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*
Miltenyi Biotec GmbH, Bergisch Gladbach, Germany; and
AmCell Corporation, Sunnyvale, CA 94089
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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From analyses of freshly isolated lin- BDC it
became evident that BDC do not represent a homogeneous cell population,
but, rather, a mixture of at least two populations (3, 4, 5, 6, 7, 8, 10, 14): 1) CD123bright
CD11c- BDC, which possess a plasmacytoid
morphology, express CD45RA, and depend on IL-3 for their survival and
differentiation into mature DC with typical dendritic morphology and
potent T cell stimulatory function; and 2)
CD123dim CD11cbright BDC,
which are rather monocytoid in appearance, express CD45RO, and
spontaneously develop into typical mature DC even when cultured without
any exogenous cytokines. Plasmacytoid CD123bright
CD11c- BDC display some features, such as the
expression of the pre-TCR 
-chain, that indicate that they may arise
from lymphoid precursors (4, 14, 15), whereas
CD123dim CD11cbright BDC
display all the criteria of myeloid DC (3, 4, 5, 6, 7). DC
resembling plasmacytoid CD123bright
CD11c- BDC have been detected in the T cell-rich
areas of lymphoid tissue (16) and were initially
erroneously designated plasmacytoid T cells or plasmacytoid monocytes
due to their morphology and phenotype (17, 18). DC
resembling CD123dim
CD11cbright BDC have been found in the dark and
light zones of germinal centers (19).
Here we describe a panel of new mAb raised against immunomagnetically purified CD4+ lin- BDC that identify three presumably novel BDC Ags: BDCA-2, BDCA-3, and BDCA-4. In fresh human blood, expression of BDCA-2 and BDCA-4 is strictly confined to plasmacytoid CD123bright CD11c- BDC, whereas expression of BDCA-3 is restricted to a small population of CD123- CD11c+ BDC. This small population of BDCA-3+ BDC shares many immunophenotypic features with classical CD123dim CD11cbright BDC, but unlike CD123dim CD11cbright BDC, BDCA-3+ BDC lack expression of CD1c (BDCA-1), CD2, and several of the Fc receptors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five 6- to 8-wk-old female BALB/c mice (Simonsen, Gilroy, CA)
were inoculated with 
5 x 105 to 1
x 106 purified HLA-DR+
lin- BDC under anesthesia on days 0, 4, 7, 11,
and 14 in the right hind footpad and with 1 x
106 HLA-A2+ Bristol-8 B
lymphoblastoma cells in the left hind footpad on days -3, 0, 4, 7, 11,
and 14 (30). Both cell types were incubated with 1/100 PHA
(Life Technologies, Gaithersburg, MD) for 10 min at room temperature
and washed with PBS before injection.
On day 15 the cells of the mouse right hind popliteal lymph nodes were fused to SP2/0 Ag14 myeloma cells. Fused cells were plated on 96-well plates in DMEM supplemented with 20% FCS (HyClone, Logan, UT), 2 mmol/L L-glutamine, 15 mmol/L HEPES, 10-4 mmol/L hypoxanthine (Life Technologies), and 2 µg/ml azaserine (O-diazoacetyl-L-serine; Sigma, St. Louis, MO) and placed in a 37°C incubator with 9% CO2.
When visible hybridoma colonies were apparent, flow cytometric analysis
was used to screen supernatants from these wells for Ab secretion and
for nonreactivity (
1% positive cells) to PBMC. Briefly, a mixture of
rat anti-mouse 
mAb-conjugated polystyrene beads (2.5 µm in
diameter; Interfacial Dynamics, Portland, OR) and PBMC was incubated
with 50 µl of hybridoma supernatant for 20 min at room temperature.
The bead/cell mixture was then washed twice with PBS, pH 7.4,
containing 5 mmol/L EDTA and 0.5% BSA (PBS/EDTA/BSA), and binding of
mouse IgM, IgG1, Ig2a, and Ig2b from the supernatants to the beads and
the test cells was detected by staining with PE-conjugated rat
anti-mouse IgM mAb (clone X54; BD Biosciences, San Jose, CA), rat
anti-mouse IgG1 mAb (clone X56; BD Biosciences), and rat
anti-mouse IgG2 mAb (clone X57; BD Biosciences).
Culture supernatants that fulfilled the screening criteria of the first
round were then flow cytometrically screened for reactivity to a
significant proportion of BDC. Briefly, a mixture of rat anti-mouse
mAb-conjugated polystyrene beads and enriched BDC (PBMC depleted of
B cells, T cells, and monocytes) was incubated with 50 µl of
hybridoma culture supernatant for 20 min at room temperature. The
mixture was then washed twice with PBS/EDTA/BSA and stained with
PE-conjugated rat anti-mouse IgM mAb, rat anti-mouse IgG1 mAb,
and rat anti-mouse IgG2 mAb to detect binding of mouse IgM, IgG1,
Ig2a, and Ig2b from the supernatants to the beads and the enriched BDC.
For discrimination of HLA-DR+ BDC from
HLA-DR- cells, the bead/cell mixture was then
washed once, free binding sites of the PE-conjugated rat anti-mouse
IgG2 mAb and the bead-conjugated rat anti-mouse mAb were
saturated by incubation with 100 µg/ml mouse IgG2a, and the mixture
was counterstained with anti HLA-DR-FITC (clone AC122, IgG2a).
Selected hybridoma cells were expanded, subclones were established, and the isotype of the mAb was determined by the ISOTYPE Ab-STAT Kit (SangStat Medical, Palo Alto, CA).
Cell preparations
Buffy coats from normal healthy volunteers were obtained form the Institute for Transfusionmedicine, Hospital Merheim (Cologne, Germany). PBMC were prepared from buffy coats by standard Ficoll-Paque (Pharmacia, Uppsala, Sweden) density gradient centrifugation. Peripheral blood leukocytes were prepared from buffy coats by lysis of erythrocytes in isotonic ammonium chloride buffer.
