The mannose receptor fails to enhance processing and presentation of a glycoprotein antigen in transfected fibroblasts

Catherine E. Napper and Maureen E. Taylor1

Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

Received on February 28, 2004; revised on June 3, 2004; accepted on June 4, 2004


    Abstract
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 Abstract
 Introduction
 Results
 Discussion
 Materials and methods
 References
 
One function proposed for the mannose receptor found on dendritic cells as well as on macrophages and hepatic endothelial cells is in enhancing uptake and processing of glycoprotein antigens for presentation by major histocompatibility complex (MHC) class II molecules. In this study, a direct assessment of the possible role of the mannose receptor in this process was made in the absence of other endocytic receptors that can internalize glycoproteins. Presentation of RNase A and B peptides was compared in transfected fibroblasts coexpressing the mannose receptor and MHC class II molecules. RNase B bears a high-mannose oligosaccharide and is a ligand for the mannose receptor, whereas RNase A is not glycosylated and is taken up by pinocytosis. Incubation of RNase A or B with the transfected cells resulted in identical stimulation of ribonuclease-specific T cells, indicating that endocytosis of the glycosylated protein by the mannose receptor does not enhance presentation of this antigen. The postulated role of the mannose receptor in presentation of glycoprotein-derived antigen is reevaluated in light of these results.

Key words: antigen presentation / endocytosis / mannose receptor / MHC class II


    Introduction
 Top
 Abstract
 Introduction
 Results
 Discussion
 Materials and methods
 References
 
In the adaptive immune response, peptide antigens in complex with cell surface major histocompatibility complex (MHC) molecules are presented to the T cell receptor (Watts and Powis, 1999Go). Proteins derived from extracellular pathogens must be internalized by antigen-presenting cells and degraded in endosomal or lysosomal compartments. The resulting peptides are bound by MHC class II molecules for presentation to CD4-positive T cells. Dendritic cells, which are the major antigen-presenting cells, internalize antigens mainly by fluid-phase pinocytosis, although these cells also express several endocytic receptors that may participate in antigen uptake (Banchereau and Steinman, 1998Go).

One receptor proposed to be involved in uptake of glycoprotein antigens is the mannose receptor, which was initially characterized on macrophages and liver endothelial cells but has more recently been identified on dendritic cells (Avrameas et al., 1996Go). The mannose receptor binds and mediates endocytosis of glycoconjugates with terminal mannose, fucose, or N-acetylglucosamine residues. Calcium-dependent recognition of these sugars is mediated by several C-type carbohydrate-recognition domains in the extracellular region of the receptor (Taylor, 2001Go). The mannose receptor is thought to act as a molecular scavenger, binding and internalizing potentially harmful glycoconjugates. Endogenous ligands recognized by the receptor include lysosomal hydrolases, tissue plasminogen activator, and collagen propeptides, and many different pathogenic microorganisms have also been shown to bind to the receptor.

The ability of the mannose receptor to mediate internalization of glycoproteins suggests that peptides derived from glycoconjugates could associate with MHC class II molecules resulting in enhanced presentation to T cells. The presence of the mannose receptor on dendritic cells is consistent with this proposal, but no direct evidence for enhancement of uptake and presentation of glycoprotein antigens by the mannose receptor has been obtained. Studies showing that mannosylated proteins or peptides are presented more efficiently by dendritic cells than nonmannosylated proteins or peptides (Engering et al., 1997Go; Tan et al., 1997Go) do not provide conclusive evidence that the mannose receptor is involved in this process because dendritic cells are now known to express other mannose-specific receptors, such as DC-SIGN, which could be responsible for uptake of the glycoprotein antigens (Figdor, 2002Go). Thus a more direct assessment of the possible role of the mannose receptor in enhancing presentation of glycoprotein antigens is required.

In this study, the ability of the mannose receptor to enhance presentation of a glycoprotein antigen has been assessed directly. The results suggest that the receptor does not have a general role in processing and presentation of glycoprotein antigens.


