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Synergize in the Activation and Maturation of Human Dendritic Cells1
Division of Clinical Pharmacology, Department of Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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synergized in the activation of DC.
Stimulated with a combination of ATP and TNF-, DC expressed the
maturation marker CD83, secreted large amounts of IL-12, and were
potent stimulators of T cells. In the presence of the P2 receptor
antagonist suramin, the effects of ATP were completely abolished. Our
results suggest that extracellular ATP may play an important
immunomodulatory role by activating DC and by skewing the immune
reaction toward a Th1 response through the induction of IL-12
secretion. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-1ß, or IL-6 induce an activation
process, referred to as maturation, upon which DC loose their
phagocytic activity, up-regulate costimulatory and adhesion molecules,
present Ags on MHC more effectively, and produce a number of cytokines,
including TNF- and IL-12 (2). These changes in
phenotype and function lead to the capability of DC to potently
activate T cells and to induce Ag-specific immune responses. However,
the physiological signals for DC activation are still not fully
understood. The role of the intracellular adenine nucleotide ATP regarding energy metabolism in biological systems has been described by Lipmann and Kalckas as early as 1941 (3). Since then it has been recognized that nucleotides also represent a ubiquitous class of signaling molecules in many tissues, including the immune system (4). ATP is stored in the cytosol of most cells in a concentration of 5–10 mM and can be found in the 100 mM range in intracellular compartments. Due to its size and high density of charge, ATP cannot permeate membranes. However, release of ATP has been observed from a variety of cells, including tumor cells and lymphocytes, as well as from virtually all tissues under conditions of hypoxia, ischemia, inflammation, and cell necrosis (5, 6, 7, 8). The sources of released ATP include exocytotic granula from secretory cells, release from lysed cells, and nonlytic release from cytoplasmatic stores. Extracellular ATP mediates biological responses by activating P2 receptors (9). Two groups of P2 receptors have been characterized: P2X receptors, which are ligand-gated cation channels (10), and P2Y receptors coupled to G proteins (11). In the immune system, ATP triggers mainly proinflammatory reactions, such as the release of IL-1ß, exocytosis of granula containing superoxide and reactive oxygen species, phagocytosis, giant cell formation, chemotaxis, cytolysis, and cell adhesion to endothelium (4, 12). Recently, it has been shown that DC express P2 receptors, but their physiological role is unclear. Proposed functions include improved Ag presentation (13), cytokine production (14), chemotaxis (15), and induction of apoptosis (16).
Based on the hypothesis, that ATP released at sites of cell stress, damage, or necrosis signals danger to the immune system, we investigated the effects of extracellular ATP on endocytosis, phenotype, IL-12 secretion, and T cell stimulatory capacity of human monocyte-derived DC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All cell cultures were maintained in RPMI 1640 medium (Biochrom, Berlin, Germany) supplemented with 2% human pooled AB serum (BioWhittaker, Walkersville, MD), 2 mM L-glutamine (Life Technologies, Paisley, U.K.), 50 U/ml penicillin, and 50 µg/ml streptomycin (both from Sigma, Munich, Germany), hereafter referred to as complete medium.
Reagents
Human rGM-CSF (Leucomax, sp. act., 1.11 x
107 U/mg) was purchased from Novartis (Basel,
Switzerland), and IL-4 (sp. act., 1 x 107
U/mg) from Promega (Madison, WI). TNF- (sp. act., 1.1 x
108 U/mg) was obtained from R&D
Systems (Wiesbaden, Germany). ATP, ,ß-methylene-ATP (ßmeATP),
ß,
-methylene-ATP (ßmATP),
adenosine-5'-O-(3-thio)triphosphate (ATPS),
P1,P5-di(adenosine-5')pentaphosphate (AP5A), UTP,
benzoylbenzoyl-ATP, 2-methylthio-ATP (2 MeSATP), ATP-2',3'-dialdehyde
(oxyATP), adenosine, PGE2, FITC-dextran
(Mr = 40,000), and suramin were
purchased from Sigma-Aldrich (Steinheim, Germany). All reagents were
tested for endotoxin contamination with the sensitive
Limulus amebocyte lysate assay (LAL assay; BioWhittaker),
according to the manufacturer’s instructions, and were found to be
negative (endotoxin content in stock solutions <1 pg/ml).