CD4+ lin- BDC were isolated from PBMC by two-step immunomagnetic cell sorting (MACS) as described in detail previously (13, 20). Briefly, monocytes, T cells, B cells, and NK cells were depleted using mAb against CD3 (clone BW264/56), CD11b (clone M1/70.15.11.5), CD16 (clone VEP-13), and in a few experiments a poorly defined Ag expressed on B cells and monocytes (clone L179; BD Biosciences). From the depleted cell fraction, BDC were then enriched using an mAb against CD4 (clone M-T321). To screen hybridoma culture supernatants (see above), BDC were merely partially enriched by immunomagnetic depletion of T cells, B cells, and monocytes based on CD3 and L179 Ag expression.
CD1c-, BDCA-2-, and BDCA-3-expressing cells were isolated from PBMC by indirect magnetic labeling with PE- or FITC-conjugated mAb (AD5-8E7, AC144, and AD5-5E8, respectively) and anti-PE or anti-FITC mAb-conjugated microbeads (Miltenyi Biotec) and enrichment of labeled cells by MACS. In some experiments BDCA-3+ cells were isolated based on direct magnetic labeling with anti-BDCA-3 mAb (AD5-5E8)-conjugated microbeads. Highly pure CD1c+ BDC without contaminating CD1c+ B cells were obtained by immunomagnetic depletion of CD19+ B cells using CD19 mAb-conjugated microbeads (Miltenyi Biotec) followed by immunomagnetic enrichment of CD1c+ cells.
Basophils were purified from PBMC by immunomagnetic depletion of nonbasophils based on indirect magnetic labeling of CD3-, CD7-, CD14-, CD15-, CD36-, CD45RA-, and HLA-DR-expressing cells with a magnetic labeling kit (Miltenyi Biotec). CD14+ monocytes, CD34+ hemopoietic progenitor cells, and CD3+ T cells were immunomagnetically purified based on direct magnetic labeling with CD14, CD34, and CD3 mAb-conjugated microbeads (Miltenyi Biotec), respectively.
Cell culturing
For generation of immature monocyte-derived DC (Mo-DC), purified
CD14+ monocytes were cultured at a cell density
of 5 x 105 to 1 x
106 cells/ml in medium (RPMI 1640 (Life
Technologies) supplemented with 2 mmol/L L-glutamine, 10%
FCS (Sigma), 110 mg/L sodium pyruvate (Life Technologies), 100 U/ml
penicillin (Life Technologies), and 100 µg/ml streptomycin (Life
Technologies)) at 37°C in a humidified 5%
CO2-containing atmosphere in the presence of
500-1000 U/ml rIL-4 (PeproTech, Rocky Hill, NJ) and 100 ng/ml rGM-CSF
(PeproTech) for 7 days. For generation of mature Mo-DC, immature Mo-DC
were washed once and cultured in medium in the presence of 20 ng/ml
TNF- (PeproTech) for another 3 days. For generation of
CD34+ hemopoietic progenitor cell-derived DC
(CD34-derived DC), purified CD34+ cells were
cultured at a cell density of 5 x 104
cells/ml in medium in the presence of 100 ng/ml rFlt3 ligand
(PeproTech), 0.5 ng/ml rTGF-
1 (PeproTech), 10 ng/ml rTNF-, 20
ng/ml recombinant stem cell factor (PeproTech), and 100 ng/ml rGM-CSF
for 11 days. Freshly isolated CD4+
lin- BDC were cultured at a cell density of
5 x 105 to 1 x
106 cells/ml in medium in the presence of 10
ng/ml rIL-3 (PeproTech) for up to 48 h. Isolated
CD1c-, BDCA-2-, and BDCA-3-expressing BDC were cultured at a
cell density of 5 x 105 to 1 x
106 cells/ml in medium without any cytokines or
in the presence of 10 ng/ml rIL-3, 20 ng/ml IL-4 (PeproTech), and 100
ng/ml GM-CSF for up to 48 h.
Flow cytometric analysis
A FACScalibur (BD Biosciences) was used for one-, two-, three-, or four-color flow cytometry. Data for 5 x 103 to 2 x 105 cells/sample were acquired in list mode and analyzed using CellQuest software (BD Biosciences).
The following mAb (clone names) were used in this study for flow
cytometry: CD1a (HI149), CD10 (HI10a), CD11a (G43-25B), CD11c (B-ly6),
CD25 (M-A261), CD27 (M-T271), CD32 (FL18.26), CD38 (HIT2), CD40 (5C3),
CD43 (1G10), CD54 (HA58), CD62L (Dreg 56), CD64 (10.1), CD69 (FN50),
CD98 (HIM6), anti-HLA-DQ (Tü169), and anti-TCR
(T10B9.1A-31) from PharMingen (San Diego, CA); CD2 (S5.2), CD8 (SK1),
CD13 (L138), CD14 (MFP9), CD19 (SJ25-C1), CD33 (P67.6), CD34 (8G12),
CD45RO (UCHL-1), CD56 (NCAM16.2), CD62L (SK11), CD71 (L01.1), CD123
(9F5), anti-IgD (TA4.1), anti-mouse IgG1 (X56), anti-mouse
IgG2 (X57), and anti-mouse IgM (X54) from BD Biosciences; CD5
(CLB-T11/1, 6G4), CD7 (CLB-T-3A1/1, 7F3), CD16 (CLB-FcR Gran1, 5D2),
CD45RA (F8-11-13), and CD80 (CLB-DAL1) from CLB (Amsterdam, The
Netherlands); CD18 (7E4), CD23 (9P25), CD58 (AICD58), CD77 (38.13),
CD83 (HB15A), CD86 (HA5.2B7), and CD116 (SC06) from Coulter-Immunotech
(Marseilles, France); CD3 (BW264/56), CD4 (M-T321), CD11b
(M1/70.15.11.5), CD14 (TUK4), CD15 (VIMC6), CD16 (VEP-13),
anti-HLA-DR (910/D7), anti-AC133 (AC133/1), and anti-TCR
(BW242/412) from Miltenyi Biotec; CD36 (AC106), CD123 (AC145),
anti-HLA-DR (AC122 and AC123), and anti-glycophorin A (AC107)
from Amcell (Sunnyvale, CA); CD1c (M241) from Ancell (Bayport, MN);
polyclonal anti-IgG, anti-IgM (SA-DA4), polyclonal anti-,
and polyclonal anti-
from Southern Biotechnology Associates
(Birmingham, AL); CD61 (VIPL2) from W. Knapp (Institute of Immunology,
University of Vienna, Vienna, Austria); CD44 (IM7) from J. Moll
(Forschungszentrum Karlsruhe, Karlsruhe, Germany); CD20 (HI47) from
Caltag (Burlingame, CA); anti-CLA (HECA-452) from E. Butcher
(Department of Pathology, Stanford University, Stanford, CA);
anti-Fc
RI (15-1) from J. P. Kinet (Molecular Allergy and
Immunology Section, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD); CD11c (Ki-M1)
from M. R. Parwaresch (Department of Pathology, Christian
Albrechts University, Kiel, Germany); CMRF-44 and CMRF-56 from D.
