* Institute of Immunology, University of Vienna, A-1090 Vienna, Austria; and
Institute of Immunology— Vienna International Research Cooperation Center at NFI, University of Vienna, A-1235 Vienna, Austria
Correspondence: Dr. Peter Steinberger, Institute of Immunology, University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria. E-mail: peter.steinberger{at}univie.ac.at
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120 kDa O-sialoglycoprotein that within the
hematopoietic system is selectively expressed on cells of the myeloid
lineage. So far, its primary structure and function were unknown. We
used retroviral-expression cloning to isolate the CD93 cDNA. Sequence
analysis revealed that CD93 is identical to a protein on human
phagocytes termed C1q receptor (C1qRp). C1qRp was shown previously to
mediate enhancement of phagocytosis in monocytes and was suggested to
be a receptor of C1q and two other structurally related molecules. When
studying CD93 transductants and control cells, we found that cells
expressing CD93 have enhanced capacity to bind C1q. Furthermore, we
show that immature dendritic cells (DC) express CD93/C1qRp, and mature
DC, known to have reduced capacity for antigen uptake and to have lost
the ability to phagocytose, show weak-to-negative CD93/C1qRp
expression.
Key Words: dendritic cells • cell-surface molecules • complement • molecular biology
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Still, the primary structure as well as the function of the CD93 molecule remained unknown. We used a previously described retrovirus-based cDNA expression library constructed from a human myeloid cell line, KG1a (unpublished results), to clone the CD93 cDNA. Sequence analysis and database comparison revealed that CD93 is identical to the C1qRp (C1q receptor), which was cloned recently by Tenner and co-workers [5 ]. Studies by the same group suggest that three structurally similar proteins, the complement protein C1q, the mannose-binding lectin (MBL), and the pulmonary surfactant protein A (SPA), are able to enhance immunoglobulin G (IgG)- or complement opsonization-mediated phagocytosis by human monocytes [6 7 8 ]. Furthermore, they found that antibodies to C1qRp are able to inhibit this phagocytosis-stimulating effect. This would indicate that the C1qRp protein is interacting directly with the phagocytosis-enhancing ligands or is a common component of a phagocytosis-enhancing receptor complex. Here, we therefore analyzed the binding of C1q to cells expressing CD93/C1qRp.
Because of their unique ability to prime naive T cells, dendritic cells (DC) have recently attracted considerable interest, and they are now thought the most potent antigen-presenting cells (APC) of the immune system [9 ]. During their development, DC go through an immature stage where they have a high capacity to take up soluble and particulate matter. Upon maturation, DC almost completely lose this capacity but show increased potency to stimulate T cells [10 , 11 ]. We show here that immature DC express CD93/C1qRp and down-regulate this surface marker upon maturation, which points to a potential role of this receptor in uptake of particles by DC.
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The human cell line KG1a and the murine cell lines EL-4,
BW5147
ß-, Sp2/6, and P815 that were used as target cells for
retrovirus infection were maintained in RPMI-1640 medium supplemented
with 2 mM glutamine and 10% fetal bovine serum (FBS). The ecotropic
retroviral packaging cell line Phoenix-E [12
,
13
] (a kind gift from G. P. Nolan and colleagues)
was maintained in Dulbecco’s modified Eagle’s medium (DMEM)
containing 2 mM glutamine and 10% FBS. For activation of lymphocytes,
peripheral blood mononuclear cells (PBMC) were cultivated in the
presence of phorbol 12-myristate 13-acetate (PMA; 50 ng/ml; Sigma
Chemical Co., St. Louis, MO) and ionomycin (1 µM; Sigma Chemical Co.)
for 2 days. Monocytes were separated from freshly isolated PBMC by
magnetic cell sorting (MACS) using the mAb specific to CD14 (VIM13 and
MEM18 as described [14
]). Monocyte-derived DC were
generated by culturing monocytes in RPMI containing 10% FBS in the
presence of recombinant human granulocyte-macrophage colony-stimulating
factor (rhGM-CSF; 50 ng/ml) and rh interleukin (IL)-4 (100 U/ml) for 8
days. Both reagents were kind gifts of the Novartis Research Institute
(Vienna, Austria). In some experiments, DC maturation was induced by
cultivating day 6 monocyte-derived DC for another 2 days in the
presence of lipopolysaccharides (LPS; 1 µg/ml; Sigma Chemical Co.) or
ionomycin (1 µM). Human peripheral DC were isolated from PBMC as
follows: Cells were labeled with a mixture of biotinylated mAb against
the lineage-specific markers CD3, CD14, CD16, CD56, CD19, CD34, CD41,
and CD11b. The cells were incubated with streptavidin-immunomagnetic
beads (Miltenyi Biotech, Bergisch Gladbach, Germany), and labeled cells
were removed by MACS. The resulting cells lacked lineage markers and
were identified as LIN- HLA-DR+ peripheral DC.
