Published online before print April 14, 2006
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,
* Clinical Immunology Unit and
Cancer Gene Therapy Unit, Cancer Immunotherapy & Gene Therapy Program, H. San Raffaele Scientific Institute, Milano, Italy;
Istituto Clinico Humanitas, Rozzano, Italy;
Centro di Eccellenza per l’Innovazione Diagnostica e Terapeutica (IDET), Institute of General Pathology, University of Milan, Italy; and
¶ Vita-Salute San Raffaele University, Milano, Italy
1 Correspondence: Cancer Immunotherapy & Gene Therapy Program, Clinical Immunology Unit, H. San Raffaele Scientific Institute, via Olgettina 58, Milano 20132, Italy. E-mail: rovere.patrizia{at}hsr.it
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Key Words: Toll-like receptor • systemic lupus erythematosus • lipopolysaccharide • apoptosis • inflammation
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Interaction between soluble, innate factors and the reciprocal influences on their functions is not well understood. The classical PTX, such as C-reactive protein (CRP) and serum amyloid protein (SAP), are known to bind to C1q and activate the complement cascade [10
]. A similar role has been attributed to PTX3, which shares structural homology in the PTX domain with the classical PTX. Immobilized PTX3 binds C1q and activates the complement cascade [11
]. Classical PTX and components of the complement pathways are predominantly produced in the liver [12
]. In contrast, C1q and PTX3 are produced by cells of the innate immune system, such as macrophages and dendritic cells (DC) [13
, 14
]. Immature DC are a major source of C1q [14
], and PTX3 production by DC and macrophages is induced in response to microbial components such as lipopolysaccharide (LPS) [13
] and proinflammatory stimuli—tumor necrosis factor 
(TNF-). In addition, C1q and PTX3 have differing effects on the phagocytosis of apoptotic cells by professional phagocytes. C1q enhances phagocytosis of apoptotic cells [14
], and PTX3 has been described to inhibit phagocytosis by DC and macrophages [2
, 15
]. C1q and PTX3 are present at the sites of tissue inflammation and necrosis. Their cross-talk possibly has connotations for the safe clearance of dying tissue cells. In this study, we show that C1q and PTX3, produced from DC, together contribute to regulate the clearance of bystander dying cells.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cells
Peripheral blood mononuclear cells were obtained from buffy coats of healthy donors by sedimentation over Ficoll Hypaque as described [16
]. Monocytes were differentiated into DC by culture in RPMI 1640 (Gibco, Life Technologies, Italy) supplemented with 100 U/ml penicillin, 100 µg/ml streptomycin, 1.5 mM L-glutamine, and 10% heat-inactivated fetal calf serum (FCS) in the presence of granulocyte macrophage-colony stimulating factor (800 U/ml) and interleukin (IL)-4 (800 U/ml; BD Biosciences PharMingen, San Diego, CA) [17
]. The phenotype of the DC was monitored by flow cytometry, using fluorochrome-labeled monoclonal antibodies (mAb) against CD1a, CD14, CD40, CD83, CD86, human leukocyte antigen (HLA)-DR, and HLA-ABC surface markers (BD Biosciences PharMingen). Maturation of DC was induced by stimulation with LPS (10–1000 ng/ml; Sigma Chemical Co., St. Louis, CA), lipoteichoic acid (LTA; 10–1000 ng/ml, Invivogen, San Diego, CA), and peptidoglycan (PGN; 10 µg/ml, Fluka, Switzerland). HeLa and Jurkat cell lines were purchased from American Type Culture Collection (Manassas, VA) and maintained in culture in RPMI with 10% FCS.
Induction of apoptosis
Apoptosis was triggered by C-band ultraviolet light (UVC) irradiation (254 nm wavelength) at the dose of 3.5 mW/cm2/s for 60 s (HeLa cells) or of 1.8 mW/cm2/s for 45 s (Jurkat cells) followed by incubation of irradiated cells for up to 24 h. Induction and phase of apoptosis were verified by flow cytometry using fluorescein isothiocyanate (FITC)-conjugated annexin V and propidium iodide (PI; Bender MedSystem, GmbH, Austria) as per the manufacturer’s instructions. Confocal microscopy analysis was done using a Leica microscope in selected experiments, as described previously [2
].