N. Hart (Mater Medical Research Institute, Mater Misericordiae
Hospitals, South Brisbane, Australia); and anti HLA-A,B,C (W6/32) from
Sigma.
All Abs were used as FITC-, PE-, biotin-, or Cy5-conjugated mAb. For indirect immunofluorescent staining with biotinylated mAb, streptavidin-APC (BD Biosciences) was used. For exclusion of dead cells in the flow cytomeric analysis, cells were stained with propidium iodide. To minimize FcR-mediated mAb binding, cells were stained in most experiments in the presence of FcR-blocking reagent (Miltenyi Biotec) containing human IgG.
Microscopic analysis
Cells were spun down on slides in a cytocentrifuge (Cytospin 3; Shandon, Pittsburgh, PA). A Zeiss Axioscope microscope (Zeiss, Oberkochen, Germany) was used for analysis. Digital pictures were made using the Xillix MicroImager MI1400-12X (Xillix, Vancouver, Canada).
Endocytosis assay
To assess endocytosis of BDC subsets, purified CD1c+, BDCA-2+, and BDCA-3+ BDC, and (as controls) purified CD3+ T cells and immature Mo-DC were incubated at 37°C in medium with 1 mg/ml Lucifer Yellow (LY) for 0, 15, 45, and 75 min. Afterward, cells were washed three times in ice-cold PBS/EDTA/BSA and analyzed by flow cytometry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mAb listed in Table I
fulfilled
the initial screening criteria for BDC-specific mAb (see
Materials and Methods) and were further characterized.
According to their reactivity with blood cells, the mAb could be
divided into four groups: 1) AC144, AD5-13A11, and AD5-4B8; 2)
AD5-17F6; 3) AD5-5E8 and AD5-14H12; and 4) AD5-8E7.
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A). In a dot plot of forward
and side scatter signals, these rare cells constitute a homogeneous
cell population that is located between small resting lymphocytes and
monocytes (Fig. 1B). Accordingly, these rare cells do not
express TCR, CD14, CD19, and CD56 (Fig. 1A), lineage
markers that are expressed on T cells, monocytes, B cells, and NK
cells, respectively. Staining of highly purified BDC (>95%
HLA-DR+, TCR-,
CD14-, CD19-, and
CD56-) with CD123-PE vs CD11c-FITC reveals three
BDC subsets (Fig. 2): 1)
CD11c- CD123bright BDC, 2)
CD11cbright CD123dim BDC,
and 3) CD11c+ CD123- BDC.
The mAb of the first group clearly stained all
CD11c- CD123bright BDC,
but, except for a very few cells, not the CD11c+
BDC (Fig. 2). To analyze whether all mAb of the first group react with
a single Ag, we performed two-color stainings and cross-inhibition
studies (data not shown). The results showed that all mAb of this group
recognize a single epitope of the same Ag. We named this Ag BDCA-2.
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, the mAb of the second
group, AD5-17F6, recognizes the same cells among PBMC as AC144, one of
the BDCA-2-specific mAb of the first group. Nevertheless, AD5-17F6
stains an Ag that is different from BDCA-2. This was unequivocally
demonstrated by cointernalization experiments, where AD5-17F6 showed
surface staining with equal intensity before and after anti-BDCA-2
mAb-mediated internalization of BDCA-2 (data not shown), and by
staining of BDC after culture, where AC144 mAb and AD5-17F6 mAb showed
entirely different staining patterns (see below and Fig. 4). The Ag recognized by AD5-17F6 was
named BDCA-4.
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A).
According to scatter signals (Fig. 1B) and counterstaining
with mAb against TCR, CD14, CD19, and CD56 (Fig. 1A),
these cells are distinct from lymphocytes and monocytes and are
slightly larger than the cells recognized by the Abs of the first
group. Accordingly, staining of BDC shows that a different subset is
recognized by AD5-5E8 and AD5-14H12, namely
CD11c+ CD123- BDC (Fig. 2). According to two-color stainings, cross-blocking studies and
cocapping experiments (data not shown), both mAb appear to recognize
two spatially unrelated epitopes of the same Ag. We named this Ag
BDCA-3.
The fourth group mAb AD5-8E7 reacts with 2.39 ± 0.76%
(n = 10) of unfractionated PBMC (Fig. 1A).
Light scatter analysis (Fig. 1B) and counterstaining of the
lineage markers TCR, CD14, and CD19 revealed that the mAb is not
reactive to T cells and monocytes, but is reactive to a major subset of
small resting CD19+ B cells. Staining of purified
BDC shows that AD5-8E7, in addition to B cells, stains a third subset
of BDC distinct from those subsets recognized by the mAb of the first
and second groups, namely CD11cbright
CD123dim BDC. A significant proportion of the
CD11cbright CD123dim BDC
expresses CD56 (see below). For this reason, some AD5-8E7-reactive PBMC
stain for CD56 (Fig. 1A). AD5-8E7 is not reactive to
purified NK cells (data not shown). The Ag recognized by AD5-8E7 was
initially named BDCA-1, as it appeared to be a new Ag. However, it
later transpired that AD5-8E7 completely blocked binding of the CD1c
mAb M241 to MOLT-4 cells (Fig. 5). Thus,
the Ag recognized by AD5-8E7 is CD1c.