For maturation of peripheral DC, these cells were cultured in RPMI-1640
containing 10% FBS in the presence of rhIL-3 (100 U/ml; R&D Systems,
Minneapolis, MN) and rh tumor necrosis factor (TNF-; 100 U/ml;
Ernst Boehringer Institut f. Arzneimittelforschung, Vienna, Austria)
for 2 days.
Retroviral cDNA expression library
The generation of a retroviral expression library derived
from KG1a cDNA is described elsewhere (unpublished results).
Recombinant retroviral vector DNA (60 µg) representing the cDNA
library was mixed with 50 ml DMEM containing Nuserum IV culture
supplement (Becton Dickinson, San Jose, CA) and glutamine (2 mM). In a
second tube, 50 ml DMEM containing Nuserum and glutamine was mixed with
1 ml (diethylamino)ethyl (DEAE)-dextran (10 mg/ml) and with 0.5 ml
chloroquine diphosphate (10 mM). Both mixtures were incubated for 10
min (37°C), combined, and added to 4 x 107
ecotropic packaging cells (Phoenix-E). After incubation for 2 h at
37°C, cells were spun down and resuspended in 20 ml DMEM containing
10% FBS and seeded in two 175 cm2 culture dishes. After
72 h of culture at 32°C, the supernatant was harvested. The
filtered (45 µm filter) supernatant was supplemented with 50 µl
polybrene (4 mg/ml) and added to 2 x 107 target cells
in 20 ml RPMI containing 10% FBS, and cells were incubated for 24 h at 32°C. Subsequently, the cells were spun down and resuspended in
100 ml RPMI containing 10% FBS, incubated for 24 h (37°C), and
then used for the selection procedure.
Isolation of CD93-expressing cells from the retrovirus-based cDNA
library-transduced cell pool
The retrovirus-infected cell pool (4x107 cells) was
washed with phosphate-buffered saline (PBS) containing 1% bovine serum
albumin (BSA) and 0.02% NaN3. The cells were then
incubated with VIMD2 (10 µg/ml) for 20 min on ice in a volume of 400
µl in PBS containing 1% BSA and 0.02% NaN3. After two
washing steps, cells were resuspended in 320 µl PBS with 1% BSA and
0.02% NaN3. Magnetically labeled goat anti-mouse IgG
MicroBeats (80 µl, Miltenyi Biotech) were added, and cells were
incubated for 20 min at 4°C. Cells were washed twice in degassed PBE
[PBS containing 0.5% BSA and 2 mM ethylenediaminetetraacetate
(EDTA)] and resuspended in 500 µl PBE. A MACS-RS+
separation column (Miltenyi Biotech) was equilibrated with 500 µl
PBE, and the cell suspension was applied to the column attached to a
magnetic cell separator (Miltenyi Biotech). The column was washed three
times with 500 µl PBE. Subsequently, the column was removed from the
cell separator, and the retained cells were flushed out with 1 ml PBE,
using the plunger supplied with the column. The eluted cells were put
into culture and expanded. When the cell number reached approximately
4 x 107, the selection procedure was repeated. Four
rounds of MACS were done. After the fourth cycle of selection,
single-cell clones were obtained by limiting dilution culturing.
Cloning of the CD93 cDNA insert from the selected cell
pool—polymerase chain reaction (PCR) recovery of the expressed
proviral cDNA insert
After four rounds of selection, 1 x 107 target
cells were used for total RNA preparation with the TRI Reagent (Sigma
Chemical Co.) following the manufacturer’s instructions. Oligo
TT-primed first-strand cDNA was generated from 5 µg total RNA using
the first-strand cDNA synthesis kit from Life Technologies (Paisley,
UK), according to the provided protocol. The retrovirus-encoded cDNA
insert was PCR-amplified from 1 µl first-strand cDNA with the
oligonucleotide primers LIB S: 5'-GCTCACTTACAGGCTCTCTA-3' and LIB A:
5'-CAGGTGGGGTCTTTCATTCC-3', specific for the flanking retroviral
sequences. The Expand PCR system (Roche Molecular Biochemicals,
Indianapolis, IN) was used for the PCR amplification under standard
conditions. The obtained PCR products were gel-purified and digested
using the restriction endonuclease EcoRI. The digested PCR
product was ligated into appropriately cut pBabeMN vector DNA
([15
]; a kind gift of G. P. Nolan and colleagues)
and introduced into the Escherichi coli strain DH5a by
electroporation. Plasmid DNA obtained from transformed clones was
analyzed by restriction endonuclease digest, and selected plasmids were
transfected into Phoenix-E cells using LipofectAmine (Life
Technologies), according to the manufacturer’s instructions to confirm
that the transfected cells react with the CD93 mAb VIMD2.
