Human dendritic cells shed a functional, soluble form of the mannose receptor
Reina Jordens,
Allan Thompson,
Reinout Amons and
Frits Koning
Department of Immunohaematology and Blood Bank, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, The Netherlands
Correspondence to:
F. Koning
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Abstract
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Human monocyte-derived dendritic cells (DC) use mannose receptor (MR)-mediated endocytosis for efficient antigen capture and targeting to the endosomal/lysosomal compartment. Active biosynthesis of the MR takes place in such cells. We now report that a substantial percentage (up to 20%) of these newly synthesized MR are secreted into the culture medium. The secretion of the soluble MR (sMR) was found to be proportional to the rate of synthesis. The addition of the inflammatory mediator lipopolysaccharide (LPS) to DC, known to induce maturation, strongly reduced MR synthesis, expression and shedding of the MR. The sMR is ~10 kDa smaller than the membrane-bound form, but contains an intact N-terminus, indicating the lack of the cytoplasmic and transmembrane region. The sMR appeared to be directly generated from the cell-bound form, indicative of proteolytic cleavage. Importantly, the sMR has maintained its mannose-binding properties since it was capable of binding a mannosylated ligand. The high amount of sMR released by DC and its ability to bind mannosylated ligand might indicate that this molecule plays a role in the transport of mannosylated proteins from the site of inflammation to other parts of the body. Whether that contributes to the generation of immune responses remains to be determined.
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Introduction
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Dendritic cells (DC) are the initiators of specific primary immune responses. In vitro immature DC differentiate from CD34+ cells (1) and monocytes isolated from human peripheral blood (24) in the presence of granulocyte macrophage colony simulating factor (GM-CSF) and IL-4 or IL-13. These immature DC are characterized by a high antigen uptake due to macropinocytosis and receptor-mediated endocytosis. One of those receptors is the mannose receptor (MR). Two types of MR are expressed by human DC. One shows high homology to the DEC-205 MR found in mice (5,6), whereas the other is similar to that expressed in human macrophages (7,8). The latter MR is a type I, 180 kDa transmembrane glycoprotein (7,9) that consists of five domains. First, an N-terminal cysteine-rich (CR) domain that binds sulphated glycoproteins or neoglycoproteins terminating in SO4-4GalNAcß1,4GlcNAcß1- (10,11). Second, a domain containing a fibronectin type II repeat with unknown function. Third, a series of eight tandem lectin-like carbohydrate recognition domains (CRD), responsible for the specific binding of mannose, fucose or N-acetylglucosamine. Finally, a hydrophobic transmembrane domain of 34 amino acids and a cytoplasmic C-terminal domain consisting of 41 amino acids, crucial for the endocytic and phagocytic function of the MR (12). This MR is expressed by tissue macrophages (13), subsets of endothelial cells (14), retinal pigment epithelium (15), Kaposi sarcoma cells (16), and (cultured) DC, macrophages and monocytes (17,18). This MR binds glycoconjugates terminating in mannose, fucose or N-acetylglucosamine in a calcium-dependent manner (8). These carbohydrates are normally not displayed in an exposed form on mammalian cells. Glycoproteins on the surface of many bacteria, fungi and parasites, however, are rich in mannose and N-acetylglucosamine, allowing specific uptake of such pathogens by MR+ antigen-presenting cells (APC).
A number of cell surface receptors have been reported to exist as soluble forms due to truncation of their cytoplasmic domains and transmembrane region. These soluble forms can be generated by limited proteolytical cleavage of the membrane-bound receptor (shedding) or by expression of an alternatively spliced mRNA (19,20). It has been postulated that soluble receptors may have physiological roles as carrier proteins since ligand-binding activity is retained in many of these truncated receptor molecules (21,22).
Recently, Martinez-Pomares et al. observed that a Fc chimeric protein that contained the CR domain of the murine macrophage MR specifically bound to cells in the germinal centers of lymphoid organs in mice (10). Based on that observation they speculated that a soluble form of the MR in complex with its mannosylated ligand could be directed to cells in the lymphoid organs that recognize the CR region of the MR. In this way a soluble MR (sMR) may transport antigens to APC that do not express the MR. In the present study we describe that such a sMR is shed by human DC.