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is reactive to granulocytes,
platelets, erythrocytes, purified basophils, or purified
CD34+ hemopoietic progenitor cells (data not
shown). Expression of BDCA-2, BDCA-3, and BDCA-4 on cultured BDC
Expression of BDCA-2, BDCA-3, and BDCA-4 on
CD11c- and CD11c+ BDC was
analyzed after various periods of culturing total BDC in the presence
of rIL-3. The results are shown in Fig. 4. Expression of
BDCA-2 is completely down-regulated within 48 h on
CD11c- BDC. In contrast, BDCA-4 is even further
up-regulated on CD11c- BDC and, unlike BDCA-2,
is also expressed to a high level on most, if not all,
CD11c+ BDC. Expression of BDCA-3 is rapidly
induced on CD11c- BDC, reaching the highest
expression level after 24 h. Thereafter, BDCA-3 expression appears
to be down-regulated again. Analyzing the expression of BDCA-3 on
CD11c+ BDC is complicated by the fact that
BDCA-3- CD11cbright and
BDCA-3+ CD11c+ subsets are
present at the onset of the culture. Expression of BDCA-3 appears to
remain unchanged at least until 6 h of culture on the
BDCA-3+ CD11c+ BDC
population and is induced within 3 h on at least some cells of the
BDCA-3- CD11cbright BDC
subset.
Expression of BDCA-2, BDCA-3, and BDCA-4 on Mo-DC and CD34-derived DC
Functional CD1a+ DC can be generated ex vivo
from monocytes (21, 22, 23) and CD34+
hemopoietic progenitor cells (24). Fig. 6 shows that immature Mo-DC (25, 26) and CD34-derived DC express CD1a, CD1c, and BDCA-4, but not
BDCA-2 or BDCA-3.
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The possibility that 37°C incubation of anti-BDCA-2 mAb-labeled
BDCA-2+ cells results in mAb internalization was
addressed by staining of PBMC with FITC-conjugated AC144 mAb (IgG1).
Then, following incubation at 37°C, the remaining cell
surface-associated mAb was detected by staining with PE-conjugated rat
anti-mouse IgG1 mAb. As shown in Fig. 7, when cells were incubated at 37°C,
the intensity of the rat anti-mouse IgG1-PE staining decreased
extremely rapidly to background levels. In contrast, the intensity of
the AC144-FITC staining decreased only temporarily to a level of
50%, but thereafter nearly returned to the preincubation level.
This demonstrates that BDCA-2 is internalized upon anti-BDCA-2 mAb
labeling, with kinetics similar to those of receptor-mediated
endocytosis. The transient decrease in AC144-FITC staining intensity is
probably due to patching and capping of the BDCA-2/anti-BDCA-2 mAb
complex before endocytosis.
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CD1c+, BDCA-2+, and
BDCA-3+ cells were isolated from PBMC by MACS
(Fig. 8). On May-Grünwald Giemsa
staining of cytocentrifuge slides (Fig. 8), freshly isolated
BDCA-2-expressing cells displayed the typical lymphoplasmacytoid
morphology of CD11c- CD4+
lin- DC from blood and tonsils: that is,
medium-sized round cells with oval or indented nuclei (3, 6, 16). In contrast, both freshly isolated
CD1c+ BDC as well as freshly isolated
BDCA-3+ BDC displayed the typical morphological
characteristics of CD11c+
CD4+ lin- DC from blood or
tonsils: that is, less rounded cells with short cell processes and more
hyperlobulated nuclei (3, 19). In addition to
CD1c+ BDC, CD1c+ B cells
with the typical morphology of small resting lymphocytes can be seen on
the cytocentrifuge slides of isolated CD1c+ PBMC.
Highly pure CD1c+ BDC were obtained if, before
the enrichment of CD1c+ cells,
CD19+ B cells were magnetically depleted from
PBMC (data not shown).
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The phenotypes of fresh CD1c+,
BDCA-2+, and BDCA-3+ BDC
were analyzed by two-color (BDCA-2+ and
BDCA-3+ BDC) or three-color
(CD1c+ BDC) immunofluorescence, respectively. The
results of the phenotypic analysis are shown in Table II and can be summarized as follows. None
of the BDC subsets expressed CD1a, CD8, CD15, CD16, CD19, CD20, CD23,
CD25, CD27, CD34, CD61, CD69, CD71, CD77, CD80, CD83, glycophorin A,
TCR, AC133, IgD, IgM, or the CMRF-56 Ag. All BDC subsets
expressed CD43, CD44, CD54, and MHC class I molecules at similar
levels. BDCA-2+ BDC differed from the other two
subsets in that they did not express CD13, CD40, CD45RO, and CD56, but
did express CD45RA and small amounts of CD10, and in that they
expressed lower levels of CD18, CD38, CD58, CD98, CD116, and CLA, but
higher levels of CD4. Minor proportions of
BDCA-2+ BDC are CD2 and CD7 positive,
respectively. CD1c+ BDC differ from the other two
subsets in that they express higher levels of MHC class II molecules,
but lower levels of CD62L, and in that they are all positive for CD2
and the Fc receptors CD32, CD64, and FcRI. Probably due to the Fc
receptor expression, CD1c+ BDC are also positive
for IgG, and . Furthermore, some CD1c+ BDC
are positive for CD14 and CD11b, whereby the level of expression
inversely correlates with the level of both CD1c and CD2 expression
(data not shown). BDCA-3+ BDC differ from the
other two subsets in that they express CD36 at a much lower level, and
they appear to express low levels of CD5. Finally, apart from CD11c and
CD123, at least one additional Ag, CD33, is useful for discrimination
of all three subsets: CD33 is expressed at low levels on
BDCA-2+ BDC, at intermediate levels on
BDCA-3+ BDC, and at high levels on
CD1c+ BDC.
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Freshly isolated CD1c+ BDC and
BDCA-3+ BDC were cultured for 2 days in medium
without any supplemented cytokines, and freshly isolated
BDCA-2+ BDC were cultured for 1 day in medium
supplemented with IL-3 and CD40 mAb on CD32-transfected fibroblasts.
