Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received on February 4, 2002; revised on April 15, 2002; accepted on April 15, 2002
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Abstract |
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Key words: antigen uptake/C-type lectin/dendritic cells/glycosylated antigen
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Introduction |
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DCs are known to incorporate antigens by phagocytosis, macropinocytosis, and receptor-mediated endocytosis through a variety of putative antigen receptors having C-type lectin domains. At least two such receptors, DEC-205 and the macrophage mannose receptor (MMR), type I Ca2+-dependent C-type multilectins, appear to be involved in antigen uptake and processing (Jiang et al., 1995; Mahnke et al., 2000
; Sallusto et al., 1995
). Recently, many novel C-type lectins, such as DCIR (Bates et al., 1999
), Langerin (Valladeau et al., 2000
), DC-SIGN (Geijtenbeek et al., 2000
), Dectin-1 (Ariizumi et al., 2000b
), and Dectin-2 (Ariizumi et al., 2000a
), all type II transmembrane proteins, have also been reported to be expressed on DCs and Langerhans cells. Their contributions to antigen recognition and processing are not clear, although Langerin was shown to be an endocytic receptor (Valladeau et al., 2000
). Among them, MMR, DC-SIGN (Mitchell et al., 2001
), and Langerin were previously shown to be specific for mannose. Other C-type lectins expressed on DCs do not seem to recognize carbohydrates.
Mannose-specific recognition should be effective to incorporate and to process glycoproteins with high-mannose type carbohydrate chains expressed on pathogens and truncated or unprocessed N-glycans expressed by defective and apoptotic cells. However, none of these C-type lectins recognize galactose or N-acetylgalactosamine, which also seem to be important pathogenic substances. The macrophage galactose-type C-type lectin (MGL) has a binding capacity to galactose and N-acetylgalactosamine as monosaccharides and is a type II transmembrane glycoprotein that contains a single carbohydrate recognition domain. Murine MGL (mMGL) was originally detected on tumoricidal peritoneal macrophages (Sato et al., 1992) and human MGL (hMGL) was cloned from IL-2-treated peripheral blood monocytes (Suzuki et al., 1996
). The Mgl gene consists of ten exons and has been mapped to mouse chromosome 11 (Tsuiji et al., 1999
), and the MGL gene has been mapped to human chromosome 17p13.2. The chromosome localization of MGL is distinct from that of many C-type lectins, MMR, DEC-205, DCIR, langerin, DC-SIGN, and Dectin-1, previously claimed to be specific for DCs (Bates et al., 1999
; Kato et al., 1998
; Soilleux et al., 2000
; Valladeau et al., 2000
). mMGL is expressed on histiocytic macrophages but not on Langerhans cells (Imai et al., 1995
; Mizuochi et al., 1997
). However, it has not previously been examined whether or not DCs express MGL.
We have examined the expression of mMGL on bone marrow (BM)derived DCs by flow cytometry using mMGL-specific monoclonal antibody (mAb) LOM-14. We found that only immature DCs expressed high levels of mMGL and that such immature cells were also able to bind and uptake soluble polyacrylamides with clusters of GalNAc residues. We hypothesize that mMGL expressed on BM-derived immature DCs can function as a recognition and internalization molecule with distinct carbohydrate specificity from other DC lectins and potentially participates in the presentation of antigens bearing clusters of GalNAc.
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Results |
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Discussion |
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It has already been reported that many C-type lectins, such as MMR, DEC-205, DCIR, Langerin, DC-SIGN, Dectin-1, and Dectin-2, were expressed on DCs. None of them recognize Gal or GalNAc residues. Alterations in O-glycosylation such as an increased expression of T (Gal-GalNAc-Thr/Ser) and Tn (GalNAc-Thr/Ser) antigens are known to be associated with malignant cells. These epitopes are potential targets for antitumor immunity. It is suggested that terminal sialic acid residues of glycoproteins are lost and Gal or GalNAc residues are exposed on apoptotic cells (Savill, 1997). Structural alterations in O-glycans are known to occur during the differentiation, activation, and migration of T-lymphocytes (Baum et al., 1995
; Gillespie et al., 1993
; Lowe, 2001
; Reisner et al., 1976
). Therefore, cell surface receptors for truncated O-glycans should play important roles in the immune system in the protection from infection, antitumor immunity, and the clearance of apoptotic cells.
-GalNAc polymers were used to test whether cell surface mMGL on DCs functions as a lectin, because mMGL and hMGL were shown to have high affinity with clusters of O-linked GalNAc residues (Iida et al., 1999
;Yamamoto et al., 1994
).