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Methods
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Isolation of human DC from peripheral blood
DC were prepared according to the protocol of Sallusto and Lanzavecchia (2). Briefly, peripheral blood mononuclear cells were isolated from heparinized fresh buffy coats by flotation on Ficoll (Pharmacia, Uppsala, Sweden). After T cell depletion using triethanolamine-treated sheep red blood cells (Biotrading Benelux, Mijdrecht, The Netherlands), the cells were resuspended in HBSS (Gibco, Grand Island, NY) and allowed to adhere to six-well plates (Costar, Cambridge, MA). After 2 h at 37°C in a humidified CO2 incubator the non-adherent cells were removed with several wash steps with HBSS (Gibco). The adherent cells were cultured in IMDM (Gibco) supplemented with 10% FCS, 800 U/ml GM-CSF (kindly provided by Dr S. Osanto, Department of Clinical Oncology, Leiden University Medical Centre) and 1000 U/ml IL-4 (Genzyme, Cambridge, MA). At day 4, fresh culture medium containing 800 U/ml GM-CSF and 1000 U/ml IL-4 was added to the cultured DC. Unless stated otherwise the DC were used for experiments at day 5.
Surface iodination
Approximately 107 cells were harvested, washed 3 times with PBS and lactoperoxidase-catalyzed cell surface iodination was carried out as described previously (23,24). The surface iodinated cells were cultured in IMDM (Gibco), supplemented with 10% FCS, 800 U/ml GM-CSF and 1000 U/ml IL-4, and cultured for 648 h at 37°C in a humidified CO2 incubator.
Metabolic labeling
Approximately 107 cells were harvested and cultured in MEM without L-methionine (Gibco), supplemented with 10% FCS, 800 U/ml GM-CSF and 1000 U/ml IL-4. Labeling was performed during various time periods at 37°C in a humidified CO2 incubator in the presence of 1 mCi L-[35S]methionine 35S-Protein Labeling Mix (Nen Dupont, Dreiech, Germany).
Immunoprecipitation and SDSPAGE analysis
Labeled cells were lysed in 1 ml lysis buffer (0.5% NP-40, 50 mM TrisHCl, 150 mM NaCl, 0.1 mM PMSF, 10 mM iodoacetamide, 1 µg/ml leupeptin, 1 µg/ml chymostatin, 1 µg/ml antipain and 1 µg/ml pepstatin, pH 8.0). After an incubation for 30 min at 4°C the lysates were centrifuged at 13000 g for 15 min. at 4°C to remove insoluble material. Culture supernatants were passed over a 0.2 µm filter, spun at 100,000 g for 1 h at 4°C, and 0.1 mM PMSF, 10 mM iodoacetamide, 1 µg/ml leupeptin, 1 µg/ml chymostatin, 1 µg/ml antipain and 1 µg/ml pepstatin was added. The lysates and supernatants were precleared by adding 50 µl normal rabbit serum and 100 µl Protein ASepharose beads (Pharmacia), followed by gentle shaking at 4°C for 1 h. After removal of the beads the supernatants and the lysates were further precleared by sequential adding of 100 µl Protein ASepharose beads. Immunopreciptation was carried out with the mouse anti-human MR mAb D547 (kindly provided by Dr A. Lanzavecchia, Basel, Switzerland) and the mouse anti-HLA-DR mAb B8.11.2 (25) as described previously (4) followed by analysis on 7% SDSPAGE under reduced conditions. The gels were dried and autoradiography carried out at 70°C. Quantification was carried out on a Phosphor Imager.
Purification and amino acid sequencing
Precleared culture supernatant was mixed with mAb D547 immobilized on CNBrSepharose beads (Pharmacia). The beads were subsequently washed on a glass filter with 30 bed volumes 20 mM TrisHCl and 120 mM NaCl, pH 8.0; followed by 30 bed volumes 20 mM TrisHCl and 1 M NaCl; and finally 30 bed volumes 20 mM TrisHCl, pH 8.0 and 10 mM TrisHCl, pH 8.0. The bound material was subsequently eluted with 10% acetic acid, freeze-dried and taken up in reducing sample buffer. A SDSPAGE 7% gel was run and protein bands were detected with zinc staining (26). Gel slices containing the sMR were excised, and the proteins electroeluted and concentrated on 1% agarose prior to analysis by Edman degradation with a HP1100 protein sequencer (Hewlett Packard).