Interaction of C1q and PTX3 with living and apoptotic cells
Apoptotic or viable HeLa and Jurkat cells (1x105) were incubated with various concentrations of C1q (5–100 µg/ml) or biotinylated human PTX3 (2.5–50 µg/ml) in a final volume of 50 µl phosphate-buffered saline (PBS) for 30 min at 4°C. C1q binding to cells was detected by staining with FITC-conjugated anti-C1q antibody (Dako, Denmark), and PTX3 was detected by subsequent incubation with streptavidin-FITC (BD Biosciences PharMingen) prior to flow cytometric analysis. When indicated, cells were incubated with C1q or PTX3 as above, washed, and chased for different time periods (0–24 h at 4°C or 37°C) before analysis. Moreover, in selected experiments, 1 x 105 apoptotic HeLa cells were incubated with PTX3 (10 or 50 µg/ml) or buffer alone for 30 min at 4°C. Cells were then washed with PBS containing bovine serum albumin (1%) and incubated with or without C1q (10 µg/ml) for 30 min at 4°C. Alternatively, for the coincubation experiments, C1q (10 µg/ml) and PTX3 (10 or 50 µg/ml) were added together to the apoptotic cells. C1q was then revealed with FITC-conjugated anti-C1q antibody. For confocal microscopy, apoptotic cells were incubated with C1q (10 µg/ml) and/or biotinylated PTX3 (50 µg/ml) simultaneously for 30 min at 4°C. Cells were then stained with FITC-conjugated anti-C1q antibody or streptavidin-FITC or -phycoerythrin (PE). Cells were adhered to polylysinated glass coverslips, washed, and fixed with 4% paraformaldehyde in PBS. Nuclei were counterstained with Hoechst 33342 (Molecular Probes, Invitrogen SRL, Italy). The coverslips were mounted on glass slides using Moviol and stored at 4°C until analysis.
Assessment of C3b deposition on apoptotic cells
Apoptotic HeLa cells were incubated with C1q, PTX3, or both for 1 h, followed by incubation with C1q-depleted serum supplemented with 10% heat-inactivated FCS at 37°C for 1 h. Detection of C3b on apoptotic cells was done using a purified mouse antibody anti-C3b (Research Diagnostics) and subsequent incubation with a FITC-conjugated goat anti-mouse antibody (BD Biosciences PharMingen). Assessment of C3b deposition on apoptotic cells was evaluated using flow cytometry.
Phagocytosis assay
Apoptotic HeLa cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) as described [8
]. Labeled apoptotic cells (5x105) were incubated with 2 x 105 DC in medium containing heat-inactivated serum alone or in the presence of C1q and PTX3 for varying time periods. Then, the cells were harvested, stained with PE-conjugated mAb anti-CD11c to label DC, and analyzed by flow cytometry. DC were gated according to forward-scatter (FSC) properties and CD11c positivity. The DC, which bound or phagocytosed apoptotic cells, were identified as double-positive cells [3
].
DC maturation
Maturation of DC was induced by stimulation with LPS (10–1000 ng/ml; Sigma Chemical Co.). C1q and/or PTX3 were added at a final concentration of 50–100 µM. Apoptotic HeLa cells (1x106) were added to a final DC:apoptotic cell ratio of 1:4. After 24–48 h, the cells were harvested, and the expression of HLA-ABC, HLA-DR, and CD86 was assessed by flow cytometry using fluorochrome-conjugated mAb (BD Biosciences PharMingen). The supernatants were collected and stored frozen until cytokine quantification by enzyme-linked immunosorbent assay (ELISA).