    Results
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 Abstract
 Introduction
 Results
 Discussion
 Materials and methods
 References
 
A model system was developed to investigate the potential role of the mannose receptor in the adaptive immune response (Figure 1). Transfected fibroblasts expressing MHC class II molecules take up antigen by fluid-phase pinocytosis. Antigen is degraded into peptide fragments in acidified endosomal compartments and loaded onto MHC class II molecules for presentation at the cell surface. Peptide–MHC complexes are recognized by specific T cell clones, leading to T cell proliferation and release of interleukin-2 (IL-2), which can be assayed to give a measure of antigen presentation. Introduction of the mannose receptor into these cells avoids confounding effects of other sugar-binding receptors present in dendritic cells. Fibroblasts expressing both the receptor and MHC class II molecules would be able to take up glycosylated antigens by receptor-mediated endocytosis as well as fluid-phase pinocytosis, and the mannose receptor is predicted to increase uptake of glycosylated antigens resulting in enhanced presentation and increased IL-2 release.



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Fig. 1. A model system for direct assessment of the contribution of the mannose receptor to presentation of glycoprotein antigens. TCR, T cell receptor.

 
Ribonuclease (RNase) exists in two forms, RNases A and B, which have identical amino acid sequences but differ by the presence of a high-mannose oligosaccharide attached to Asn-34 of RNase B (Carr and Roberts, 1986Go). Thus RNase B can be taken up by mannose receptor-mediated endocytosis, whereas RNase A is not. Mouse MHC class II IAk molecules present peptides from RNase (Mallissen et al., 1984Go; Miller and Germain, 1986Go), so if the mannose receptor does play a role in antigen presentation, cells expressing both mannose receptor and MHC class II IAk molecules should present peptides from RNase B more efficiently than peptides from RNase A.

Processing and presentation of RNases A and B were first compared in cells not expressing the mannose receptor. Mouse fibroblasts (L cells) transfected with MHC class II IAk (Germain et al., 1985Go) were incubated with increasing concentrations of RNase A or B. RNase-specific T cells were used to recognize complexes of MHC class II and RNase peptide 43–56 presented at the surface of the L cells (Lorenz et al., 1988Go). IL-2 release in response to antigen presentation was quantified using an enzyme-linked immunosorbent assay (ELISA). For both RNase A and B, concentration-dependent release of IL-2 is seen up to an antigen concentration of about 10 µg/ml, above which no further increase in IL-2 production occurs (Figure 2). Identical responses are produced with RNases A and B, indicating that fibroblasts process these two proteins at similar rates. Thus RNases A and B are appropriate test antigens for studying whether the mannose receptor can enhance antigen uptake and presentation.



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Fig. 2. Antigen processing and presentation by L cells expressing MHC class II. L cells expressing MHC class II IAk together with RNase-specific T cells were incubated with RNase A or B for 48 h prior to harvesting of supernatant. IL-2 concentration in the supernatant was measured using ELISA.

 
Attempts to express the mannose receptor in the L cells expressing MHC class II molecules were unsuccessful. Several different vectors were used, but only low levels of mannose receptor were expressed, and uptake of mannosylated ligands was too low to use these cells for testing presentation of glycosylated antigens. The reasons for this low level of expression are unclear, but failure to achieve expression of DEC-205, another member of the mannose receptor family, in mouse L cells expressing MHC class II IEk has been reported previously (Mahnke et al., 2000Go). Because it was not possible to express the mannose receptor in the L cells, expression of MHC class II IAk molecules in a rat-6 fibroblast cell line stably expressing the mannose receptor was carried out.