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Results
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Cultured DC release a soluble form of the MR
To investigate the expression of the MR, DC were metabolically labeled with [35S]methionine. Subsequently the MR was immunoprecipitated from the cell lysate and the culture supernatant with the MR-specific antibody D547 and analyzed on SDSPAGE (Fig. 1A
). Typically the MR from the DC cell lysate runs as a protein of 185 kDa. In contrast, a protein with an apparent mol. wt of 175 kDa was detected in the culture supernatant of the DC. As a negative control, similar immunoprecipitates were carried out with a lysate and culture supernatant of [35S]methionine-labeled EpsteinBarr virus-transformed B cells. In these immunoprecipitates no MR-specific bands were present (not shown). HLA class II molecules could be detected in the cell lysates of both DC and B cells but not in the culture supernatants (not shown). The difference in molecular weight between the MR receptor present in the cell lysate and the sMR in the culture supernatant was not due to a difference in the extent of N-linked glycosylation: both before and after removal of the N-linked glycans an ~10 kDa difference was observed between the cell-bound MR and the sMR (Fig. 1A
). From this we conclude that cultured DC release a truncated, presumably soluble form of the MR (sMR) in the culture supernatant.


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Fig. 1. Cultured DC release a soluble form of the MR. (a) SDSPAGE analysis of specific immunoprecipitates from cell lysates (lane 1 and 2) and supernatants (lane 3 and 4) of [35S] methionine-labeled DC with the MR-specific antibody D547. Labeling period was 4 h. The immunoprecipitates were either not treated (: lane 1 and 3) or treated with N-glycanase prior to SDSPAGE analysis (+: lane 2 and 4) as indicated. (b) SDSPAGE analysis of specific immunoprecipitates from cell lysates (lane 1 and 2) and supernatants (lane 3 and 4) of 125I-labeled DC that were cultured overnight after labeling. The immunoprecipitates were either not treated (: lane 1 and 3) or treated with N-glycanase prior to SDSPAGE analysis (+: lane 2 and 4) as indicated.
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Next we examined whether the sMR was derived from the membrane-bound, cell surface expressed MR. For this purpose DC were surface labeled with 125I and subsequently cultured for 24 h. Next the MR was immunoprecipitated from the cell lysate and the culture supernatant and analyzed on SDSPAGE (Fig. 1B
). Whereas in the cell lysate a MR receptor with a mol. wt of 185 kDa was present, a 175 kDa sMR was present in the culture supernatant of the cell surface labeled DC. Moreover, the extent of N-linked glycosylation is identical to that observed in metabolically labeled cells (Fig. 1A and B
). Together these results strongly indicate that the sMR is directly generated from cell surface expressed receptors.
The sMR has an intact N-terminus
Next we determined the N-terminal amino acid sequence of the sMR. For this purpose we immunopurified the sMR from the culture supernatant of DC cultures and sequenced the N-terminus by Edman degradation. The first 14 amino acids were sequenced and compared to the known sequence of the macrophage MR (27) (Table 1
). This analysis revealed an intact N-terminus and a strong sequence similarity between the N-terminal sequence of the sMR and the known sequence of the human macrophage MR, confirming that the sMR is a MR-like protein. Since the N-terminus of the sMR is identical to that of the cell-bound receptor, and the absence of the intracellular and transmembrane regions is predicted to result in an ~10 kDa smaller protein, these observations strongly suggest that the sMR is a C-terminal truncated form of the cell-bound receptor.