-GalNAc polymers, but not ß-GlcNAc polymers, bind to immature DCs in a Ca2+-dependent and GalNAc-specific manner, but the binding of
-GalNAc polymers was not inhibited by Gal. This was probably due to differences in the affinity of mMGL expressed on the surfaces of DCs toward these monosaccharides. The mMGL expression profile clearly correlated with the profile of
-GalNAc polymer binding in day 6 and day 8 DC populations. Furthermore, flow cytometric analyses and confocal microscopic studies indicated that cells strongly reactive with
-GalNAc polymers expressed high levels of mMGL. Therefore, the binding of
-GalNAc polymers is highly likely to be mediated by mMGL although the presence of another lectin expressed in parallel with mMGL remains to be possible. It has been suggested by several observations that mMGL can participate in carbohydrate binding at the cell surfaces. First, macrophages elicited by thioglycolate treatment are able to internalize glycoproteins through mMGL (Kawakami et al., 1994
). Second, CTLL-2 T lymphoma cells transfected with mMGL cDNA acquire the ability to bind galactose or lactose-conjugated microspheres (Hosoi et al., 1998
; Ichii et al., 1997
). Third, K562 human erythroleukemia cells transfected with hMGL are able to internalize
-GalNAc polymers in an MGL-dependent manner (Fujita et al., unpublished data). Recently, we have also found that hMGL expressed on monocyte-derived immature DCs was involved in the uptake of
-GalNAc polymers (Higashi et al., 2002).
Immature DCs that expressed high levels of mMGL bound and internalized carbohydrate antigens. The binding of -GalNAc polymers was not inhibited anti-mMGL mAb LOM-14 or LOM-8.7, although it has already been reported that mAb LOM-8.7, but not LOM-14, blocked the binding of galactosylated poly-L-lysine to recombinant mMGL (Kimura et al., 1995
). On the other hand, the internalization of
-GalNAc polymers was partially inhibited by both mAb LOM-14 and mAb LOM-8.7. It has already been shown that mAb LOM-14 was internalized by immature DCs (data not shown). Furthermore, internalized
-GalNAc polymers colocalized with mAb LOM-14-reactive mMGL as observed by confocal microsopy. Therefore, it is strongly suggested that
-GalNAc polymers were internalized with mMGL. However, taking into account the fact that Gal and anti-mMGL blocking mAb LOM-8.7 could not inhibit the binding of
-GalNAc polymers, we cannot exclude a possibility that mMGL on DCs functions in accordance with another molecule having high affinity to GalNAc polymers.
The internalization of mMGL was expected from the fact that mMGL had tyrosine-based amino acid sequences (YENL) involved in endocytosis in the cytoplasmic domain (Sato et al., 1992). Macrophages elicited by thioglycolate were previously shown to internalize glycoproteins through mMGL (Kawakami et al., 1994
). The antigens internalized by immature DCs were known to enter the endocytic pathway and transported to early endosomes, late endosomes, or lysosomes (Banchereau and Steinman, 1998
). In immature DCs, newly synthesized MHC class II molecules accumulate in late endosomes or lysosomes (MIICs). During the DC maturation, antigen processing and peptide loading are known to occur in MIICs (Inaba et al., 2000
; Pierre et al., 1997
; Turley et al., 2000
). The MMR and DEC-205 are involved in the antigen presentation. The MMR mainly releases its ligand in early endosomes and recycles to plasma membranes (Engering et al., 1997
; Tan et al., 1997
), although some of them are also located in MIICs (Prigozy et al., 1997
). In contrast to the MMR, DEC-205 targets to MIICs and is more efficient than the MMR in antigen presentation (Mahnke et al., 2000
). Thus, the delivery of antigens into MIICs is considered important event in the antigen presentation. To assess whether mMGL is involved in antigen presentation, the fate of
-GalNAc polymers bound to the surface of immature DCs was examined by confocal laser scanning microscopy.
-GalNAc polymers were internalized and colocalized with MGL, LAMP-1, and MHC class II. These results suggest that mMGL is also capable of targeting antigens to MIICs and presenting effectively. When DCs were cultured with
-GalNAc polymers for a day in our preliminary experiment, their maturation did not occur unless a maturation signal was provided by LPS, judging from the expression levels of cell surface markers, such as MHC class II, CD86, and DEC-205. Therefore, glycan binding to mMGL alone does not seem to provide a maturation signal.
In conclusion, we observed that mMGL, which is involved in the recognition and internalization of glycoproteins, is transiently expressed on BM-derived immature DCs. mMGL should be useful as a novel marker for immature DCs.
