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Laboratoire Allergie, Centre Recherche du CHUM, Campus Notre-Dame, Université de Montréal, Montréal, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, GM-CSF, and IL-6 by
iDCs. 4N1K, a peptide derived from the CD47-binding site of
thrombospondin, also inhibits cytokine release. The inhibition of IL-12
and TNF- is IL-10-independent inasmuch as IL-10 production is
down-modulated by CD47 mAb and blocking IL-10 mAb fails to restore
cytokine levels. CD47 ligation counteracts the phenotypic and
functional maturation of iDCs in that it prevents the up-regulation of
costimulatory molecules, the loss of endocytic activity, and the
acquisition of an increased capacity to stimulate T cell proliferation
and IFN-
production. Interestingly, regardless of CD47 mAb treatment
during DC maturation, mature DC restimulated by soluble CD40 ligand and
IFN-, to mimic DC/T interaction, produce less IL-12 and more IL-18
than iDCs. Finally, CD47 ligation on iDCs does not impair their
capacity to phagocytose apoptotic cells. We conclude that following
exposure to microorganisms, CD47 ligation may limit the intensity and
duration of the inflammatory response by preventing inflammatory
cytokine production by iDCs and favoring their maintenance in an
immature state. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by T cells and NK cells,
enhancing NK cell cytotoxicity and promoting the development of
cytotoxic T cells (7). Due to their capacity to produce
IL-12, it is generally accepted that DCs are critically positioned to
initiate the Th1 immune response required for the clearance
of several pathogens (8).
Because of its potentially deleterious effects, the inflammatory
response must be coordinated with mobilization of antiinflammatory
mechanisms that will allow the return to the steady state. These may
down-regulate IL-12 production and/or inhibit the maturation of
immature DCs (iDCs) into potent T cell stimulators. Inhibitors of IL-12
include IL-4, IL-10, IL-13, TGF-ß, PGE2,
glucocorticoids, as well as phagocytic receptors CR3, FcR, and
scavenger receptors (1, 9, 10, 11, 12, 13, 14, 15). IL-10, produced by various
cell types including DCs themselves, may inhibit DCs maturation
(16); moreover, IL-10-treated DCs were found to induce
tolerance in naive T cells (17) or to bias their
development into Th2 effectors (18, 19). TGF-ß and
glucocorticoids have also been recently found to alter the maturation
of DCs in response to stimulation by bacterial products (20, 21).
CD47 Ag, also known as integrin-associated protein, is a widely
expressed multispan transmembrane protein that is physically and
functionally associated with
vß3 integrin, the
vitronectin receptor (22). Indeed,
CD47- cell lines expressing
vß3 do not bind
vitronectin-coated beads (23), and CD47-deficient mice
rapidly die of Escherichia coli peritonitis, a phenomenon
directly associated with a reduction in leukocyte activation in
response to ß3, but not
ß2, integrin ligation (24). CD47
has also been implicated in leukocyte transendothelial migration
(25, 26).
In this report, we show that CD47 is functionally expressed on human DCs. Ligation of CD47 by mAb or a synthetic peptide derived from its natural ligand, i.e., thrombospondin (TSP) (27, 28, 29), inhibits cytokine production and the maturation of iDCs in response to bacterial stimulation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant human IL-4, soluble CD40 ligand, and GM-CSF were
kindly provided by Immunex (Seattle, WA) and Dr. D. Bron (Institut
Bordet, Brussels, Belgium), respectively. IL-12 was a generous gift
from Dr. M. Gately (Hoffmann-LaRoche, Nutley, NJ), and IFN- was
obtained from Genzyme (Boston, MA). Staphylococcus aureus
Cowan I strain (SAC) was used at 0.02% (w/v; Pansorbin,
Calbiochem-Behring, La Jolla, CA). Anti-CD47 mAb B6H12 (mouse IgG1) and
neutralizing anti-IL-10 mAb (clone 19 F1.1) were obtained from
American Type Culture Collection (Manassas, VA). The anti-CD47 mAb
2D3 (mouse IgG1) was kindly provided by Dr. E. Brown (University of
California, San Francisco, CA). Isotype-matched negative control mAb
(mouse IgG1) was prepared in our laboratory.