Cross-presentation
Cross-presentation experiments were performed as described previously [18
]. Briefly, NIH-3T3 fibroblasts, transduced or not with MELAN-A/melanoma antigen-reactive T cell 1 (MART-1; 3T3M and 3T3, respectively), were committed to apoptosis by UVC irradiation (254 nm wavelength) at the dose of 1.8 mW/cm2/s for 45 s. Induction and phase of apoptosis were verified by flow cytometry using FITC-conjugated annexin V and PI (Bender MedSystem, GmbH). HLA-A2+ immature DC (2x104) were incubated with 5 x 104 apoptotic 3T3 and 3T3M fibroblasts per well in Iscoves’ modified Dulbecco’s medium (Gibco, Invitrogen SRL) with 10% inactivated human serum and IL-2 (50 Cetus units/ml) and challenged with 1 x 104 MT27–-35 MELAN-A/MART-1 epitope-specific CD8+ T cells for 24 h. LPS (10 ng/ml) was added for the last 16 h of culture. Parallel cross-presentation assays were run in the presence of C1q (50 µg/ml) and/or PTX3 (50 µg/ml). The supernatants were collected after 24 h and assessed for interferon-
(IFN-) by ELISA.
ELISA
C1q, in culture supernatants, was measured by ELISA using mouse mAb (Quidel, San Diego, CA) for coating and rabbit polyclonal antibodies anti-C1q (Dako) for detection. Samples were analyzed in duplicates, and C1q concentration was determined by reference to standard curves. To measure PTX3 concentrations in the culture supernatants, a sandwich ELISA (Alexis Italia, Vinci) was used as per the manufacturer’s instructions. This assay is highly sensitive and specific; no cross-reactions were observed with other PTX and in particular, with the CRP or SAP [19
]. IL-12, IFN-, TNF-, and IL-10 levels in culture supernatants were measured using a commercial Duotech ELISA kit (R&D Systems, Minneapolis, MN) according to the manufacturer’s instructions
Statistical analysis
Statistical analysis was performed using the two-tailed Student’s t-test for unpaired samples with unequal variance. P values less than 0.05 were considered statistically significant.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Figure 1. C1q and PTX3 bind stably to apoptotic cells. Apoptotic HeLa cells were incubated with C1q and biotinylated PTX3 (x-axis) for 1 h at 4°C. Bound C1q and PTX3 were detected by using FITC-conjugated polyclonal rabbit anti-C1q antibodies and FITC-conjugated streptavidin, respectively. C1q and PTX3 were found to bind to apoptotic cells in a dose-dependent manner (filled symbols) (A, B). Viable cells bound low amounts of C1q and no PTX3 (open symbols). Apoptotic cells were incubated with C1q and PTX3 for 1 h at 4°C and 37°C, washed, and chased for the indicated periods of time. Bound C1q and PTX3 were detected using FITC-conjugated polyclonal rabbit anti-C1q antibodies and FITC-conjugated streptavidin, respectively. Binding of C1q and PTX3 was higher at 37°C than at 4°C (C, D). Results are representative of three independent experiments. MFI, Mean fluorescence intensity.
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Figure 2. C1q and PTX3 exhibit different patterns of binding to apoptotic cells. Viable and apoptotic cells were incubated with C1q and biotinylated PTX3 and analyzed by confocal microscopy. Bound C1q and PTX3 were detected using FITC-conjugated polyclonal rabbit anti-C1q antibodies and FITC-conjugated streptavidin, respectively. The apoptotic nuclei were counter-stained with Hoechst 33342 (blue). The binding of C1q (green) to the apoptotic cells displayed a patchy distribution (A, right panel). PTX3 (green) bound to the apoptotic cells in a diffuse, reticular pattern (B, right panel). Viable cells are also shown (A, B, left panels). Apoptotic cells were incubated with C1q and biotinylated PTX3 simultaneously, and detection of the binding was done using FITC-conjugated polyclonal rabbit anti-C1q antibodies and PE-conjugated streptavidin, respectively. C1q and PTX3 bound to different sites on the apoptotic cells (C). Results are from representative, routine experiments.
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Figure 3. PTX3 inhibits C1q binding on apoptotic cells. Apoptotic HeLa cells were incubated with C1q alone (10 µg/ml) or in the presence of PTX3 (10 µg/ml and 50 µg/ml) or ß2-GPI (60 µg/ml), and C1q binding was assessed. C1q binding to apoptotic cells was inhibited significantly in the presence of PTX3 (P<0.05), and ß2-GPI did not change C1q deposition (A). No change in C1q binding was seen when the apoptotic cells were preincubated with PTX3 (A). ELISA plates were coated with anti-C1q mAb followed by addition of C1q, biotinylated PTX3, or a mixture of both. After washing, plates were incubated with streptavidin-FITC to detect PTX3 (P<0.01), which was detected only in the wells where the mixture of C1q and PTX3 was added (B). No signal was elicited in the wells where either protein was added alone (B). Samples were analyzed in duplicates. Results are representative of three independent experiments. Asterisks refer to the statistical significance versus controls: *, P < 0.05; **, P < 0.01. O.D. (a.u.), Optical density (arbitrary units); w/o, untreated.