After the culture period, cells were analyzed for the expression of
CD1a, CD80, CD83, CD86, and HLA-DR. For the purpose of comparison,
immature Mo-DC and mature Mo-DC were also included (25, 26). As shown in Fig. 9, in
contrast to immature Mo-DC and mature Mo-DC, none of the BDC subsets
expressed CD1a after the culture period. However, the costimulatory
molecules CD80 and CD86, the dendritic cell activation Ag CD83
(27), and HLA-DR molecules were up-regulated upon
culturing all three BDC subsets to a similar level compared with mature
Mo-DC. The results were not significantly different in another
experiment in which all three BDC subsets were cultured for 2 days in
medium supplemented with IL-3, IL-4, and GM-CSF (data not shown).
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The endocytic capacity of purified CD1c+,
BDCA-2+ and BDCA-3+ BDC,
and, as controls, purified CD3+ T cells and
immature Mo-DC was examined by culturing the cells at 37°C in the
presence of LY and analyzing the uptake of LY after various periods by
flow cytometry. As shown in Fig. 10, unlike purified CD3+ T cells, purified
CD1c+ BDC, BDCA-3+ BDC, and
to some extent BDCA-2+ BDC have the ability to
endocytose LY. Similar results were obtained using FITC-dextran (data
not shown). The endocytic capacities of all BDC populations are much
lower if compared with immature Mo-DC.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This immunization technique combined with a powerful procedure for rapid isolation of large numbers of BDC has permitted us to produce a panel of mAb that recognize three presumably novel BDC Ags: BDCA-2, BDCA-3, and BDCA-4. We found that in noncultured human blood BDCA-2 and BDCA-4 are exclusively expressed by a CD123bright CD11c- DC population. This DC population is now commonly referred to as plasmacytoid BDC (4, 5, 6, 7, 10, 14, 16). Using BDCA-2 or BDCA-4 as a surface marker for immunomagnetic isolation and/or flow cytometric identification of plasmacytoid BDC, our results on frequency, immunophenotype, morphology, endocytic capacity, and maturation of these cells were consistent with most previous reports where a large panel of leukocyte Ags was used (3, 4, 5, 6, 7, 8, 10, 14). This clearly illustrates that both Ags are useful markers for plasmacytoid BDC in noncultured human blood. Preliminary results from stainings of tonsilar cells indicate that the T cell zone-associated plasmacytoid DC in peripheral lymphoid organs can also be discriminated from other lymphoid tissue-associated DC populations, such as germinal center DC, interdigitating DC, and follicular DC based on the expression of BDCA-2 and BDCA-4 (data not shown).
Concerning this point it is interesting that, unlike BDCA-2, BDCA-4 is also expressed on several in vitro differentiated DC populations: 1) in contrast to BDCA-2, BDCA-4 is expressed on both Mo-DC and CD34-derived DC; 2) whereas expression of BDCA-2 is completely down-regulated on plasmacytoid BDC once they have undergone IL-3-mediated maturation in culture, expression of BDCA-4 is, in fact, up-regulated on cultured plasmacytoid BDC; and 3) in contrast to BDCA-2, BDCA-4 is expressed within 12 h by a majority of cultured CD11c+ BDC, although it is unclear whether this is only true for the larger CD1c+ CD11cbright population or is also true for the smaller CD1c- CD11c+ CD123- population. The finding that no other BDCA-4+ cells than plasmacytoid BDC appear to be present in noncultured human blood, in fact, indicates that no counterparts of the in vitro differentiated BDCA-4+ DC populations are present in blood.
Labeling of BDCA-2 by anti-BDCA-2 mAb and incubation at 37°C induce rapid internalization of the Ag-mAb complex. In analogy to other endocytic receptors on DC that are down-regulated upon maturation, such as langerin (39), it is tempting to speculate that BDCA-2 may be a receptor with Ag capture function.
Expression of BDCA-3 was found to be restricted to a small population
of CD1c- CD11c+
CD123- BDC in noncultured human blood. With
respect to phenotype, morphology, endocytic capacity, and maturation
requirements, this BDC population is quite similar to the
CD1c+ CD11cbright
CD123dim BDC population. However, apart from
BDCA-3 and CD1c expression, our immunophenotypic analysis has revealed
some striking differences: in contrast to CD1c+
BDC, BDCA-3+ BDC do not express the Fc receptors
CD32, CD64, and FcRI, and they do not express CD2. The lack of Fc
receptor expression indicates that BDCA-3+ BDC,
unlike CD1c+ BDC (40, 41), do not
have the capability of Ig-mediated Ag uptake.
In principle, BDCA-3+ BDC and CD1c+ BDC may represent maturational stages of the same cell type or unrelated DC types. The fact that BDCA-3 expression is induced on a reasonable proportion of CD1c+ BDC after culture-induced maturation may be considered an argument in favor of the former concept, but because the same observation was also made for IL-3-stimulated plasmacytoid BDC, such data could also be taken as an argument in favor of a similar relationship between BDCA-3+ BDC and plasmacytoid BDC.
A recent study by Ito et al. (7) has provided evidence
that CD1c+ CD11cbright BDC,
in contrast to CD1c-
CD11c+ BDC, have the capacity to acquire
Langerhans cell characteristics (expression of Lag Ag, E-cadherin, and
langerin, and presence of Birbeck granules) when cultured with GM-CSF,
IL-4, and TGF-1. If BDCA-3+ BDC and
CD1c+ BDC represent maturational stages of the
same cell type, this would indicate that BDCA-3+
BDC have either already lost or not yet acquired the capacity to
differentiate into Langerhans cells.
In contradiction to our results, Ito et al. (7) have reported that CD1c+ CD11cbright BDC, unlike CD1c- CD11c+ BDC, express CD1a. This is, in fact, more than doubtful. The authors stated that they have used the two mAb, BL-6 and B-B5, for staining of CD1a and that a difference in staining intensity was actually observed when the two mAb were compared (staining with B-B5 was probably brighter). We found that staining of BDC was clearly negative using optimal titers of the CD1a mAb BL-6 and HI149, but positive using B-B5. Moreover, it turned out that B-B5, unlike BL-6 and HI149, stained a high proportion of CD19+ B cells in blood. Thus, the staining pattern of B-B5 was quite reminiscent of a CD1c mAb rather than a CD1a mAb, and, in fact, we could show that our CD1c mAb AD5-8E7 inhibits binding of B-B5 to MOLT-4 cells (data not shown). Therefore, we conclude that B-B5 recognizes CD1c and that CD1c+ BDC do not express CD1a.