The best rat-6 cell line expressing both mannose receptor and MHC class II IAk processes and presents RNase less efficiently than the L cell line (Figure 3). However, no IL-2 release is detected when the cells are fixed with paraformaldehyde before incubation with antigens (Figure 3b) and cells not expressing MHC do not stimulate any release of IL-2 (Figure 3d), indicating that the MHC class II presentation pathway is functioning in the doubly transfected cells. The levels of antigen processing and presentation were sufficient for comparison between RNases A and B to be made. When IL-2 release was measured 16 h, 24 h, and 48 h after incubation of the doubly transfected rat-6 cell line with antigens and T cells (Figure 3), no difference was observed between the responses to RNases A and B at any of the three incubation times. Thus RNase B is not presented any more efficiently than RNase A.



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Fig. 3. Antigen processing and presentation by cells expressing the mannose receptor and MHC class II. Rat-6 cells expressing MHC class II IAk and the mannose receptor together with RNase-specific T cells were incubated with RNase A or B for (a) 16 h, (b) 24 h, or (c) 48 h prior to harvesting of supernatant. Rat-6 cells expressing mannose receptor only (d) were incubated for 24 h. IL-2 concentration in the supernatant was measured using ELISA. Coexpression of MHC class II (e, g) and mannose receptor (f, h) in all cells is documented by staining permeabilized (e, f) and nonpermeabilized cells (g, h) with labeled antibodies. Scale bar represents 20 µm.

 
Characterization of mannose receptor function showed that the doubly transfected rat-6 cells mediate efficient internalization and degradation of 125I-labeled RNase B as well as 125I-labeled mannose–bovine serum albumin (BSA) (Figure 4), so the possibility that expression of MHC class II molecules in these cells affects mannose receptor function can be ruled out. Thus even though the mannose receptor mediates uptake of RNase B, presentation of this mannosylated antigen is not enhanced compared to that of RNase A.



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Fig. 4. Uptake and degradation of ligand by cells expressing the mannose receptor and MHC class II. Rat-6 cells expressing the mannose receptor and MHC class II IAk were preincubated with (a) 125I-RNase B at 2 µg/ml or (b) 125I-mannose-BSA at 1 µg/ml for 30 min at 4°C. Untransfected rat-6 cells (c) were preincubated with 125I-RNase B. Following incubation at 37°C for the time periods indicated, radioactivity associated with cells (open symbols) and acid soluble fragments in the medium (closed symbols) was analyzed. Triangles represent values at 5 h when a 50-fold excess of unlabeled mannose-BSA was present.

 

    Discussion
 Top
 Abstract
 Introduction
 Results
 Discussion
 Materials and methods
 References
 
The experiments presented herein allowed a direct assessment of the role of the mannose receptor in presentation of glycoprotein antigens. Because the results show that the mannose receptor does not enhance processing and presentation by MHC class II molecules of a mannosylated antigen RNase B, previous indirect evidence for a role of the receptor in enhancing presentation of antigens by dendritic cells needs to be reexamined. In particular, the possibility that another endocytic mannose-specific C-type lectin, DC-SIGN, was responsible for the effects observed needs to be considered.

Two previous studies linking the mannose receptor to enhanced antigen presentation involved experiments with monocyte-derived dendritic cells and mannosylated BSA or mannosylated peptide antigens (Engering et al., 1997Go; Tan et al., 1997Go). Both studies showed that mannosylated antigens are presented more efficiently than nonmannosylated forms. However, although the presence of the mannose receptor on the dendritic cells was documented, no direct link between the mannose receptor and the enhanced presentation of the mannosylated antigens was demonstrated. Involvement of the mannose receptor was assumed because mannan, which inhibits binding to the mannose receptor, blocks the enhanced presentation. However, it is now known that DC-SIGN, which has the same monosaccharide specificity as the mannose receptor and is inhibited by mannan, is expressed at higher levels than the mannose receptor on monocyte-derived dendritic cells (Mitchell et al., 2001Go; Turville et al., 2002Go). DC-SIGN mediates endocytosis of mannosylated and fucosylated ligands, including mannose-BSA (Frison et al., 2003Go; Guo et al., 2004Go). In addition, studies showing that peptides derived from an internalized anti-DC-SIGN antibody are efficiently presented by MHC class II molecules provide evidence for a role of DC-SIGN in antigen processing and presentation (Engering et al., 2002Go). Thus DC-SIGN could have been responsible for the increased presentation of mannosylated antigens seen in the studies with monocyte-derived dendritic cells.