F(ab')2 of CD47 mAb were prepared using a Pierce
(Rockford, IL) commercial kit. The 4N1K peptide (KRFYVVMWKK) and 4NGG
(KRFYGGMWKK) were obtained from Genosys (The Woodlands, TX); 4N1K
corresponds to the C-terminal domain of TSP, and 4NGG is a control
mutant (27). FITC-labeled BSA was purchased from Sigma
(St. Louis, MO).
Cell purification and culture conditions
Generation of monocyte-derived DCs. PBMCs were isolated by density gradient centrifugation of heparinized blood from healthy volunteers using Lymphoprep (Nycomed, Olso, Norway). Enriched monocytes were prepared by cold aggregation as described (30), followed by one cycle of rosetting with S-2-aminoethylisothiouronium bromide (Aldrich, Milwaukee, WI)-treated SRBC to deplete residual T and NK cells. Monocyte purity was shown to be >95% by flow cytometry (FACScan, Becton Dickinson, Mountain View, CA) using PE-conjugated anti-CD14 mAb (Ancell, London, Ontario).
Human monocyte-derived iDCs were prepared exactly as described (31) except that two-thirds of culture medium was replaced by fresh medium containing GM-CSF and IL-4 every other day, and nonadherent cells were harvested at day 5. Upon microscopic analysis, >98% nonadherent cells presented cellular projections. Analysis by flow cytometry revealed that preparations consisted in a homogenous (>96%) population of CD2-, CD14low/-, CD16-, CD40+, CD54+, CD80low, CD83low/-, CD86+, HLA-DR+ large cells, and <1% CD3+, CD19+, or CD56+ cells could be detected.
DCs cultures were performed in complete serum-free HB101 medium (Irvine Scientific, Santa Ana, CA) and supplemented with 2 mM glutamine, 1 mM sodium pyruvate, 10 mM HEPES, 100 IU penicillin, and 100 µg/ml streptomycin. DCs were cultured at (0.5 x 106/ml) in 24-well flat-bottom Falcon plates (Becton Dickinson).
Mature DCs (mDCs) were generated by stimulating day 5 monocyte-derived DC (0.5 x 106/ml) in HB101 medium with SAC (0.02% w/v) for 2 days in the presence of GM-CSF and IL-4 as above.
T Lymphocytes and allogeneic MLR. Highly purified T cells were obtained from the monocyte-depleted PBMC by rosetting with 2-aminoethylisothiouronium bromide-treated SRBC, followed by treatment of rosette-forming cells with Lympho-Kwik T (One Lambda, Los Angeles, CA) following manufacturer’s recommendations. Cell purity was assessed by flow cytometry using PE-conjugated anti-CD3, anti-CD4, or anti-CD8 mAbs (Ancell) and was shown to be >98%.
These T cells (106/ml) used as responder cells were stimulated in 96-well flat-bottom microplates (Falcon) with different numbers of mitomycin C-treated DCs. All cultures were performed in complete RPMI 1640 medium (BioWhittaker, Walkersville, MD) containing 2 mM L-glutamine, 1 mM sodium pyruvate, 10 mM HEPES, 100 IU penicillin, 100 mg/ml streptomycin (BioWhittaker), and 10% FCS. Culture supernatant was collected at day 4, and cytokine content was determined.
DNA synthesis was assessed by adding 1 µCi/well of [methyl-3H]thymidine (10 Ci/mmol; Amersham, Arlington Heights, IL) during the last 16 h of culture. Triplicate cultures were then harvested onto glass fiber filters, and the radioactivity was counted using liquid scintillation.
