against intracellularly situated epitopes of Pgp (mAb
JSB-1) and MVP (mAb LRP-56 and MVP-9) revealed neither of the proteins
in the CD14+ MO. Immature MO-DC displayed weak
expression of Pgp (MFI, 1.6), which was slightly increased in fully
matured MO-DC (MFI, 1.8). Clear MVP expression was found in immature
MO-DC (MFI, 1.9), which was further increased in fully matured MO-DC
(MFI, 4.3; Fig. 1A).
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B). With two anti-Pgp mAbs,
JSB-1 and C494, we observed cytoplasmic immunoreactivity, sometimes in
mature MO-DC associated with the plasma membrane. Three different
anti-MVP mAbs, i.e., MVP-9, MVP-37, and LRP-56 (shown in Fig. 1B) displayed the characteristic coarsely granular
cytoplasmic staining of MVP, which was significantly increased in fully
mature MO-DC as compared with immature MO-DC. In addition, both
immature and mature MO-DC showed parallel overexpression of MVP and a
minor vault component, the 193-kDa minor vault protein (p193),
indicating that whole vault particles are up-regulated during MO-DC
differentiation and maturation (15).
To further establish overexpression of Pgp and MVP molecules in mature
MO-DC, postnuclear supernatants were prepared and immunoblotted by
using anti-Pgp mAb C494 and anti-MVP mAb MVP-37. Although a
protein band of 
170 kDa was readily detectable in the control
postnuclear supernatant of Pgp-positive SW-1573/2R160 tumor cells, no
Pgp could be identified in mature DC, indicating that the expression
level of Pgp in mature MO-DC remains below the level of detection by
Western blotting (data not shown). High levels of MVP in mature MO-DC
were confirmed by Western blotting; a clear band of 110 kDa was
detected, corresponding to the molecular mass of MVP (Fig. 1C).
In vitro, DC-like cells can be generated from a number of sources by
culturing hemopoietic precursor cells in the presence of a variety of
cytokines and medium supplements (4, 5). To elaborate on
the correlation between differentiation stage and expression of Pgp and
vaults that was found in MO-DC, we further evaluated their expression
in CD34-derived DC and CML-derived DC. Immunocytochemical analyses
showed that also in these cell types cellular
differentiation/maturation, as reflected by up-regulated expression of
CD1a and CD83, was accompanied by increased expression of Pgp and MVP
(Table I). Given its prominence in DC
propagated from three different sources under different culture
conditions, up-regulation of Pgp and vaults seems to reflect a common
developmentally regulated event. Thus, in parallel to functional
changes accompanying the differentiation from precursor cells and
subsequent activation, as a response to danger-signaling agents present
in the microenvironment (such as TNF- and LPS), DC may rapidly
up-regulate Pgp and vault expression.
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In chemotherapeutic treatment strategies, the induction or
up-regulation of transmembrane transporter molecules, such as Pgp, in
cancerous cells represents a major obstacle. In this view one might
speculate that expression of the same MDR-related molecules by DC,
known to literally scavenge their environment for potentially toxic
materials, fulfills an evolutionary conserved defense mechanism that
may also protect DC during chemotherapy. Therefore, we evaluated the
functional activity of Pgp in fully mature MO-DC by investigating the
efflux of the Pgp-transported fluorescent cytostatic drug DNR in the
absence and presence of established Pgp inhibitors, PSC833 and VER
(Fig. 2A). Pgp-positive
control SW-1573/2R160 tumor cells transported the substrate DNR into
the surrounding medium, showing no retention as reflected by a decrease
in mean fluorescence intensity down to the level of unloaded cells.
This efflux was inhibited by PSC833 (DFI, 2.0) as well as VER (DFI,
1.8). Pgp-negative control SW-1573 tumor cells did not efflux DNR
mediated by Pgp as was shown by full retention, which was not further
affected by the Pgp antagonists. Also, in mature MO-DC, neither PSC833
nor VER affected the mean fluorescence intensity level (DFI,
1.0).
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B). Thus, although Pgp could
be detected by immunocytochemical and flow cytometric analyses using
permeabilized MO-DC (Fig. 1, A and B), no
surface-exposed Pgp could be detected nor could Pgp-dependent
trans-plasma membrane transport activity be shown. These
results confirm those reported earlier by Randolph et al.
(3), Chao et al. (27), and Laupeze et al.
(28) in showing that DC cultured from MO do not exhibit
Pgp-mediated trans-plasma membrane transport, but extend
those data in revealing distinct intracytoplasmic Pgp expression.
Importantly, in the former study extracellular epitopes of Pgp could be
detected in epidermal skin-derived DC, as collected from human skin
explant culture media, and were found to be functionally associated
with their migratory capacity. This suggests that Pgp can be
differentially expressed in DC depending on environmental conditions.
Intracellular Pgp expression as well as inactive forms of Pgp have also
been observed in tumor cells and in lymphocytes (29, 30, 31).