Isolation and culture of human DC
DC were generated from PBMC, as described elsewhere, with minor
modifications (17). In brief, PBMC were isolated from
healthy donors by standard density-gradient centrifugation on Ficoll
separating solution (Biochrom), washed three times, and resuspended in
complete medium. PBMC (5 x 106/ml) were
allowed to adhere in 75-cm2 culture flasks for 60
min. Nonadherent cells were removed by pipetting. After an overnight
incubation, the initially adherent cells were transferred into six-well
plates (1.5 x 106 cells/2 ml) in fresh
complete medium supplemented with 1000 U/ml GM-CSF and 500 U/ml IL-4.
After 6 days of culture, DC were incubated with ATP or other P2R
agonists in the presence or absence of TNF- (1000 U/ml) for
48 h.
mAbs and flow cytometry
Mouse anti-human mAbs and the appropriate isotype controls were all obtained from PharMingen (San Diego, CA): TÜ36 (IgG2b, anti-HLA-DR, PE conjugated), BB1 (IgM, anti-CD80, PE conjugated), 2331/FUN-1 (IgG1, anti-CD86, PE conjugated), HB15e (IgG1, anti-CD83, FITC conjugated), HA58 (IgG1, anti-CD54, PE conjugated), G46-2.6 (IgG1, anti-HLA-ABC, FITC conjugated), and M5E2 (IgG2a, anti-CD14, FITC conjugated). For FACS analysis, 105 DC suspended in 100 µl PBS were incubated with 10 µl of the fluorochrome-labeled mAbs for 20 min on ice. After the staining procedure, the samples were washed once in PBS and measured immediately (FACS-Calibur; Becton Dickinson, Heidelberg, Germany). Data were analyzed using FlowJo software (version 2.7.8).
Quantification of IL-12
On day 6, DC were incubated for 48 h with various stimuli, and supernatants were collected for IL-12 measurements with a commercial ELISA kit (Endogen, Woburn, MA) that detects both IL-12 p40 and the bioactive p70 heterodimer.
Endocytosis
On day 6, DC were incubated in the absence or presence of ATP, and endocytotic activity was assessed adding FITC-dextran (0.5 mg/ml) to the culture medium for 30 min at 37°C (control on ice). Thereafter, cells were extensively washed and analyzed by flow cytometry.
T cell proliferation assay
DC were harvested and cocultured in complete medium with a constant number of allogeneic nonadherent PBMC (2 x 105/200 µl) in 96-well round-bottom microtiter plates at ratios ranging from 1:20 to 1:320 in triplicates. On day 5, the cells were pulsed with [3H]thymidine (1 µCi/well; Amersham Buchler, Freiburg, Germany) and harvested after 18 h onto a filtermate. The amount of incorporated [3H]thymidine was analyzed in a liquid scintillation counter (Wallac, Turku, Finland).
Statistics
Data were expressed as means ± SEM. Statistical significance was determined by the unpaired two-tailed Student’s t test. Significance at 95% confidence limits (asterisks in figures) is presented for individual experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immature DC have a high endocytotic activity that is
down-regulated upon maturation (18). To test the influence
of ATP on endocytosis, DC were incubated with ATP, and the ability to
incorporate FITC-dextran was determined over the course of 2 days.
Immature DC incubated with 100 µM ATP transiently up-regulated
endocytosis (Fig. 1
). This effect was
only short-lived (
1 h) and was followed by a long-lasting
down-regulation. At higher ATP concentrations (500–1000 µM), the
initial rise of dextran uptake was blunted (data not shown).