Cytokine measurement
IL-12 p70 release was assessed by a two-site sandwich ELISA
using mAb 20C2 as the capture mAb and HRP-coupled mAb 4D6 as detection
probe. Both mAbs were generously provided by Dr. M. Gately
(Hoffmann-LaRoche). The sensitivity of the assays was 6 pg/ml. IFN-
was measured by a sandwich solid-phase RIA using two anti-IFN-
mAbs as previously described. TNF-, GM-CSF, and IL-10 were measured
using a sandwich ELISA or RIA as previously described (30, 32). IL-13 was measured using a sandwich ELISA using rat
anti-IL-13 mAb (clone 5A2; American Type Culture Collection) as
capture mAb and a polyclonal rabbit anti-IL-13 Ab (Accurate
Chemicals, Westbury, NY) as a detecting probe. IL-6, IL-8, IL-18, and
TGF-ß ELISA kits were purchased from R&D Systems (Minneapolis, MN).
All the measurements were performed in duplicate.
Ag uptake assay
Two identical aliquots of DC were washed and resuspended (106/ml) in complete HB101 culture medium at 37°C or 4°C (ice-cold). An equal volume of BSA-FITC (50 µg/ml final concentration; Sigma) was then added and cells were incubated for 30 min. Ag uptake was stopped by extensive washing using cold PBS containing 1% BSA and 10 mM sodium azide before analysis with a FACScan (Becton Dickinson). Negative controls were the experiments performed at 4°C. For testing the effect of CD47 engagement on endocytosis, anti-CD47 mAb or isotype-matched control (IgG1) (10 µg/ml) mAbs were added during the incubation with BSA-FITC.
Phagocytosis of apoptotic cells
B cells from chronic lymphocytic leukemia patients were isolated by density gradient centrifugation of heparinized blood followed by one cycle of rosetting with S-2-aminoethylisothiouronium bromide (Aldrich)-treated SRBC to deplete T cells. B cell purity was shown to be >98% by flow cytometry (FACSort, Becton Dickinson). Freshly purified B cells from chronic lymphocytic leukemia patients were stained with PKH26 red fluorescent cell linker (Sigma) according to the manufacturer’s instructions before induction of apoptosis by culture for 16 h in the presence of hydrocortisone (5 x 10-4 M). More than 95% cells appeared apoptotic as determined using FITC-annexin V/PI staining. Cells were washed and were given to iDCs (2 x 105/ml) as a phagocytic meal (10 apoptotic cells per one iDC) for 3 h at 4°C (control) or 37°C, in the presence of anti-CD47 mAb (B6H12, 10 µg/ml) or its isotype-matched control. Endocytosis of PKH26-stained B cells was determined by FACS after gating on live DCs.
Flow cytometry analysis
CD47 surface expression was assessed using a two-step procedure. Briefly, cells were first incubated for 1 h at 4°C with a biotinylated mouse anti-CD47 mAb (B6H12) or class-matched negative control mAb (5 µg/ml). After washing, cells were incubated with PE-labeled streptavidin (Ancell) for 1 h at 4°C. Stained cells were analyzed using FACScan (Becton Dickinson). All other FITC- or PE-conjugated mAbs were purchased from Ancell.
Statistical analysis
The paired t test was used to determine statistical significance of the data.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first demonstrated CD47 expression on human monocyte-derived
iDCs and bacteria-stimulated mDCs. As previously reported, all
monocytes coexpressed CD14 and CD47 (33). CD14 expression
was drastically reduced during the process of monocyte differentiation
into iDCs in the presence of GM-CSF and IL-4, while CD83 was slightly
induced (Fig. 1
). As shown in Fig. 1, CD47 remained highly expressed on iDCs and was not modulated following
SAC-induced maturation. Mature DCs became CD14-,
CD47+, and CD83bright.
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We next evaluated the effect of CD47 ligation by soluble mAb on
cytokine production by maturing DCs. iDCs stimulated for 24 h with
SAC produced large amounts of proinflammatory cytokines (Fig. 2). As seen, CD47 engagement potently
suppressed IL-12 (n = 13, p < 0.0001),
TNF- (n = 13, p < 0.0001), IL-6
(n = 8, p < 0.05), and GM-CSF
(n = 6, p < 0.04) production. CD47
ligation did not inhibit the production of IL-8 nor alter the viability
of DCs, which was >80%, as revealed by trypan blue staining. Note
that spontaneous release of TGF-ß was not affected by SAC stimulation
regardless of the presence of CD47 mAb.