DNA sequence analysis
Plasmid DNA was prepared from selected clones (Plasmid Maxi Kit;
Qiagen, Chatsworth, CA) and used for sequence analysis (VBC Genomics,
Vienna, Austria). To minimize the risk of sequence errors introduced
during PCR amplification, another DNA fragment generated from a
separate PCR amplification was cloned into the pBabeMN vector DNA, and
the resulting plasmid was also used for DNA sequencing.
Analysis of CD93/C1qRp interaction with C1q
Purified C1q (200 µg; Calbiochem, San Diego, CA) was incubated
with 1 µg Biotin-X-NHS (Calbiochem) for 40 min at room temperature
with intermittent agitation. We stopped the reaction by adding glycine
to a final concentration of 50 mM. The reaction mixture was
subsequently dialyzed against PBS. The biotinylated C1q
(C1qbio) was stored at -70°C in aliquots. After thawing,
the C1qbio was stored at 4°C for up to 3 days. For flow
cytometric-binding studies with C1qbio, a low
ionic-strength buffer [70% Hanks’ balanced saline solution without
Mg++ and Ca++ and 30%
of a 5% glucose-0.2% gelatin solution] was used throughout the
staining. Cells (1.5x105) were incubated with
C1qbio in a total volume of 20 µl for 10 min at room
temperature. Cells were washed and incubated with a
streptavidin-phycoerythrin (PE) conjugate (Becton Dickinson; final
concentration, 0.1 µg/ml).
Flow cytometric analysis using antibodies
For flow cytometric analysis using murine mAb, cells
(1x107/ml) were incubated with primary antibody (10
µg/ml) for 20 min on ice, washed, and incubated with fluorescein
isothiocyanate (FITC)-conjugated F(ab')2 fragments of sheep
anti-mouse Ig Abs (An der Grub) as described [16
]. In
some experiments, an Oregon Green-labeled anti-mouse Ig conjugate
(Molecular Probes, Eugene, OR) was used as a secondary reagent.
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Figure 1. Enrichment of VIMD2-reactive target cells during activated MACS.
Untransduced target cells (control) and the cell pools obtained after
three and four rounds of selection of the target cells transduced with
the retroviral KG1a expression library were probed with isotype-control
mAb (open histograms) or CD93 mAb VIMD2 (shaded histograms). Cells were
stained with an FITC-conjugate and analyzed by flow cytometry.
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3.7 kb
PCR-product was EcoRI-cut and cloned into the retroviral
vector pBabeMN and transformed into E. coli cells. Plasmid
DNA was prepared from the transformed E. coli cells and
introduced into Phoenix-E cells by transfection to confirm that it
contained the insert of interest. The resulting transfectants were
strongly reacting with mAb VIMD2 by flow cytometry. No reactivity was
seen with cells transfected with the control vector pBabeMN-lacZ that
contained the ß-galactosidase cDNA (Fig. 2
).
 View larger version (24K): [in a new window] |
Figure 2. CD93 mAb VIMD2 binds to cells transfected with plasmid DNA containing
the isolated cDNA. Phoenix-E cells were transfected with control
plasmid DNA (left) or with plasmid DNA containing cDNA that was
isolated from the sorted target cells (right). Two days
post-transfection, cells were probed with isotype-control mAb (open
histograms) or with VIMD2 (shaded histograms). Cells were stained with
FITC-conjugate and analyzed by flow cytometry.
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 View larger version (58K): [in a new window] |
Figure 3. Reactivity of CD93 mAb with Bw-93-4 cells and KG1a cells. Bw-93-4, a
cell clone derived from the transduced target cell pool obtained after
four rounds of selection, was probed with four different CD93 mAb and
isotype-control mAb (left). Untransduced target cells (middle) and the
myeloid cell line KG1a (right) were also analyzed. The shaded
histograms show binding of CD93 mAb (VIMD2, VIMD2b, WDS4.84, and X2).
The open histograms represent the reactivity of the isotype-control
mAb.
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 View larger version (93K): [in a new window] |
Figure 4. cDNA and deduced amino acid sequence of CD93. The cDNA insert derived
from the retrovirus library transduced target cells after screening
with the CD93 mAb VIMD2 was subjected to DNA sequence analysis.