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To test the hypothesis that extracellular adenine nucleotides
activate DC, the expression of DC surface markers was analyzed after a
48-h stimulation period with ATP. As determined by flow cytometry, ATP
induced the up-regulation of CD86 (B7-2), CD54 (ICAM-1), and MHC-II,
but did not induce the neoexpression of the maturation marker CD83 on
DC. This effect was most pronounced at concentrations of 250–500 µM,
whereas 100 µM mainly enhanced CD86 expression (Fig. 2). Because ATP is rapidly hydrolyzed by
ecto-ATP/ADPase (CD39), the chemically modified ATP derivatives
ßmeATP, ßmeATP, ATPS, or AP5A, which
are resistant to hydrolyzation by this ectonucleotidase, were applied
in subsequent experiments. At equimolar concentrations, these ATP
derivatives were more potent in inducing the expression of activation
markers than ATP (Fig. 2). Three of the ATP derivatives (ßmeATP,
ßmeATP, and ATPS) induced small subpopulations of CD83-positive
DC (up to 10% of the total DC population).
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DC have previously been shown to secrete IL-12, a heterodimeric
cytokine composed of two covalently linked chains (p40 and p35), upon
activation with LPS, with the combination of TNF- and
PGE2 or with CD40 ligation (19, 20, 21).
To investigate the effects of extracellular nucleotides on the
secretion of IL-12, DC were incubated with different concentrations of
ATP, its derivatives, or UTP. After 48 h, the supernatants were
harvested and IL-12 was quantified using a capture ELISA. Significant
amounts of IL-12 were secreted by DC stimulated with 100 µM ATP
(n = 11, p = 0.006). Fig. 3 demonstrates that extracellular ATP
induced IL-12 production in a dose-dependent fashion. The highest IL-12
levels were recovered in the supernatants of DC stimulated with 500
µM ATP, whereas ATP concentrations of 1 mM or above were found to be
toxic, as determined by the lack of trypan blue exclusion and positive
propidium iodide staining (>30% dead cells after 48 h).
Different P2 receptor agonists were tested for their potency to induce
IL-12 secretion: ßmeATP, ßmeATP, ATPS, and
benzoylbenzoyl-ATP were clearly more potent than ATP, whereas
AP5A and 2 MeSATP were not. The induction of
IL-12 secretion was specific for adenine nucleotides, because UTP, a
uracil nucleotide with agonistic activity on several P2Y receptor
subtypes, and the ATP metabolite adenosine were ineffective (data not
shown). To further test the hypothesis, that ATP-induced secretion of
IL-12 by DC is mediated by the activation of P2 receptors, DC were
incubated simultaneously with ATP (or its derivatives) and suramin (30
µM), a competitive inhibitor of P2 receptors. In the presence of
suramin, IL-12 production of ATP-activated DC was completely abolished
(Fig. 4). The specific P2X7 receptor
antagonist oxyATP did not suppress IL-12 secretion (data not
shown).
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Activated DC are potent stimulators of T cell proliferation. The
influence of ATP on the T cell stimulatory capacity of DC was assessed
in a mixed lymphocyte proliferation assay. DC were cocultured with
allogeneic nonadherent PBMC at ratios ranging from 1:20 to 1:320. DC
exposed to 500 µM ATP 2 days before coculture were four times more
potent in inducing a T cell proliferation than untreated DC, whereas
100 µM ATP had only a minor influence (Fig. 5). Again, this effect was more
pronounced for the metabolically stable P2 receptor agonists and was
abolished in the presence of suramin (data not shown).
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synergize in the activation of DC
The proinflammatory cytokine TNF- is a well-known activator of
DC. Several investigators have shown that activation by TNF- can be
enhanced in combination with other proinflammatory stimuli, such as
IL-1ß and IL-6 or PGE2 (21, 22).