Kinetics of sMR shedding
Subsequently we analyzed the kinetics of the shedding of the MR. Monocytes cultured with GM-CSF and IL-4 differentiate into CD14, MR+ DC during 5 days of culture (2,4,17,28). FACS analyses of the cell surface MR expression revealed clear MR expression after 3 days of culture (Fig. 2
). The MR expression steadily increased during the culture period (Fig. 2
). To establish the relationship between culture time, biosynthesis and shedding of sMR, equal numbers of differentiating DC were taken at daily intervals and metabolically labeled overnight with [35S]methionine. Next the presence of the MR was measured in the cell lysate and supernatant by immunoprecipitation with the MR-specific antibody, followed by SDSPAGE and quantification of the MR bands using a Phosphor Imager (Fig. 2
). MR synthesis was detectable after 3 days of culture and steadily decreased to ~40% of the maximum value at day 7 (Fig. 2A
). Shedding was also first detected after 3 days of culture. The ratio of sMR:total synthesized MR first remained constant, followed by an increase of a factor of 2 (Fig. 2B
). FACS analysis indicated that the expression of the MR on the cell surface increased steadily over time. During the first phase of the culture period, therefore, the shedding of the sMR appears proportional to the synthesis of the MR, whereas at later time points the shedding increases.

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Fig. 2. Kinetics of total MR synthesis during DC culture. DC were taken at daily intervals and metabolically labeled overnight with [35S]methionine. The presence of the MR was measured in cell lysate and supernatant by immunoprecipitation with MR-specific antibody D547 followed by SDSPAGE and quantification of the intensity of the MR bands by a Phosphor Imager. (a) Total amount of MR synthesis (MR + sMR). (b) Ratio of sMR:total of MR synthesis. (c) Cell surface expression of the MR (mean fluorescence intensity) as determined by FACS analysis. The experiment shown is representative of three independent experiments. Observed values for release of sMR varied from 8 to 20% of total MR synthesis.
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We also performed pulsechase experiments. Metabolically labeled DC were chased for 48 h, and the presence of the MR and sMR receptor was determined after 24 and 48 h. After 24 h the majority (90%) of the MR was detected on the cells surface. After 48 h, however, the cell surface expression had diminished by a factor of 10 while the amount of sMR had increased by a factor of 7 (not shown). These results indicate that a large proportion of the MR is ultimately converted into sMR.
Lipopolysaccharide (LPS) induces a decrease of MR expression and shedding
Subsequently we determined the effect of the inflammatory mediator LPS, known to induce maturation of cultured DC. These mature DC have a reduced ability to capture antigens and a low MR expression (28). Therefore, the effect of LPS on the synthesis and shedding of the MR was studied. Day 5 DC were cultured with or without LPS for 16 h. Subsequently the cells were harvested and split into two equal aliquots. One of these was labeled with 125I followed by an additional 24 h culture period in order to measure release from the cell surface. The other aliquot was cultured for an additional 24 h in methionine-free medium supplemented with [35S]methionine in order to measure synthesis of the MR. Subsequently, the sMR and MR was immunoprecipitated from cell lysates and culture supernatant, analyzed on SDSPAGE and quantified on a Phosphor Imager (Fig. 3
). The addition of LPS to the DC culture reduced the MR expression to ~30% of that of the control DC (Fig. 3
), which was confirmed by FACS analysis (not shown). Similarly, the amount of shed sMR was reduced to 30% of that of the control (Fig. 3
). Even more dramatic is the effect of LPS on the biosynthesis of the MR (Fig. 3
) which was hardly detectable 16 h after the addition of LPS to the culture. As the result, no newly synthesized sMR was detectable in the culture supernatant of these LPS-treated DC (not shown).

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Fig. 3. Effect of LPS on total MR shedding and synthesis. DC were cultured in the presence or absence of LPS for 16 h and subsequently labeled with either 125I or [35S]methionine followed by an additional culture period of 24 h. Subsequently the presence of the MR was measured in cell lysate and supernatant by immunoprecipitation with the MR-specific antibody D547 followed by SDSPAGE. cell, cell lysate; sup, culture supernatant.
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Functional analysis of the sMR
The MR binds glycoconjugates terminating in mannose, fucose or N-acetylglucosamine via its CRD. To investigate if the sMR is able to bind mannosylated ligands we investigated whether the sMR and MR could be immunopurified from a DC cell lysate and culture supernatant with a MR ligand: mannosylated-BSA coupled to CNBrSepharose beads. The results of this analysis demonstrate that mannosylated-BSA as well as MR-specific antibody detect proteins of 185 and 175 kDa respectively in the cell lysates and culture supernatants of [35S]methionine- and 125I-labeled DC (Fig. 4
). In control EpsteinBarr virus-transformed B cells no such proteins were present (not shown). These results demonstrate that the sMR is a functional form of the MR.