Staining of CD1c+ BDC for CD1c, CD2, and CD14 revealed that a minor proportion of BDC expresses CD14 to a variable degree and that the level of CD1c as well as CD2 expression on these cells is inversely proportional to the level of CD14 expression (data not shown). This observation is in accordance with a linear differentiation model, in which CD1c+ CD2+ CD11cbright CD14- BDC are the progeny of CD14+ CD1c- CD2- monocytes rather than the progeny of a common precursor of both cell types. This concept finds further support in the observation of Crawford et al. (42) that a considerable proportion of CD14+ monocytes already expresses very low levels of CD2 and has the capacity to rapidly differentiate into mature DC with typical dendritic morphology and potent T cell stimulatory function when cultured with GM-CSF and IL-4.
In summary, the results of this study identify three presumably novel markers of BDC in human blood: 1) BDCA-2, 2) BDCA-4 for CD11c- CD123bright plasmacytoid BDC, and 3) BDCA-3 for CD11c+ CD123- BDC. A third population of CD11cbright CD123dim BDC can be identified based on the expression of CD1c and the lack of B cell lineage Ags. It is noteworthy that the expression profile of BDCA-2, BDCA-3, and BDCA-4 is virtually indistinguishable on all three subsets after maturation in culture. The use of CD1c (BDCA-1), BDCA-2, BDCA-3, and BDCA-4 mAb provides a convenient and efficient way to rapidly detect, enumerate, and isolate BDC populations from PBMC, leukapheresis material, or whole blood without apparent functional perturbation. This will be a valuable aid for their further functional and molecular characterization and may prove useful in elucidating their interrelationships. Furthermore, the ability to easily isolate BDC populations to homogeneity will greatly facilitate their clinical use.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: BDC, blood dendritic cell; DC, dendritic cell; lin, lineage; MACS, magnetic cell sorting; Mo-DC, monocyte-derived DC; CD34-derived DC, CD34+ hemopoietic progenitor cell-derived DC; LY, Lucifer Yellow.
Received for publication April 21, 2000. Accepted for publication August 29, 2000.
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T. D. de Gruijl, C. C. Sombroek, S. M. Lougheed, D. Oosterhoff, J. Buter, A. J. M. van den Eertwegh, R. J. Scheper, and H. M. Pinedo A Postmigrational Switch among Skin-Derived Dendritic Cells to a Macrophage-Like Phenotype Is Predetermined by the Intracutaneous Cytokine Balance. J. Immunol., June 15, 2006; 176(12): 7232 - 7242. [Abstract] [Full Text] [PDF]
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F. M. Ndungu, L. Sanni, B. Urban, R. Stephens, C. I. Newbold, K. Marsh, and J. Langhorne CD4 T Cells from Malaria-Nonexposed Individuals Respond to the CD36-Binding Domain of Plasmodium falciparum Erythrocyte Membrane Protein-1 via an MHC Class II-TCR-Independent Pathway J. Immunol., May 1, 2006; 176(9): 5504 - 5512. [Abstract] [Full Text] [PDF]
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 L. M. Ellis The role of neuropilins in cancer Mol. Cancer Ther., May 1, 2006; 5(5): 1099 - 1107. [Abstract] [Full Text] [PDF]
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 M. Stasiolek, A. Bayas, N. Kruse, A. Wieczarkowiecz, K. V. Toyka, R. Gold, and K. Selmaj Impaired maturation and altered regulatory function of plasmacytoid dendritic cells in multiple sclerosis Brain, May 1, 2006; 129(5): 1293 - 1305. [Abstract] [Full Text] [PDF]
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J. Zhang, A. Raper, N. Sugita, R. Hingorani, M. Salio, M. J. Palmowski, V. Cerundolo, and P. R. Crocker Characterization of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors Blood, May 1, 2006; 107(9): 3600 - 3608. [Abstract] [Full Text] [PDF]
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 B. C. URBAN, M. J. SHAFI, D. V. CORDERY, A. MACHARIA, B. LOWE, K. MARSH, and T. N. WILLIAMS FREQUENCIES OF PERIPHERAL BLOOD MYELOID CELLS IN HEALTHY KENYAN CHILDREN WITH {alpha}+ THALASSEMIA AND THE SICKLE CELL TRAIT Am J Trop Med Hyg, April 1, 2006; 74(4): 578 - 584. [Abstract] [Full Text] [PDF]
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T. M. C. Hornell, T. Burster, F. L. Jahnsen, A. Pashine, M. T. Ochoa, J. J. Harding, C. Macaubas, A. W. Lee, R. L. Modlin, and E. D. Mellins Human Dendritic Cell Expression of HLA-DO Is Subset Specific and Regulated by Maturation J. Immunol., March 15, 2006; 176(6): 3536 - 3547. [Abstract] [Full Text] [PDF]
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A. Granelli-Piperno, I. Shimeliovich, M. Pack, C. Trumpfheller, and R. M. Steinman HIV-1 Selectively Infects a Subset of Nonmaturing BDCA1-Positive Dendritic Cells in Human Blood J. Immunol., January 15, 2006; 176(2): 991 - 998. [Abstract] [Full Text] [PDF]
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 J.-J. Goval, R. Greimers, J. Boniver, and L. de Leval Germinal Center Dendritic Cells Express More ICAM-1 Than Extrafollicular Dendritic Cells and ICAM-1/LFA-1 Interactions are Involved in the Capacity of Dendritic Cells to Induce PBMCs Proliferation J. Histochem. Cytochem., January 1, 2006; 54(1): 75 - 84. [Abstract] [Full Text] [PDF]
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S. Yamagami, S. Yokoo, T. Usui, H. Yamagami, S. Amano, and N. Ebihara Distinct Populations of Dendritic Cells in the Normal Human Donor Corneal Epithelium Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4489 - 4494. [Abstract] [Full Text] [PDF]
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R. Zambello, T. Berno, G. Cannas, I. Baesso, G. Binotto, E. Bonoldi, P. Bevilacqua, M. Miorin, M. Facco, L. Trentin, et al. Phenotypic and functional analyses of dendritic cells in patients with lymphoproliferative disease of granular lymphocytes (LDGL) Blood, December 1, 2005; 106(12): 3926 - 3931. [Abstract] [Full Text] [PDF]