To determine whether TNF- synergizes with ATP, DC were incubated
with ATP (or its derivatives) and TNF- (1000 U/ml) and were
subsequently analyzed for IL-12 secretion, phenotype, and T cell
stimulatory capacity. DC stimulated with TNF- alone produced only
small amounts of IL-12, whereas a single addition of 100 µM ATP
synergistically increased IL-12 production (Fig. 6). When suramin was added, the
synergistic effect of ATP and TNF- was markedly reduced (Fig. 7). Suramin had no influence on the IL-12
secretion of DC stimulated with a combination of TNF- and
PGE2. As determined by flow cytometry, the
combination of P2 receptor agonists and TNF- induced the
up-regulation of CD86, CD54, and MHC-II molecules as well as the
neoexpression of the maturation marker CD83 (Fig. 8). Furthermore, these changes in
phenotype and the increase of IL-12 secretion correlated with an
increased T cell stimulatory capacity (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study, we demonstrate that human monocyte-derived DC
exposed to ATP transiently enhance endocytosis, which is followed by
the up-regulation of MHC-II, costimulatory molecules, adhesion
molecules, IL-12 secretion, and an increased T cell stimulatory
capacity. Furthermore, activation of DC is synergistically enhanced
when ATP is combined with TNF-. DC activation is mediated by P2
receptors, because ATP could be substituted by several other P2
receptor agonists and activation was completely abolished by suramin, a
competitive antagonist of P2 receptors. The ATP derivatives ßmeATP
and ßmeATP, which have substitutions of methylen bridges for
normal oxygen bridges at the polyphosphates, as well as ATPS, are
superior to ATP. There are two possible explanations for this
observation. First, these ATP derivatives are resistant to
dephosphorylation by the membrane-bound enzymes ecto-ATP/ADPase (CD39)
and ecto-5'-nucleotidase (CD73), which are expressed by DC and which in
concert rapidly hydrolyze ATP via ADP and AMP to adenosine (23, 24). Adenosine has no activity on P2 receptors and, as we could
demonstrate, DC are not activated by this nucleoside. Receptor
activation by ATP derivatives may therefore be prolonged. Second, P2
receptor subtypes differ substantially in their affinities to different
agonists. In fact, P2 receptor agonists are valuable pharmacological
tools, because their rank order of potency can be used to discriminate
P2 receptor subtypes (10, 25).
Different P2 receptor subtypes may be involved in DC activation. The
P2Y family includes the selective purinoceptors P2Y1 and P2Y11, which
are preferentially activated by ATP and ADP, nucleotide receptors that
are responsive to both adenine and uracil nucleotides (P2Y2, P2Y8) as
well as pyrimidinoceptors (P2Y3, P2Y4, P2Y6) (26). It has
been shown that murine DC, but not human monocyte-derived DC, are
activated by UTP. Thus, P2Y2, P2Y3, P2Y4, P2Y6, and P2Y8 are not
involved in the activation of human monocyte-derived DC. Therefore, it
is likely that the selective purinoceptors P2Y1 and P2Y11, which are
both expressed by DC (23), mediate activation of human
monocyte-derived DC. The rank order potency of ligands to activate the
P2Y11 receptor is ATPS > ATP > 2 MeSATP
(26). Interestingly, this rank order was also found in our
experiments. However, it is known that the P2Y1 receptor is not
activated by the methylated ATP derivatives ßmeATP and
ßmeATP, which were potent activators of DC in our study. To our
knowledge, the P2Y11 has not been studied in this respect. The P2X
receptor family comprises seven receptor subtypes, and ßmeATP is
used to discriminate between them. P2X1 and P2X3 receptors are
activated by both ATP and ßmeATP, whereas P2X2, P2X4, and P2X5 are
not (27). A third type of receptor is the unselective
pore-forming P2X7 receptor, which is activated by ATP in the millimolar
range and selectively inhibited by oxyATP (28). P2X7 is
involved in Ag presentation and apoptosis of murine DC (13, 16). Because oxyATP was not antagonistic in our experiments, the
P2X7 receptor appears not to be involved in the activation of human DC.
In summary, both P2X and P2Y receptors might mediate activation of
human monocyte-derived DC by ATP, with the subtypes P2Y11, P2X1, and
P2X3 being the most likely candidates. In the future, further efforts
characterizing both P2 receptor expression and selective receptor
activation would be helpful to delineate the differential role of P2
receptor subtypes in DC function.