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production was dose
dependent, and significant suppression was seen with as little as 0.5
µg/ml of 2D3 or B6H12 mAbs directed against different CD47 epitopes
(34) (Fig. 3A).
Because FcR ligation reportedly suppresses IL-12 production by
monocytes (15), we excluded this mechanism by showing that
F(ab')2 still inhibited cytokine release by
maturing DCs (Fig. 3B). Finally, because TSP is a reported
ligand of CD47, we examined the effect of 4N1K, a peptide corresponding
to the CD47 binding region of TSP (27) on IL-12 and
TNF- production. As depicted in Fig. 3C, 4N1K inhibited
SAC-induced cytokine release by maturing DCs, whereas the control
mutant peptide 4NGG remained inactive.
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Inhibition of cytokine production by CD47 ligation was IL-10
independent and not overcome by IFN-
Among the products released by macrophages and DCs following
stimulation by bacterial products, IL-10 is known to be an autocrine
inhibitor of proinflammatory cytokine production (9, 16).
Therefore, we determined whether CD47 mAb-mediated suppression of
cytokines during DC maturation resulted from increased endogenous IL-10
production. We found that CD47 ligation suppressed by 72%
(n = 7, p < 0.03) IL-10 release by
SAC-stimulated iDCs (Fig. 4A).
To further exclude a possible role for IL-10 in CD47 mAb inhibitory
effects, a neutralizing anti-IL-10 mAb was added to SAC-stimulated
cultures. In agreement with the suppression of IL-10 release by CD47
ligation, blocking of IL-10 failed to restore IL-12 and TNF-
production in these cultures (Fig. 4B).
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has been reported to provide an efficient cosignal for IL-12
p70 production by DCs stimulated by CD40 ligand or bacterial products
such as SAC or LPS (35). Therefore, we examined whether
IFN- could restore cytokine release in CD47 mAb-treated maturing
DCs. As shown in Table I, CD47 engagement
significantly suppressed IL-12, TNF-, and IL-10 in the presence of a
high dose of IFN- (500 U/ml), whereas IL-8 secretion still remained
unaltered.
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Upon stimulation with bacterial products, iDCs undergo several
phenotypic and functional changes, a process known as DC maturation and
leading to the development of fully competent Ag-presenting and
costimulatory cells (1, 2). We found that CD47 ligation
during SAC stimulation of iDCs significantly altered their maturation
(Fig. 5 and
6). The SAC-induced down-regulation of
the monocyte marker CD14 and up-regulation of the DC marker CD83 were
impaired in CD47 mAb-treated cells (Fig. 5). CD47 mAb also inhibited
the up-regulation of HLA-DR and of the costimulatory molecules CD40,
CD54, CD80, and CD86. Functionally, DC maturation is associated with a
marked reduction of the endocytic capacity. As seen, CD47 mAb-treated
DCs retained a higher capacity to uptake FITC-conjugated BSA. Similar
results were observed by using 4NIK peptide (C.E.D. and M.S.,
unpublished observations).
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). DCs that had matured in the presence
of control Ab were strikingly better than iDCs at inducing T cell
proliferation (10-fold better) and IFN- or IL-13 production. In
contrast, DCs that had been incubated with anti-CD47 mAb together
with SAC were much less efficient to initiate T cell proliferation
(3-fold less than mDCs) and not better than iDCs to induce IFN- and
IL-13 production. Note that IL-4 and IL-5, two typical Th2 cytokines,
could not be detected under these experimental conditions (data not
shown).
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production may not entirely result
from decreased IL-12 production during DC maturation. Indeed,
regardless of CD47 ligation during DC maturation, mDCs produced about
10 times less IL-12 than iDCs after restimulation with soluble CD40
ligand and IFN- (used to mimic T cell/DCs interaction), (Fig. 7). In contrast, we found that mDCs
produced about twice more IL-18 than iDCs, and this was also not
modulated by anti-CD47 treatment.