For the mannose receptor to have a role in processing and presentation of glycoprotein antigens, ligands internalized by the receptor would have to be efficiently routed to compartments containing MHC class II molecules. The mannose receptor releases its bound ligand in early endosomes and recycles to the cell surface (Wileman et al., 1984Go). Several studies have shown that the mannose receptor does not enter late endosomal or lysosomal compartments containing MHC class II molecules (Mahnke et al., 2000Go; Tan et al., 1997Go). Thus although the mannose receptor could certainly enhance uptake of glycosylated antigens, it is unlikely to route them efficiently to MHC class II compartments. In fact, lack of response to one glycoprotein tumor antigen, MUC1, has been attributed to uptake by the mannose receptor. Inhibition experiments with mannan and a mannose receptor-specific antibody suggest that MUC1 is internalized into dendritic cells by the mannose receptor, but it is retained in early endosomes and not transported to compartments containing MHC class II molecules (Hiltbold et al., 2000Go).

In contrast to the early endosomal targeting of the mannose receptor, complexes of dendritic cell receptors DC-SIGN or DEC-205 with specific antibodies are targeted to late endosomal/lysosomal compartments containing abundant MHC class II molecules (Engering et al., 2002Go; Mahnke et al., 2000Go). A three-amino-acid motif, EDE, found in the cytoplasmic tail of DEC-205 but not the mannose receptor, mediates this deeper routing. The cytoplasmic domain of DC-SIGN also contains a three-acidic-residue motif, EEE, but it is not yet known whether this motif is required for targeting of DC-SIGN to late endosomes. This deeper internalization into the cell is likely to explain why DC-SIGN and DEC-205 are effective in enhancing antigen presentation by MHC class II molecules. It should be pointed out, however, that although DEC-205 is related in structure to the mannose receptor, it does not bind mannose or other sugars; thus, unlike DC-SIGN, DEC-205 could not be responsible for processes attributed to the mannose receptor (Taylor, 1997Go).

Other evidence for involvement of the mannose receptor in antigen processing represents a more specialized case. Internalization of lipoarabinomannan by the mannose receptor on monocyte-derived dendritic cells leads to delivery of this glycolipid antigen to compartments containing CD1b molecules that bind and present the antigen at the cell surface (Prigozy et al., 1997Go). Colocalization of the mannose receptor and CD1b in intracellular vesicles is observed. Mannan inhibits presentation of lipoarabinomannan, but in this case, an antiserum against the mannose receptor also inhibits the process. Thus involvement of the mannose receptor in this specialized case of uptake and presentation of a glycolipid antigen seems more plausible than a general role for the receptor in processing and presentation of glycoprotein antigens.

Analysis of mannose receptor knockout mice indicates that the major function of the receptor is in clearance of endogenous proteins bearing high-mannose oligosaccharides, such as lysosomal enzymes that are released as part of the inflammatory response (Lee et al., 2002Go). These mice exhibit defects in clearance of mannosylated glycoproteins by the liver and accumulate several lysosomal enzymes and other inflammatory glycoproteins in the serum. In addition, the knockout mice are no more susceptible than wild-type mice to infection by either Pneumocystis carinii or Candida albicans, suggesting that although these pathogens can bind to the mannose receptor in vitro, the receptor does not play an important role in the immune response against them (Swain et al., 2003Go; Lee et al., 2003Go). Thus the results presented here showing that the mannose receptor is unlikely to play a general role in processing and presentation of glycoprotein antigens are consistent with evidence that the primary physiological role of the receptor is in clearance.