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Figure 4. DC produce C1q and PTX3. Immature DC were left alone or stimulated with LPS (10 ng/ml), LTA (10 ng/ml), and PGN (10 µg/ml) for up to 48 h. Supernatants were collected at the indicated time-points, and C1q and PTX3 were measured by ELISA. Production of C1q by immature DC was increased upon stimulation with LPS, LTA, or PGN (A). Secretion of PTX3 by DC was triggered by LPS, LTA, and PGN (B). Immature DC did not produce significant PTX3 (B). Samples were analyzed in duplicates. Results representative of three independent experiments are depicted as mean ± SD of duplicate samples.
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Figure 5. C1q-induced C3b deposition and phagocytosis of apoptotic cells are inhibited by PTX3. Apoptotic cells were treated with C1q alone or in the presence of PTX3 followed by incubation with C1q-depleted serum. mAb to C3b were used to detect C3b deposition on the apoptotic cells. C1q treatment induced C3b deposition on apoptotic cells (A). The C3b deposition was inhibited significantly in the presence of PTX3 (A). DC were incubated with CFSE-labeled apoptotic cells alone (–) or in the presence of C1q, PTX3, or both, and phagocytosis/binding was assessed by flow cytometry. DC were gated as CD11c+ cells. A dot-plot of fluorescence 1 (FL-1) versus FSC was used to quantify the phagocytosis/binding of apoptotic cells (Apo) identified as FL-1-positive DC. C1q induced a dose-dependent increase in the phagocytosis/binding of apoptotic cells by DC (B). The uptake of apoptotic cells observed with C1q was inhibited significantly in the presence of PTX3 (C, D). Results are presented as mean ± SD and are representative of three independent experiments performed with DC from different donors. Asterisks refer to the statistical significance versus controls: *, P< 0.05, **, P < 0.01.
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Effects of C1q and PTX3 on the cross-presentation of antigens from apoptotic cells by DC
DC are known to acquire antigens from apoptotic cells and activate antigen-specific CD8+ T cell responses, a process known as cross-presentation. DC that phagocytosed apoptotic murine fibroblasts expressing MELAN-A/MART-1 antigen (3T3M) activated MELAN-A/MART-1-specific CD8+ T cells, as evaluated measuring the production of IFN- (Fig. 6A
). In agreement with our recent data [18
], PTX3 significantly inhibits the cross-presentation of MELAN-A/MART-1 antigens derived from apoptotic 3T3M fibroblasts by DC, even in the presence of C1q (Fig. 6A)
. In contrast, C1q did not change the cross-presentation of apoptotic 3T3M fibroblast antigens (Fig. 6A)
. The coculture of MELAN-A/MART-1-specific CD8+ T cells with DC, which phagocytosed wild-type murine fibroblasts (3T3), did not result in production of IFN- (Fig. 6A)
. In addition, the production of IFN- by T cells stimulated with DC loaded with MELAN-A/MART-1 MT25–37 peptide did not change in the presence of C1q or PTX3, indicating that they do not interfere with the presentation of a synthetic, soluble sequence, which does not depend on internalization or intracellular processing for major histocompatibility complex-restricted presentation (Fig. 6B)
.