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G. Penna, A. Roncari, S. Amuchastegui, K. C. Daniel, E. Berti, M. Colonna, and L. Adorini Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3 Blood, November 15, 2005; 106(10): 3490 - 3497. [Abstract] [Full Text] [PDF]
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T. Burster, A. Beck, E. Tolosa, P. Schnorrer, R. Weissert, M. Reich, M. Kraus, H. Kalbacher, H.-U. Haring, E. Weber, et al. Differential Processing of Autoantigens in Lysosomes from Human Monocyte-Derived and Peripheral Blood Dendritic Cells J. Immunol., November 1, 2005; 175(9): 5940 - 5949. [Abstract] [Full Text] [PDF]
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M. Lindstedt, K. Lundberg, and C. A. K. Borrebaeck Gene Family Clustering Identifies Functionally Associated Subsets of Human In Vivo Blood and Tonsillar Dendritic Cells J. Immunol., October 15, 2005; 175(8): 4839 - 4846. [Abstract] [Full Text] [PDF]
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A. Granelli-Piperno, A. Pritsker, M. Pack, I. Shimeliovich, J.-F. Arrighi, C. G. Park, C. Trumpfheller, V. Piguet, T. M. Moran, and R. M. Steinman Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin/CD209 Is Abundant on Macrophages in the Normal Human Lymph Node and Is Not Required for Dendritic Cell Stimulation of the Mixed Leukocyte Reaction J. Immunol., October 1, 2005; 175(7): 4265 - 4273. [Abstract] [Full Text] [PDF]
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D. McIlroy, S. Tanguy-Royer, N. Le Meur, I. Guisle, P.-J. Royer, J. Leger, K. Meflah, and M. Gregoire Profiling dendritic cell maturation with dedicated microarrays J. Leukoc. Biol., September 1, 2005; 78(3): 794 - 803. [Abstract] [Full Text] [PDF]
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 K. Vermaelen and R. Pauwels Pulmonary Dendritic Cells Am. J. Respir. Crit. Care Med., September 1, 2005; 172(5): 530 - 551. [Abstract] [Full Text] [PDF]
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M. Rossi and J. W. Young Human Dendritic Cells: Potent Antigen-Presenting Cells at the Crossroads of Innate and Adaptive Immunity J. Immunol., August 1, 2005; 175(3): 1373 - 1381. [Abstract] [Full Text] [PDF]
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L. S. Brackenbury, B. V. Carr, Z. Stamataki, H. Prentice, E. A. Lefevre, C. J. Howard, and B. Charleston Identification of a Cell Population That Produces Alpha/Beta Interferon In Vitro and In Vivo in Response to Noncytopathic Bovine Viral Diarrhea Virus J. Virol., June 15, 2005; 79(12): 7738 - 7744. [Abstract] [Full Text] [PDF]
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S. Patterson, H. Donaghy, P. Amjadi, B. Gazzard, F. Gotch, and P. Kelleher Human BDCA-1-Positive Blood Dendritic Cells Differentiate into Phenotypically Distinct Immature and Mature Populations in the Absence of Exogenous Maturational Stimuli: Differentiation Failure in HIV Infection J. Immunol., June 15, 2005; 174(12): 8200 - 8209. [Abstract] [Full Text] [PDF]
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L. Galibert, G. S. Diemer, Z. Liu, R. S. Johnson, J. L. Smith, T. Walzer, M. R. Comeau, C. T. Rauch, M. F. Wolfson, R. A. Sorensen, et al. Nectin-like Protein 2 Defines a Subset of T-cell Zone Dendritic Cells and Is a Ligand for Class-I-restricted T-cell-associated Molecule J. Biol. Chem., June 10, 2005; 280(23): 21955 - 21964. [Abstract] [Full Text] [PDF]
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R. Pelayo, J. Hirose, J. Huang, K. P. Garrett, A. Delogu, M. Busslinger, and P. W. Kincade Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow Blood, June 1, 2005; 105(11): 4407 - 4415. [Abstract] [Full Text] [PDF]
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K. B. Gurney, J. Elliott, H. Nassanian, C. Song, E. Soilleux, I. McGowan, P. A. Anton, and B. Lee Binding and Transfer of Human Immunodeficiency Virus by DC-SIGN+ Cells in Human Rectal Mucosa J. Virol., May 1, 2005; 79(9): 5762 - 5773. [Abstract] [Full Text] [PDF]
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J. Dalgaard, K. J. Beckstrom, F. L. Jahnsen, and J. E. Brinchmann Differential capability for phagocytosis of apoptotic and necrotic leukemia cells by human peripheral blood dendritic cell subsets J. Leukoc. Biol., May 1, 2005; 77(5): 689 - 698. [Abstract] [Full Text] [PDF]
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N. Toyama-Sorimachi, Y. Omatsu, A. Onoda, Y. Tsujimura, T. Iyoda, A. Kikuchi-Maki, H. Sorimachi, T. Dohi, S. Taki, K. Inaba, et al. Inhibitory NK Receptor Ly49Q Is Expressed on Subsets of Dendritic Cells in a Cellular Maturation- and Cytokine Stimulation-Dependent Manner J. Immunol., April 15, 2005; 174(8): 4621 - 4629. [Abstract] [Full Text] [PDF]
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B. Drenou, L. Amiot, N. Setterblad, S. Taque, V. Guilloux, D. Charron, R. Fauchet, and N. Mooney MHC class II signaling function is regulated during maturation of plasmacytoid dendritic cells J. Leukoc. Biol., April 1, 2005; 77(4): 560 - 567. [Abstract] [Full Text] [PDF]
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E. Chung, S. B. Amrute, K. Abel, G. Gupta, Y. Wang, C. J. Miller, and P. Fitzgerald-Bocarsly Characterization of Virus-Responsive Plasmacytoid Dendritic Cells in the Rhesus Macaque Clin. Vaccine Immunol., March 1, 2005; 12(3): 426 - 435. [Abstract] [Full Text] [PDF]