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Immature DCs, as opposed to mDCs, are reported to be professional
phagocytes that efficiently eliminate apoptotic and necrotic cells
during early step of inflammatory process (36). Because
our data indicated that CD47 ligation during bacterial stimulation of
iDCs inhibited cytokine secretion and prevented their acquisition of a
mature functional phenotype, we determined whether CD47 mAb treatment
would inhibit the phagocytic activity of iDCs. As shown in Fig. 8, CD47 mAb-treated iDCs phagocytosed
apoptotic B cells as efficiently as untreated DCs, extending and
confirming previous reports that CD47 mAb failed to interfere with the
phagocytosis of aged neutrophils by.macrophages (37).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-6, and GM-CSF by maturing
DCs, without affecting that of IL-8 and TGF-ß. Second, it prevents
the phenotypic and functional changes associated with DC maturation,
including the up-regulation of MHC class II Ags, costimulatory
molecules, and the acquisition of a potent T cell stimulatory activity.
IL-10 and TGF-ß were reported to exert similar effects on the
maturation of DCs induced by bacterial products (16, 20).
It is unlikely that anti-CD47 mAb acts by increasing the endogenous
production of these inhibitory cytokines. Indeed, their production is
either suppressed (IL-10) or unaffected (TGF-ß), and inclusion of
neutralizing Abs to IL-10 (Fig. 4
) or TGF-ß (data not shown) does not
restore the cytokine production of anti-CD47-treated cells.
Cytokine production by maturing DCs is also known to be suppressed by
PGE2 (38) or by pretreatment of iDCs
with low doses of LPS (39, 40). Similar to anti-CD47
mAb, these treatments reduce IL-12 production by maturing DCs and
generate mDCs that have a impaired capacity to induce IFN-
production by allogeneic T cells; however, unlike anti-CD47 mAb,
they do not prevent DCs to acquire increased T cell stimulatory
activity.
In agreement with Kapsenberg and colleagues, we found that human mDCs
produce 10-fold less IL-12 (and TNF-) than iDCs (41),
regardless of anti-CD47 mAb treatment. This contrasts with the
increased capacity of mDCs, as compared with iDCs, to stimulate IFN-
production by adult T cells (Fig. 6), a phenomenon which is
IL-12-dependent (Ref. 42 and data not shown). Moreover,
mDCs are better at inducing IFN- production because they express
higher levels of membrane-bound (CD80, CD86, CD54, and CD58) and
soluble molecules (IL-18) that costimulate the effects of IL-12
(43). Inclusion of anti-CD47 mAb during DC maturation
did not affect the IL-12- nor the IL-18-producing capacity of mDCs,
whereas it reduced their capacity to stimulate T cell proliferation and
IFN- production; probably by inhibiting the up-regulation of
membrane bound costimulatory molecules. This interpretation is
supported by two observations. First, even in the presence of exogenous
IL-12 (50 pM), the production of IFN- by T cells stimulated with
anti-CD47-treated DCs remains significantly lower than that induced
by control mAb-treated DCs (44 ± 7 ng/ml of IFN- compared with
76 ± 11 ng/ml; mean ± SEM of four experiments,
p < 0.05). Second, anti-CD47-treated DCs also
display a reduced rather than enhanced capacity to induce IL-13
production by T cells (Fig. 6), a cytokine whose production is
suppressed by IL-12 (44).
The inhibition of DC maturation may be biologically and clinically relevant as illustrated in a recent study showing that Plasmodium falciparum may use this strategy to defeat the human immune response (45). Malaria-infected human erythrocytes reportedly exert the same effects on LPS-induced maturation of iDCs as those described in the present study. Interestingly, the ability of intact malaria-infected erythrocytes to inhibit DC maturation was linked to the expression on their surface of still undefined parasite-derived proteins binding to CD54, CD36, and TSP. It is possible that TSP bound to infected erythrocytes may engage CD47 expressed on DCs and alter their ability to induce effective T cell-dependent immunity. It is also worthy to note that P. falciparum was shown to express a TSP-related adhesive protein, capable of binding to human cells (46).