Numbering of bases and amino acids is shown on the left and right,
respectively.
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 View larger version (52K): [in a new window] |
Figure 5. Interaction of C1q with CD93/C1qRp-transduced cells. The binding of
C1qbio to CD93/C1qRp transductants was analyzed by flow
cytometry. Cells were incubated with buffer only or with increasing
concentrations of C1qbio as indicated. A low ionic-strength
buffer was used throughout the staining. Cell-bound C1qbio
was detected with a streptavidin-PE conjugate. The shaded histograms
show C1q reactivity with CD93/C1qRp transductants, and the open
histograms represent the control staining—reactivity of C1q with
untransduced cells derived from the same cell line. BSAbio
did not bind to the cells. The binding experiments were repeated
several times with a similar outcome.
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Using low ionic-strength conditions, we analyzed the binding of C1q to these cells. We found that monocytes as well as granulocytes bind C1q, whereas only a small subpopulation of lymphocytes binds to C1q (Fig. 6 ). These findings show that cells, which express CD93, are also binding C1q. Because lymphocytes are CD93-, but a small subset of these cells binds C1q, our results also indicate that there are other C1q binding structures on human leukocytes.
 View larger version (34K): [in a new window] |
Figure 6. Human leukocytes expressing CD93/ClqRp are binding Clq. (A) Human
lymphocytes, granulocytes, and monocytes were analyzed for CD93/C1qRp
expression. Cells were probed with the CD93 mAb VIMD2 (shaded
histograms) or with isotype-control mAb (open histograms). (B) Human
lymphocytes, granulocytes, and monocytes were probed with
C1qbio (30 µg/ml, shaded histograms) and control protein
(30 µg/ml BSAbio, open histograms shown in bold).
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 View larger version (41K): [in a new window] |
Figure 7. Maturation of monocyte-derived DC leads to down-regulation of
CD93/C1qRp and to a reduced binding of C1qbio. Monocytes
were isolated from peripheral blood leukocytes and cultivated in the
presence of IL-4 and GM-CSF. On day 6, the maturation stimulus
ionomycin was added to immature DC. On day 8, both cell types were
analyzed for reactivity with antibodies or with C1q by flow cytometry.
(A) Immature DC (shaded histograms) and mature DC (open histograms
shown in bold) were probed with CD93 mAb VIMD2 or with CD86-specific
mAb as indicated. The open histograms shown in a thin line represent
the reactivity of the isotype-control mAb. (B) Immature DC (shaded
histograms) and mature DC (open histograms shown in bold) were probed
with C1qbio or with control protein (BSAbio) as
indicated.
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were described to induce maturation of human
peripheral DC [29
]. When we cultivated the isolated
cells in the presence of these cytokines, we found up-regulation of
maturation markers such as CD40. It is interesting that as with
monocyte-derived DC, we found a strong reduction of CD93/C1qRp
expression on these mature peripheral DC.
 View larger version (23K): [in a new window] |
Figure 8. Peripheral DC down-regulate CD93/C1qRp upon maturation. Peripheral DC
were isolated from PBMC and were analyzed for reactivity with CD93 mAb
VIMD2 or with CD40-specific mAb as indicated (shaded histograms). The
isolated cells were also cultivated in the presence of the
maturation-inducing cytokines IL-3 and TNF- and probed with mAb as
described above (open histograms shown in bold). The open histograms
shown in a thin line represent the reactivity of the isotype-control
mAb.
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The CTLD of these proteins bear distant homology to the carbohydrate recognition domains (CRD) of the C-type lectin family, which includes endocytosis-mediating receptors such as the mannose receptor (MR) and DEC-205 [32 33 34 ]. These proteins bind and internalize carbohydrate-bearing ligands by receptor-mediated endocytosis [34 ]. However, CD93/C1qRp seems to clearly differ from these receptors. We did not observe internalization of CD93/C1qRp upon its ligation with bivalent antibody or with its natural ligand Clq as was seen for endocytic receptors such as the MR and DEC-205. We also found no evidence of binding of mannose-coupled BSA to CD93/C1qRp-expressing transductants (data not shown).
Others have speculated that CD93/C1qRp and its homologs might play a role in cell-cell interaction [19 , 25 ]. However, to date, there is no experimental evidence for such a function. An entire series of studies by Tenner and colleagues points toward a role of CD93/C1qRp in the regulation of phagocytosis [6 7 8 , 30 ].