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Materials and methods |
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Generation of BM-DCs
BM-DCs were generated as previously described with slight modifications (Inaba et al., 1992). Briefly, BM cells were collected and erythrocytes were lysed by ammonium chloride treatment (day 1). Cells (1.0 x 106 cells/ml) were plated in 24-well plates in 1 ml per well of RPMI1640 medium supplemented with 10% fetal calf serum, 10 mM HEPES, 50 µM 2-ME, 100 U/ml penicillin, 100 µg/ml streptomycin, and 1000 U/ml recombinant murine GM-CSF (Kirin Brewery, Takasaki, Japan). On day 4, the top two-thirds of the media were removed and replaced with fresh medium. On day 6, nonadherent cells were collected and replated into fresh 24-well plates, and the next day they were cultured with 1 µg/ml LPS (Bacto LPS B from Escherichia coli 0111:B4, Difco, Detroit, MI) for 24 h.
Two-color flow cytometric analysis
Nonadherent cells in the culture wells were gently suspended and used for flow cytometric analyses. Adherent cells were not included. Approximately 70% of the cells plated at day 6 were recovered at day 8 even in the presence of LPS. Cells (25 x 105 cells) were incubated with hybridoma culture supernatants or purified antibodies (0.55 µg/ml) for 30 min on ice. The following antibodies were used to analyze the DC surface phenotype. Hybridoma culture supernatants: mMGL (LOM-14, rat IgG2b, 1/10 dilution) (Kimura et al., 1995), DEC-205 (NLDC-145, rat IgG2a, 1/2 dilution, ATCC), CD11c (N418, hamster IgG, 1/10 dilution, ATCC), B220 (RA3-3A1/6.1, rat IgM, 1/2 dilution, ATCC), and MHC class I (M1/42, rat IgG2a, 1/2 dilution, ATCC). Purified antibodies: CD40 (3.23, rat IgG2a, 5 µg/ml, Immunotec Coulter, Marseilles, France), F4/80 (F4/80, rat IgG2b, 5 µg/ml, Dainippon Pharmaceutical), CD31 (MEC13.3, rat IgG2a, 2.5 µg/ml, BD Pharmingen, San Diego, CA), and Ly-6G (RB6-8C5, rat IgG2b, 2.5 µg/ml, Southern Biotechnology, Birmingham, AL). FITC-conjugated antibodies: CD11b (M1/70.15, rat IgG2b, 0.5 µg/ml, Caltag, Burlingame, CA) and CD14 (rmC5-2. rat IgG1, 2.5 µg/ml, BD Pharmingen). Biotinylated antibody: CD86 (RMMP1, rat IgG2a, 0.5 µg/ml, Caltag). For isotype controls, purified rat IgG (5 µg/ml, ICN, Costa Mesa, CA), purified rat IgM (5 µg/ml, Zymed, South San Francisco, CA), purified hamster IgG (1 µg/ml, ICN), and PE-conjugated rat IgG2b (0.2 µg/ml, Immunotech Coulter) were used. Primary rat and hamster antibodies were followed by FITC-conjugated rabbit anti-rat IgG (1/200 dilution, Zymed) and FITC-conjugated goat anti-hamster IgG (1/200 dilution, Southern Biotechnology), respectively. Incubation with biotinylated antibodies was followed by incubation with FITC-labeled streptavidin (1/200 dilution, Zymed). Following applications of the first and the second antibodies, the cells were then stained with PE-conjugated anti-mouse MHC class II (M5/114.15.2, 1/5000 dilution, rat IgG2b, BD Pharmingen). Antibodies and reagents were diluted in phosphate buffered saline (PBS) containing 0.1% bovine serum albumin (BSA), 0.1% sodium azide, and 2% normal goat serum. The cells were rinsed twice with PBS containing 0.1% BSA and 0.1% sodium azide at the end of each incubation. Samples were analyzed on an EPICS XL flowcytometer (Beckman Coulter, Fullerton, CA).
Isolation of immature and mature DCs and RT-PCR analysis
Cells were incubated with anti-mMGL mAb LOM-14 for 30 min on ice, with FITC-conjugated rabbit anti-rat IgG and then with PE-conjugated anti-mouse MHC class II. These antibodies were diluted in PBS containing 0.1% BSA and 2% normal goat serum. MHC class IIlow/moderate and mMGL-positive cells were sorted from day 6 DCs to obtain immature DCs and MHC class IIhigh and mMGL/low cells were sorted from day 8 LPS-treated DCs to obtain mature DCs by an EPICS ELITE flowcytometer (Beckman Coulter). The >90% purity was confirmed by flow cytometric analysis on an EPICS XL. Total RNAs were extracted by using Ultraspec RNA zol (BIOTECX, Houston, TX), according to the manufacturers instructions. First-strand cDNA synthesis was carried out using oligo (dT)1218 and Superscript II (Gibco BRL, Rockville, MD). The cDNA was used as the template in PCR reactions using Ampli Taq Gold polymerase (Perkin Elmer). PCR was performed with specific primers for mMGL (bp 465486 and 12391216). The condition was 94°C for 30 s, 65°C for 30 s, and 72°C for 1 min 30 s for 40 and 45 cycles. Amplification of ß-actin (bp 4263 and 10471024) was used as a control for cDNA quantity. The condition was 94°C for 30 s, 61°C for 30 s, and 72°C for 1 min for 25 and 30 cycles. The PCR products were then separated on 1.5% agarose gels, stained with ethidium bromide, and visualized with the Fluor-S image analyzer (Bio-Rad, Hercules, CA).