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Figure 6. Effects of C1q and PTX3 on cross-presentation of apoptotic cell-associated antigens by DC. Wild-type NIH-3T3 fibroblasts (3T3) and fibroblast transduced with MELAN-A/MART-1 (3T3M) were induced to apoptosis by UVC irradiation. HLA-A2+ DC (2x104) were incubated with 1 x 104 antigen-specific CD8+ T cells and 5 x 104 apoptotic 3T3 and 3T3M fibroblasts (apo) for 24 h. C1q (50 µg/ml), PTX3 (50 µg/ml), and the MELAN-A/MART-1 peptide MT27–35 (3 µM) were added as indicated. The supernatants were collected after 24 h and assessed for IFN- by ELISA. MELAN-A/MART-1-specific, HLA-A2-restricted CD8+ T cells secrete significant amounts of IFN- when challenged with DC, which phagocytosed and processed apoptotic fibroblasts expressing the MELAN-A/MART-1 antigen (3T3M; A). Stimulation of MELAN-A/MART-1-specific, HLA-A2-restricted CD8+ T cells with DC, which phagocytosed apoptotic, wild-type fibroblasts (3T3), did not alter the baseline production of IFN- elicited by unchallenged DC (A). Induction of IFN- by T cells challenged with DC, which phagocytosed apoptotic 3T3M fibroblast, did not change in the presence of C1q and was decreased by PTX3 (A). Production of IFN- by T cells stimulated with DC loaded with MT27–35 peptide was not altered by C1q or PTX3. Results are represented as mean ± SD of samples analyzed in triplicate. *, P< 0.05, statistically significant values.
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and IL-10 by DC treated with LPS alone [18
]. C1q alone did not elicit any IL-12 p70 or TNF- production from DC (Fig. 7A
and 7B
). However, C1q significantly increased the secretion of IL-12 p70 by DC stimulated with LPS (Fig. 7A
and 7C)
, and TNF- was not altered (Fig. 7B)
. PTX3 alone did not influence the IL-12 p70 production by DC stimulated with LPS (Fig. 7C)
. However, PTX3 significantly inhibited the increased production of IL-12 p70 induced by C1q (Fig. 7C)
. Apoptotic cells suppress the IL-12 p70 production by maturing DC (Fig. 7D)
. The inhibitory effect of apoptotic cells on IL-12 p70 production by maturing DC was partially reversed in the presence of C1q; PTX3 abrogated this effect (Fig. 7D)
. C1q did not have a detectable effect on the production of TNF- and IL-10 by DC stimulated with LPS alone or in the presence of apoptotic cells (Fig. 7
, E and F, and data not shown). PTX3 increased the production of IL-10 by DC stimulated with LPS, apoptotic cells, and C1q (Fig. 7E)
, and TNF- levels were unaffected (Fig. 7F)
.
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Figure 7. PTX3 inhibits the C1q-induced increase in IL-12 p70 production by DC, which were stimulated with LPS alone (100 ng/ml) or in the presence of apoptotic HeLa cells (apo) or left untreated for 24 h. C1q (50 µg/ml) and PTX3 (50 µg/ml) were added as indicated. Supernatants were evaluated for the production of TNF-, IL-10, and IL-12 by ELISA. C1q increased the production of IL-12 p70 by LPS-stimulated DC (A), and TNF- production did not change (B). PTX3 inhibited the effect of C1q on the production of IL-12 by DC stimulated with LPS alone (C) or in presence of apoptotic cells (D). Apoptotic cells decrease the production of IL-10 (E) and TNF- (F) by LPS-stimulated DC. C1q did not alter the effect induced by apoptotic cells (E, F). PTX3 increased the production of IL-10 by DC stimulated with LPS, apoptotic cells, and C1q (E), and the TNF- did not change (F). Results are represented as mean ± SD of three independent experiments performed with DC from different donors. *, P< 0.05; **, P< 0.01, statistically significant values.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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[23
]. They also produce key factors of the innate immune system (Fig. 4
and refs. [13
, 14
]). C1q and the complement cascade in particular have nonredundant functions in the recognition and immune response to microorganisms. PTX3 has an important role in immune defense to Aspergillus, and elevated levels of PTX3 have been reported in a number of inflammatory and infectious conditions [24
25
26
]. In addition to the antimicrobial functions, complement factors and PTX have a protective effect against autoimmunity in vivo. Deficiencies of the early components of the classical complement pathway (C1q, C1r, C1s, C4, and C2) are associated with development of SLE. C1q-deficient mice develop SLE and accumulate apoptotic cells in renal glomeruli, which emphasizes the importance of C1q in the clearance of cellular debris [1 ]. Moreover, patients with SLE have a well-characterized defect in the production of PTX during active phases of the disease [27 ]. Administration of CRP is reported to have an ameliorating effect on autoimmune nephritis in mouse models [28 , 29 ], suggesting a direct, protective role on tissue damage. It has been demonstrated earlier that C1q and PTX3 bind to apoptotic cells [2 , 30 31 32 ]. In this study, we show that C1q and PTX3 bind to apoptotic cells, remaining stably associated to the apoptotic cell membrane (Figs. 1 and 2) . C1q has been reported to bind PTX3 immobilized on plastic [11 ]. However, we did not observe any colocalization of the two molecules on apoptotic cells (Fig. 2C) .