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I. K. Demedts, G. G. Brusselle, K. Y. Vermaelen, and R. A. Pauwels Identification and Characterization of Human Pulmonary Dendritic Cells Am. J. Respir. Cell Mol. Biol., March 1, 2005; 32(3): 177 - 184. [Abstract] [Full Text] [PDF]
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 W. Vermi, E. Riboldi, V. Wittamer, F. Gentili, W. Luini, S. Marrelli, A. Vecchi, J.-D. Franssen, D. Communi, L. Massardi, et al. Role of ChemR23 in directing the migration of myeloid and plasmacytoid dendritic cells to lymphoid organs and inflamed skin J. Exp. Med., February 22, 2005; 201(4): 509 - 515. [Abstract] [Full Text] [PDF]
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S. Aggarwal and M. F. Pittenger Human mesenchymal stem cells modulate allogeneic immune cell responses Blood, February 15, 2005; 105(4): 1815 - 1822. [Abstract] [Full Text] [PDF]
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D C Baumgart, D Metzke, J Schmitz, A Scheffold, A Sturm, B Wiedenmann, and A U Dignass Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells Gut, February 1, 2005; 54(2): 228 - 236. [Abstract] [Full Text] [PDF]
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 P. D. Cravens, M. W. Melkus, A. Padgett-Thomas, M. Islas-Ohlmayer, M. del P. Martin, and J. V. Garcia Development and Activation of Human Dendritic Cells In Vivo in a Xenograft Model of Human Hematopoiesis Stem Cells, February 1, 2005; 23(2): 264 - 278. [Abstract] [Full Text] [PDF]
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F. Garnache-Ottou, L. Chaperot, S. Biichle, C. Ferrand, J.-P. Remy-Martin, E. Deconinck, P. D. de Tailly, B. Bulabois, J. Poulet, E. Kuhlein, et al. Expression of the myeloid-associated marker CD33 is not an exclusive factor for leukemic plasmacytoid dendritic cells Blood, February 1, 2005; 105(3): 1256 - 1264. [Abstract] [Full Text] [PDF]
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L. Broderick, S. J. Yokota, J. Reineke, E. Mathiowitz, C. C. Stewart, M. Barcos, R. J. Kelleher Jr., and R. B. Bankert Human CD4+ Effector Memory T Cells Persisting in the Microenvironment of Lung Cancer Xenografts Are Activated by Local Delivery of IL-12 to Proliferate, Produce IFN-{gamma}, and Eradicate Tumor Cells J. Immunol., January 15, 2005; 174(2): 898 - 906. [Abstract] [Full Text] [PDF]
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B. A. Zabel, A. M. Silverio, and E. C. Butcher Chemokine-Like Receptor 1 Expression and Chemerin-Directed Chemotaxis Distinguish Plasmacytoid from Myeloid Dendritic Cells in Human Blood J. Immunol., January 1, 2005; 174(1): 244 - 251. [Abstract] [Full Text] [PDF]
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G. Le Friec, F. Gros, Y. Sebti, V. Guilloux, C. Pangault, R. Fauchet, and L. Amiot Capacity of myeloid and plasmacytoid dendritic cells especially at mature stage to express and secrete HLA-G molecules J. Leukoc. Biol., December 1, 2004; 76(6): 1125 - 1133. [Abstract] [Full Text] [PDF]
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S. Beckebaum, X. Zhang, X. Chen, Z. Yu, A. Frilling, G. Dworacki, H. Grosse-Wilde, C. E. Broelsch, G. Gerken, and V. R. Cicinnati Increased Levels of Interleukin-10 in Serum from Patients with Hepatocellular Carcinoma Correlate with Profound Numerical Deficiencies and Immature Phenotype of Circulating Dendritic Cell Subsets Clin. Cancer Res., November 1, 2004; 10(21): 7260 - 7269. [Abstract] [Full Text] [PDF]
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R. Lande, E. Giacomini, B. Serafini, B. Rosicarelli, G. D. Sebastiani, G. Minisola, U. Tarantino, V. Riccieri, G. Valesini, and E. M. Coccia Characterization and Recruitment of Plasmacytoid Dendritic Cells in Synovial Fluid and Tissue of Patients with Chronic Inflammatory Arthritis J. Immunol., August 15, 2004; 173(4): 2815 - 2824. [Abstract] [Full Text] [PDF]
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J. Dai, N. J. Megjugorac, S. B. Amrute, and P. Fitzgerald-Bocarsly Regulation of IFN Regulatory Factor-7 and IFN-{alpha} Production by Enveloped Virus and Lipopolysaccharide in Human Plasmacytoid Dendritic Cells J. Immunol., August 1, 2004; 173(3): 1535 - 1548. [Abstract] [Full Text] [PDF]
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M. Mohty, E. Jourdan, N. B. Mami, N. Vey, G. Damaj, D. Blaise, D. Isnardon, D. Olive, and B. Gaugler Imatinib and plasmacytoid dendritic cell function in patients with chronic myeloid leukemia Blood, June 15, 2004; 103(12): 4666 - 4668. [Abstract] [Full Text] [PDF]
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 F. Heil, H. Hemmi, H. Hochrein, F. Ampenberger, C. Kirschning, S. Akira, G. Lipford, H. Wagner, and S. Bauer Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 Science, March 5, 2004; 303(5663): 1526 - 1529. [Abstract] [Full Text] [PDF]
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N. J. Megjugorac, H. A. Young, S. B. Amrute, S. L. Olshalsky, and P. Fitzgerald-Bocarsly Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells J. Leukoc. Biol., March 1, 2004; 75(3): 504 - 514. [Abstract] [Full Text] [PDF]
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A. Kaser, S. Kaser, N. C. Kaneider, B. Enrich, C. J. Wiedermann, and H. Tilg Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression Blood, January 15, 2004; 103(2): 648 - 655. [Abstract] [Full Text] [PDF]
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) and CD11c+ (
) BDC, respectively.
For BDCA-2 and BDCA-4, MFI values were calculated by subtracting the
values obtained with isotype control mAb from the values obtained with
the AC144 and AD5-17F6 mAb, respectively. For BDCA-3, MFI values are
calculated by subtracting the values obtained without any staining mAb
(autofluorescence) from the values obtained with AD5-5E8 mAb.
), BDCA-3+ BDC
(