Carbohydrate binding and internalization assessed by flow cytometric analysis
Cell surface binding of biotinylated -N-acetylgalactosaminide (
-GalNAc) or ß-N-acetylglucosaminide (ß-GlcNAc) conjugated with polyacrylamide carriers (GlycoTech, Rockville, MD) was examined using flow cytometry. Cells were incubated with
-GalNAc or ß-GlcNAc polymers (10 µg/ml) for 30 min on ice. Subsequently, the cells were incubated with FITC-streptavidin (10 µg/ml) and then PE-conjugated anti-mouse MHC class II. Reagents were diluted in Dulbeccos modified PBS (DPBS, contains 0.91 mM CaCl2, 0.49 mM MgCl2) supplemented with 0.1% BSA and 0.1% sodium azide. The cells were rinsed twice with this buffer at the end of each incubation. PBS containing 10 mM EDTA, 0.1% BSA, and 0.1% sodium azide was used as the incubation medium devoid of Ca2+. To confirm the carbohydrate specific binding, cells were preincubated with 0.1 M GalNAc, GlcNAc, or Gal for 5 min on ice and then incubated with FITC-conjugated
-GalNAc polymers (GlycoTech) in the presence of monosaccharides. In the inhibition assay data was analyzed after gating on MHC class II expression. In three-color flow cytometric analysis,
-GalNAc polymers were monitored by streptavidin-RED670 (Gibco BRL).
For the internalization assays, FITC-conjugated -GalNAc or ß-GlcNAc polymers (GlycoTech) were used as model compounds for glycosylated antigens. Day 6 DCs were incubated with FITC-
-GalNAc or ß-GlcNAc polymers (10 µg/ml) in RPMI 1640 medium supplemented with 10% fetal calf serum at 37 °C for various time periods and washed with PBS containing 10 mM EDTA, 0.1% BSA, and 0.1% sodium azide to remove the polymers attaching on the cell surfaces. In the inhibition assays DCs were incubated in the presence of anti-mMGL mMAb LOM-14 (partially purified, diluted to equivalent to 1/10 of hybridoma culture supernatants), anti-mMGL mAb LOM-8.7 (rat IgG2a, partially purified, diluted to equivalent to 1/2 of hybridoma culture supernatants) (Kimura et al., 1995
), or normal rat serum (1/40 dilution). Data were analyzed after gating on MHC class II expression.
Confocal laser scanning microscopy
Day 6 DCs (5 x 105 cells) were plated on poly-L-lysine-coated coverslips (Iwaki, Tokyo) and allowed to adhere for 20 min at 37°C. The cells were incubated with 10 µg/ml FITC-GalNAc polymers for 1 h at 37°C, washed with DPBS, and then fixed with acetone for 30 s at room temperature. Nonspecific bindings were blocked with a blocking solution (2% normal goat serum and 3% BSA in DPBS) for 10 min, and DCs were incubated with anti-mMGL (mAb LOM-14, 1/10 dilution of hybridoma culture supernatant in the blocking solution), anti-LAMP-1 (mAb 1D4B, rat IgG2b, 1 µg/ml, BD Pharmingen), or anti-MHC class II (M5/114.15.2, 1/10 dilution of hybridoma culture supernatants, ATCC) for 40 min. After fixation in 4% paraformaldehyde dissoloved in 0.1 M sodium phosphate (pH 7.0) containing 0.91 mM CaCl2, DCs were incubated with biotinylated mouse anti-rat /
mAb (1/100 dilution, Sigma, St. Louis, MO) for 30 min and with Texas Redavidin D (1/100 dilution, Vector, Burlingame, CA) for 30 min. The coverslips were mounted in PermaFluor aqueous mounting medium (Shandon, Pittsburgh, PA) on glass slides and observed on a confocal microscope (MRC-1024; Bio-Rad).
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Acknowledgments |
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Abbreviations |
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Footnotes |
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References |
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