TSP is an homotrimeric extracellular matrix protein that is produced not only by platelets but also by monocytes and macrophages (27). TSP is transiently expressed at high concentration in damaged and inflamed tissues (28, 29), and there is growing evidence that it has potent antiinflammatory properties. These may involve at least two distinct mechanisms. First, TSP binds to immature TGF-ß and activates it into a potent immunoregulatory cytokine (47). TSP-deficient animals display diffuse inflammatory lesions that are corrected by treatment with the active form of TGF-ß and are reminiscent of those observed in TGF-ß-deficient animals (48). The second mechanism involves the binding of TSP to CD47 expressed on inflammatory cells and/or APC. In addition to the present findings, engagement of CD47 by TSP reportedly inhibits IL-12 production by human monocytes stimulated via T cell-dependent mechanisms or bacterial products (49). Whether or not some pathogens exploit the CD47-mediated inhibition of DC maturation, our observations are consistent with a role for this molecule and its ligand (TSP) in regulating the early stages of the innate and adaptive immune response.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. M. Sarfati, University of Montreal, Laboratoire Allergie (M4211-K), Centre Recherche CHUM, Campus Notre-Dame, 1560 Sherbrooke Street East, Montreal, Quebec, H2L 4 M1, Canada. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell; iDC, immature DC; mDC, mature DC; TSP, thrombospondin; SAC, Staphylococcus aureus Cowan I strain.
Received for publication August 30, 1999. Accepted for publication December 3, 1999.
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References |
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vß3-dependent ligand binding. J. Cell Biol. 123:485.vß3 and 4ß1 integrins regulates lymphocyte migration on vascular cell adhesion molecule 1. Eur. J. Immunol. 27:3242.[Medline]
priming of human monocytes differentially regulates gram-positive and gram-negative bacteria-induced IL-10 release and selectively enhances IL-12p70, CD80, and MHC class I expression. J. Immunol. 161:2011.vß5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188:1359. and prostaglandin E2. Blood 91:3112. and to bacterial IL-12 inducers: decreased ability of mature dendritic cells to produce IL-12 during interaction with T helper cells. J. Immunol. 163:3231.
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S. Latour, H. Tanaka, C. Demeure, V. Mateo, M. Rubio, E. J. Brown, C. Maliszewski, F. P. Lindberg, A. Oldenborg, A. Ullrich, et al. Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-{alpha}: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation J. Immunol., September 1, 2001; 167(5): 2547 - 2554. [Abstract] [Full Text] [PDF]
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Z. Li, L. He, K. E. Wilson, and D. D. Roberts Thrombospondin-1 Inhibits TCR-Mediated T Lymphocyte Early Activation J. Immunol., February 15, 2001; 166(4): 2427 - 2436. [Abstract] [Full Text] [PDF]
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M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors J. Immunol., October 15, 2000; 165(8): 4624 - 4631. [Abstract] [Full Text] [PDF]
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C.-C. J. Chang, A. Wright, and J. Punnonen Monocyte-Derived CD1a+ and CD1a- Dendritic Cell Subsets Differ in Their Cytokine Production Profiles, Susceptibilities to Transfection, and Capacities to Direct Th Cell Differentiation J. Immunol., October 1, 2000; 165(7): 3584 - 3591. [Abstract] [Full Text] [PDF]
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) or
2D3 (
) CD47 mAbs, (B) B6H12 F(ab')2, and
(C) 4N1K (derived from the CD47-binding site of TSP) or
4NGG (mutant peptide), each at 50 µg/ml. The dotted line in
A indicates SAC-induced cytokine production in the
presence of a high dose (20 µg/ml) of isotype-matched control Ab
(CIg). A and B show one representative
experiment of five, and C shows the means ± SD of
four experiments. *, p < 0.05.