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Fig. 4. Functional analysis of the sMR. SDSPAGE analysis of immunoprecipitates from cell lysates and culture supernatants of 125I surface-labeled (lanes 13) and 35S metabolically labeled (lane 46) DC. C, cell lysate; S, culture supernatant. Specific immunoprecipitations were carried out with either the MR-specific antibody D547 (lanes 1, 2, 5 and 6) or with mannosylated-BSA coupled to CNBrSepharose (M-BSA, lanes 3 and 4). No sMR or MR was detected in control immuoprecipitations with irrelevant antibodies or BSA-beads (not shown).
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Discussion
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The MR is present on only a limited number of cell types including macrophages and subsets of DC. Because it facilitates the endocytosis and subsequent delivery of antigens to MHC class II compartments (4,17), the MR plays an important role in the immune response against pathogens like Mycobacterium tuberculosis (29), Pneumocystis carinii (30), Candida albicans (31), Leishmania promastigotes (32) and Trypanosoma cruzi (33). It has been suggested that there may be another way by which the MR plays a role in the eradication of pathogens: via a soluble form of the MR that directs bound antigen to lymphoid organs (8,10). This is based on the observation that a chimeric protein containing the CR domain of the mouse macrophage MR fused to the Fc region of human IgG1 (CR-Fc) bound to macrophages in spleen marginal zone and lymph node subcapsular sinus, and to cells in B cell areas of splenic white pulp (10). After antigen stimulation the chimeric protein also bound to cells in germinal centers in spleen and lymph nodes (10). Moreover, kinetic analysis of the pattern of CR-Fc labeling in lymph nodes during a secondary immune response to ovalbumin showed that cells with CR-binding ligand expression migrated towards B cell areas and accumulate in developing germinal centers of draining lymph nodes (10). Thus, a soluble murine MR with intact CR and carbohydrate recognition domains could target glycoproteins from pathogens to cells in lymphoid organs that express a ligand for the CR domains of the receptor. More recent evidence has demonstrated that such a sMR is shed by murine macrophages and is present in mouse serum (34). This illustrates the existence of such sMR in vivo and such sMR could thus play a role in the induction of (humoral) immune responses against bacteria, fungi and parasites. Because the CR domain is conserved (86%) between human and murine forms of the MR (11) a human sMR could therefore have a similar function. We now provide evidence that such human sMR are generated by shedding from the cell surface of human monocyte-derived DC. These DC shed up to 20% of the synthesized MR. It is at present not clear how the human sMR receptor is generated from the cell surface expressed MR. It is conceivable that this is the result of protease activity since multiple proteolytic cleavage sites are present in the extracellular, membrane proximal part of the MR. Blocking studies with protease inhibitors, however, have so far failed to indicate which protease(s) are involved in the generation of the human sMR (not shown). Alternatively, cleavage may occur at an acid labile peptide bond (DP) near the transmembrane region. This will be the subject of further studies.
During inflammatory reactions monocytes and immature DC are recruited to the site of inflammation where they will endocytose antigens. Simultaneously, activation and maturation will result in the expression and shedding of MR by (monocyte-derived) DC. It is thus conceivable that during inflammation substantial amounts of the sMR are released at a site where high concentrations of ligands for the MR are present, presumably binding to both cells surface expressed receptors and the sMR. Whereas the endocytosed and processed antigens will be targetted to the draining lymph nodes due to migration of the mature APC, the sMR would facilitate the targeting of its bound antigen to other sites in the body, potentially aiding in the induction of an immune response.
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Acknowledgments
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We thank Drs M. C. A. A. Tan and P. Kluin for their advice, and Drs C. J. M. Melief, J. W. Drijfhout and F. Ossendorp for critical reading of the manuscript. This work was financially supported by the Netherlands Organization for Scientific Research grant 030-93-001.
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Abbreviations
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APC antigen-presenting cell |
CR cysteine-rich |
CRD carbohydrate recognition domain |
DC dendritic cell |
GM-CSF granulocyte macrophage colony stimulating factor |
LPS lipopolysaccharide |
MR mannose receptor |
sMR soluble mannose receptor |
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Notes
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Transmitting editor: G. Hämmerling
Received 11 February 1999,
accepted 2 July 1999.
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