    Materials and methods
 Top
 Abstract
 Introduction
 Results
 Discussion
 Materials and methods
 References
 
Mouse L cell line RT7.3 expressing MHC class II IAk was kindly provided by Dr. R. Germain, National Institutes of Health (Germain et al., 1985Go). T cell clone TS12 (RNase specific, recognizing amino acids 43–56) (Lorenz et al., 1988Go) was a gift of Dr. P. Allen, Washington University. Type X-II RNase A and RNase B were from Sigma-Aldrich (St. Louis, MO). RNase B was purified on Concanavalin A-Sepharose (Sigma-Aldrich) to remove RNase A contaminant (Kennedy and Rosevear, 1973Go). RNase A and Concanavalin-A purified RNase B were dialyzed against water, lyophilized, redissolved in water, and filter-sterilized. Transfected rat-6 cells or mouse L cells were plated in duplicate at a density of 3 x 104/well in 100 µl assay medium (RPMI medium supplemented with 2 mM glutamine and 10% fetal calf serum) in 96-well tissue-culture plates. After incubation at 37°C for 4 h, aliquots (50 µl) of RNase A or B dilutions in assay medium were added to each well, followed by 105 TS12 T cells in 100 µl assay medium. In some experiments, the fibroblasts were fixed with paraformaldehyde (Harlow and Lane, 1988Go) prior to addition of antigens and T cells. After incubation at 37°C for 16–48 h, cell medium was harvested, and IL-2 production was determined using the OptEIA mouse IL-2 ELISA kit (BD Biosciences, San Diego, CA).

Production of rat-6 fibroblast cell lines stably transfected with the human mannose receptor has been described (Taylor et al., 1990Go). cDNA clones for murine MHC class II IAK{alpha} and IAKß were provided by Dr. C. Benoist, INSERM. DNA coding for each MHC class II IAK chain was cloned into the expression vector pIREhyg2 (Invitrogen, Carlsbad, CA). A 1:1 of mixture of IAK{alpha} and IAKß expression vectors (5 µg each) was transfected into rat-6 cells expressing the mannose receptor using the calcium phosphate method (Wigler et al., 1979Go). Following incubation with the calcium phosphate–DNA coprecipitate for 4 h at 37°C, cells were grown overnight in Dulbecco's modified Eagle's medium containing 10% fetal calf serum, before selection was initiated by inclusion of 400 µg/ml hygromycin in the medium.

After ~2 weeks, colonies were isolated by trypsinization using cloning cylinders. Cells expressing functional MHC class II molecules were identified by assaying presentation of RNase A. Coexpression of MHC class II and mannose receptor was confirmed by immunofluorescence. Paraformaldehyde-fixed cells were incubated with a 1:1 mixture of monoclonal anti-mannose receptor antibody (BD Biosciences) labeled with Zenon Alexa Fluor 594 (Molecular Probes, Eugene, OR) and monoclonal anti-MHC I-Ak {alpha}-chain antibody (BD Biosciences) labeled with Zenon Alexa Fluor 488.

RNase B and mannose30-BSA (E-Y Labs, San Mateo, CA) were iodinated with Na125I (Amersham Pharmacia, Little Chalfont, UK) using the chloramine T method (Greenwood et al., 1963Go). Analysis of uptake and degradation of iodinated ligands was performed as described previously (Mellow et al., 1988Go).


    Acknowledgements
 
We thank Kurt Drickamer for helpful discussions and comments on the manuscript. This work was supported by a grant from the Mitzutani Foundation for Glycoscience and Wellcome Trust Grant 041845.


    Footnotes
 
1 To whom correspondence should be addressed; e-mail: mt{at}glycob.ox.ac


    Abbreviations
 
BSA, bovine serum albumin; ELISA, enzyme-linked immunosorbant assay; IL, interleukin; MHC, major histocompatibility complex; RNase, ribonuclease


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 Introduction
 Results
 Discussion
 Materials and methods
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