Intracellularly, MO-DC-associated Pgp might still exert unknown
functions in the vacuolar system, whereas on the cell surface Pgp might
be expressed as a truncated product (32) and/or require
functional activation through conformational changes under specific
environmental conditions (33). Whether Pgp overexpression
in DC may facilitate the release of proinflammatory mediators, like
recently reported for another transmembrane transporter molecule, i.e.,
multidrug resistance protein (MRP1), is still unknown
(34). Subcellular localization of MVP in MO-DC
The presence and function of vaults in DC have not been
investigated before. To find clues as to a possible role for vaults in
the functional and phenotypical development of DC, the subcellular
localization of the MVP protein was studied in cytospin preparations of
MO-derived immature and mature DC with the anti-MVP mouse mAb
LRP-56 and MVP-9 using confocal laser scan microscopy (Fig. 3). Similar to what was seen by
conventional immunocytochemistry, a typical cytoplasmic, granular MVP
staining was observed in immature DC and an even stronger MVP staining
in mature DC. No distinct colocalization could be observed of the MVP
protein with MHCII or MHCI, distributed along the pathways for
presentation of exogenous and endogenous protein Ag, respectively (Fig. 3A). Thus, no direct association with Ag presenting routes
was revealed. Furthermore, the MVP protein did not colocalize with
anti-TGN-46, specific for the trans-Golgi network (Fig. 3A). Clear partial colocalization was found for MVP and
CD63, a lysosomal marker (Fig. 3B). Most likely, in the
lysosomal degradative compartment the MVP protein, along with many
other proteins, is ultimately destroyed.
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Next, during both differentiation and LPS-induced maturation,
MO-DC were cultured in the absence or continuous presence of
anti-MVP polyclonal or an oligoclonal mix of three different
anti-MVP mAbs or nonspecific control sera. Staining of the
internalized Abs was conducted on cytospin preparations, applying only
biotinylated secondary step reagent and the
streptavidin-biotin-peroxidase complex. In all MO-DC cultured with Abs,
cytoplasmic immunostaining was observed (Fig. 4A), revealing uptake of the
administered Abs, irrespective of their specificity, through their
strong endocytotic capacity. Strikingly, the internalization of the
anti-MVP polyclonal serum had a distinct effect on the phenotypic
characteristics of MO-DC. When examining cytospin preparations,
typically CD1a, CD86, CD83, and CD54 increased upon maturation. In
contrast, MO-DC cultured with polyclonal anti-MVP showed reduced
expression of each these markers in seven individual experiments as
compared with the control cultures (Fig. 4B). Along with
this reduced expression of distinctive surface molecules, the addition
of polyclonal anti-MVP during MO-DC culture led to a reduced
viability of the mature MO-DC population when compared with cultures
with control serum (Fig. 4C; paired t test,
p = 0.007, n = 7). MO-DC cultured with
the anti-MVP mAb mixture also remained low in their expression of
DC markers, but the slight decrease of viability under this condition
did not reach statistical significance (Fig. 4C;
p = 0.310, n = 4). Culturing MO-DC in
the presence of any of the individual, single-epitope confined, mouse
anti-MVP mAb had no detectable effects on expression of
costimulatory membrane molecules or viabilities (data not shown).
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D) and IFN- release assays (paired t test,
p = 0.001 for anti-MVP polyclonal and
p = 0.005 for anti-MVP monoclonal mixture; Fig. 4E). Thus, in the absence of gross effects on Ag uptake as
reflected by intracellular dextran-FITC staining, the latter results
support the view that intracellular targeting of vault particles with
Abs binding the major vault protein interferes with appropriate
handling and presentation of exogenously administered Ag.
Interestingly, the lack of significant effects with the individual mAbs
argues against interference with functionally relevant epitopes. Most
likely, therefore, this blockade results from events secondary to this
binding, e.g., from aggregation of vault particles. Concluding remarks
Taken together, we propose that vaults act as components in the
cascade of events regulating DC effector function. Since their
discovery, the occurrence and abundance of vaults in eukaryotic cells
have argued for an important general function. From studies in the
slime mold Dictyostelium discoideum, it is known that
disruption of MVP results in a phenotype incapable of growing under
nutritional stress (35). From studies in tumor cell lines,
vaults have been implied in drug resistance (12, 15, 16, 36, 37). The present findings first demonstrate that, even more so
than Pgp, vault particles are increased during the differentiation of
DC and that their numbers are further increased upon maturation. An
attractive hypothesis is that this reflects a fundamental response to
stress signals and that in mature DC vaults may serve as
protection of their integrity during migration to the draining lymph
node. Whether this involves a nucleo-cytoplasmic shuttle of signal
transduction (7, 14) or association with microtubular
functions (9, 11) remains to be seen. The present findings
point to a role of vaults in DC functioning, more specifically in their
capacity to induce Ag-specific T cell proliferative and IFN- release
responses. Obviously, future studies should also clarify whether vault
particles might also play roles in other DC functions, e.g., migratory
behavior and CTL activation. To further address all of these questions,
we are currently developing MVP gene knockout mice.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Rik J. Scheper, Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: rj.scheper{at}vumc.nl
3 Abbreviations used in this paper: DC, dendritic cell; CML, chronic myeloid leukemia; DFI, dye fluorescence index; DNR, daunorubicin; MDR, multidrug resistance; MFI, mean fluorescence index; MO, monocyte; MVP, major vault protein; Pgp, P-glycoprotein; VER, verapamil.
Received for publication February 5, 2001. Accepted for publication December 4, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103:757.[Medline]
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