The authors demonstrated that the addition of C1q as well as of SPA or MBL could enhance phagocytosis of opsonized RBC (red blood cells) by human monocytes. C1q, SPA, and MBL are structurally similar proteins that are known to recognize pathogen-associated molecular patterns (PAMPS) [35 ]. Tenner and colleagues demonstrated that C1qRp-specific antibodies are able to inhibit this enhancement of phagocytosis. Taken together, these data suggest that this mAb-defined monocyte-surface structure, which seems to be involved in the C1q-mediated regulation of phagocytosis, is a receptor for C1q or physically or functionally linked with a molecule recognizing C1q.
The identification of C1q receptors is notoriously difficult. The analysis of C1q interaction with whole cells is hampered by the stickiness and delicacy of C1q and by the presence of more than one C1q binding protein. A number of C1q binding proteins have been described, but their nature as specific C1q receptors is often not generally accepted [18 , 19 ]. This also holds true for the C1qRp described by Tenner and co-workers [5 , 30 ], which was also doubted to actually bind C1q.
The availability of CD93/C1qRp transfectants allowed us to compare directly C1q binding of CD93/C1qRp-expressing cells with CD93/C1qRp-negative control cells of the same cell type. In this system, we could detect enhanced binding of C1q to CD93/C1qRp transductants using low ionic-strength conditions. We think that these results support the notion that the effect of C1q on the enhancement of monocyte phagocytosis is mediated through binding of C1q to CD93/C1qRp as suggested by Tenner and co-workers [30 ]. Because we were unable to detect specific binding of soluble C1q to CD93/C1qRp-expressing cells at physiological conditions, we could not show that CD93/C1qRp is indeed a receptor of C1q. Tenner and co-workers [23 ] argue that in vivo, C1q would generally be presented to CD93/C1qRp-bearing cells as aggregates because most C1-binding substances are multivalent in structure. Therefore, it is conceivable that in vivo, CD93/C1qRp binds to clusters of C1q at normal ionic strength. However, the identity of C1qRp as a receptor for C1q is still controversial, and even the research group that coined the term C1qRp recently referred to this receptor as the "C1q receptor/receptor component" [36 ]. Furthermore, the rat as well as the mouse homolog of this protein was termed AA4 rather than C1qRp by some groups [19 , 25 ]. We hope that the CD designation will offer a way out of the confusion regarding the nomenclature of this molecule.
Recently, a phagocytosis-enhancing effect of C1q was also shown in murine cells that express the mouse homolog of the C1qRp [36 ]. This effect was inhibited by intracellular application of a polyclonal antibody that binds to the cytoplasmic tail of the murine as well as the human C1qRp [36 , 37 ]. This indicates that the intracellular domain, which is highly conserved in those two species, plays a role in transducing a signal that leads to enhancement of phagocytic function. The cytoplasmic tail of the human CD93/C1qRp and the rat homolog comprise a carboxy-terminal tyrosine phosphorylation motif [5 , 24 , 25 ], and coprecipitation studies showed evidence that CD93 is associated with protein kinases [38 ].
We found an interesting correlation of the expression pattern of CD93/C1qRp in DC with their functional state. So-called immature DC, known to be particularly potent in the uptake of antigens by phago-, endo-, and pinocytosis but relatively inefficient in antigen presentation [10 , 26 ], are strongly CD93-positive. In contrast, mature DC, which are good T-cell stimulators but barely take up antigen and have lost the capacity to phagocytose [28 , 39 ], have also lost expression of the phagocytic CD93/C1qRp (Figs. 7 and 8) . This concomitant reduction of phagocytic capacity and CD93/C1qRp density during DC maturation would be in line with a potentially relevant role of CD93/C1qRp in DC phagocytosis in general but does not prove such a linkage. It can be envisaged, however, that in vivo, the CD93/C1qRp molecules we found on immature DC contribute to an enhanced uptake of antigen if complexed with C1q. This could help to direct the adaptive immune response toward C1q-activating structures such as foreign antigen complexed by IgG- or IgM-opsonized particles.
Note added in proof: The construction of the retroviral cDNA library that was the source of the CD93-cDNA has been published recently: Wille, S., Szekeres, A., Majdic, O., Prager, E., Staffler, G., Stöckl, J., Kunthalert, D., Prieschl, E. E., Baumruker, T., Burtscher, H., Zlabinger, G. J., Knapp, W., Stockinger, H. (2001) Characterization of CDw92 as a Member of the Choline Transporter-Like Protein Family Regulated Specifically on Dendritic Cells. J. Immunol. 167, 5795–5804.
Received April 1, 2001; revised August 26, 2001; accepted August 27, 2001.
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