Activation of DC is required for the initiation of many adoptive immune
responses. In the self-nonself model by Janeway (29), the
immune system responds to exogenous signals such as microorganisms.
These signals include bacterial products such as LPS, nonmethylated CpG
motifs in bacterial DNA and dsRNA of viral genomes (30).
This view has been expanded by the danger model, which postulates that
DC are activated by endogeneous mediators released from stressed or
damaged cells (31, 32). In favor of this model is the
observation that healthy or apoptotic cells do not activate DC, whereas
stressed, virally infected, or necrotic cells can stimulate a primary
immune response (33, 34). According to this theory, danger
signals are either inducible or exist in a prepacked form only to be
released in situations in which cells are threatened. To date, these
danger signals have not been identified. We propose that the ubiquitous
molecule ATP, which is closely linked to energy metabolism, is an ideal
candidate for such a prepacked danger signal. This nucleotide is stored
in the cytosol at a concentration of 5–10 mM. Therefore, it is not
unlikely that large amounts of ATP accumulate in the interstitial space
upon plasma membrane damage or acute cell death caused by inflammation,
microbial invasion, or rapid tumor growth. Moreover, ATP can be
released from vital cells, such as tumor cells (5),
activated T cells (35), macrophages (36), and
microglial cells (37), thereby enhancing the extracellular
ATP concentration at inflammatory sites. Immediately after exposure to
ATP, quiescent tissue DC would be rapidly activated to internalize Ags
such as mannosilated glycoprotein precursors from necrotic cells, which
are believed to be ligands for mannose receptors (38).
This short-lived response to extracellular ATP would be followed by a
second phase, in which activated DC migrate to the draining lymph nodes
to present the captured Ags to T cells, inducing a Th1 immune response
by secreting IL-12. In this respect, ATP could also amplify the effects
of other activators of DC, such as TNF-, which accumulate at sites
of inflammation.
We conclude that ATP released in a proinflammatory environment might be a potent stimulus for the initiation of immune responses. ATP can be used to improve therapeutic strategies with ex vivo generated DC. Furthermore, stable ATP analogues might be useful in vaccination protocols in vivo.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Stefan Endres, Medizinische Klinik Innenstadt, Ziemssenstr. 1, 80336 München, Germany.
3 Abbreviations used in this paper: DC, dendritic cell; AP5A, P1,P5-di(adenosine-5')pentaphosphate; ßmeATP, ,ß-methylene-ATP; ßmATP, ß,-methylene-ATP; ATPS, adenosine-5'-O-(3-thio)triphosphate; 2 MeSATP, 2-methylthio-ATP; oxyATP, ATP-2',3'-dialdehyde.
Received for publication March 27, 2000. Accepted for publication July 19, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Exp. Med. 179:1109. cooperate to activate human dendritic cells: synergistic activation of interleukin 12 production. J. Exp. Med. 186:1603.This article has been cited by other articles:
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F. Wilkin, X. Duhant, C. Bruyns, N. Suarez-Huerta, J.-M. Boeynaems, and B. Robaye The P2Y11 Receptor Mediates the ATP-Induced Maturation of Human Monocyte-Derived Dendritic Cells J. Immunol., June 15, 2001; 166(12): 7172 - 7177. [Abstract] [Full Text] [PDF]
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S.-f. Hsu, P. J. O'Connell, V. A. Klyachko, M. N. Badminton, A. W. Thomson, M. B. Jackson, D. E. Clapham, and G. P. Ahern Fundamental Ca2+ Signaling Mechanisms in Mouse Dendritic Cells: CRAC Is the Major Ca2+ Entry Pathway J. Immunol., May 15, 2001; 166(10): 6126 - 6133. [Abstract] [Full Text] [PDF]
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F. Di Virgilio, P. Chiozzi, D. Ferrari, S. Falzoni, J. M. Sanz, A. Morelli, M. Torboli, G. Bolognesi, and O. R. Baricordi Nucleotide receptors: an emerging family of regulatory molecules in blood cells Blood, February 1, 2001; 97(3): 587 - 600. [Abstract] [Full Text] [PDF]
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