It has been proposed that C1q and other opsonins prevent autoimmunity and maintain self-tolerance by supporting the efficient clearance of apoptotic material [8 , 33 ]. The in vivo relevance of the complement system in maintaining immune tolerance is well-established, as homozygous deficiency of any of the classical pathway proteins (C1q, C4, C2) is strongly associated with the development of SLE [34 ]. Deficiencies of these factors are, however, exceedingly rare, and complement deposition in inflamed tissues suggests a possibly harmful role of complement; indeed, complement activation is regulated tightly in physiological conditions to prevent immune-mediated tissue damage [34 ]. C1q associates to apoptotic cells, even in the absence of other innate factors [21 , 31 ], but this event is highly enhanced by the presence of natural immunoglobulin M antibodies [35 , 36 ]. Mevorach and co-workers [37 ] have shown that complement opsonization of apoptotic cells, besides targeting them to DC for phagocytosis, induces tolerant, immature DC, which are able to migrate to lymph nodes. The amount of complement, in particular, of iC3b [37 ], which associates to dying cells, is crucial to determine the final outcome of the phagocytic clearance in vivo. Dying cells are a source of autoantigens, which in predisposed, genetic backgrounds, is sufficient to induce and maintain systemic autoimmunity. Disease induction in vivo depends on the presence of environmental factors, including proinflammatory signals, in addition to dying cells [38 , 39 ].
Here, we show that C1q increases phagocytosis by DC (Fig. 5B) but does not increase cross-presentation of apoptotic cell-associated antigens (Fig. 6A) . In contrast, PTX3 decreases phagocytosis of apoptotic cells (Fig. 5C and ref. [2 ]) and the cross-presentation of apoptotic cell-associated antigens (Fig. 6A , and ref. [18 ]). Preincubation of apoptotic cells with PTX3 has been reported to enhance C1q deposition and complement activation on apoptotic cells [40 ]. Here, we observe that when both factors are present simultaneously in the microenvironment, possibly mimicking what happens in the close proximity of DC or macrophages upon recognition of pathogen-associated molecular patterns, PTX3 can sequester soluble C1q, decreasing the activation of C3 on apoptotic cells (Fig. 5A) and the C1q-mediated phagocytosis (Fig. 5C) . These events can represent an additional level of protection against autoimmunity. In addition, apoptotic cells inhibited the IL-12 p70 production by DC stimulated with LPS. This inhibition was reversed in the presence of C1q, but this effect of C1q abated in the presence of PTX3 (Fig. 7D) .
In conclusion, apoptotic cells in the steady-state are phagocytosed by macrophages and immature DC, which clear dying cells and induce tolerance to autoantigens [41 ]. When microbial components are present, DC initiate their maturation program. This event may favor the loss of tolerance against peripheral antigens, especially if dying cells are present in the microenvironment [42 , 43 ]. We show that in physiological conditions, maturing DC also secrete and produce innate factors in the microenvironment, including C1q and PTX3. Both factors per se are capable of anchoring to ligands in the microenvironment such as the ones exposed on apoptotic cells. Furthermore, PTX3, produced by DC, will interact with the C1q in the DC milieu, inhibiting complement activation on apoptotic cells and phagocytosis by maturing DC and cross-presentation of self-antigens. Thus, the interaction of C1q and PTX3 could have important implications for the safe disposal of cell debris under inflammatory conditions.
Received August 10, 2005; revised February 24, 2006; accepted March 8, 2006.
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