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PLENARY PAPER
From the Department of Cell Biology, Faculty of
Biology, Complutense University, Madrid, Spain; and Faculté de
Médecine Pasteur, INSERM U364, Nice, France.
We describe a new B220+ subpopulation of immaturelike
dendritic cells (B220+ DCs) with low levels of expression
of major histocompatibility complex (MHC) and costimulatory molecules
and markedly reduced T-cell stimulatory potential, located in the
thymus, bone marrow, spleen, and lymph nodes. B220+ DCs
display ultrastructural characteristics resembling those of human
plasmacytoid cells and accordingly produce interferon- Maintenance of immunologic self-tolerance is an
essential process directed at preventing harmful autoimmune diseases
caused by autoreactive T cells capable of responding to self-antigens. Avoidance of pathologic reactivity of self-reactive T cells may occur
as a consequence of T-cell deletion, T-cell unresponsiveness, or, in
some instances, T helper cell type 2 (TH2) skewing (reviewed in
Hackstein et al1). Deletion of autoreactive T-cell clones, resulting in T-cell-negative selection, takes place essentially in the
thymus under the control of thymic dendritic cells (DCs) and epithelial
cells (reviewed in Ardavín2). In contrast, the
molecular mechanisms controlling T-cell unresponsiveness or anergy,
which is the basis of peripheral tolerance, are not fully understood.
However, increasing evidence supports that T regulatory (Treg) cells play an essential role in the control of
autoreactive T-cell clones and, therefore, in the maintenance of T-cell
peripheral tolerance because of their capacity to suppress
antigen-specific T-cell responses (reviewed in Roncarolo and
Levings3). Interestingly immature DCs have been
demonstrated to participate in the differentiation of Treg
cells (reviewed in Jonuleit et al4). In this sense, human
and mouse interleukin-10 (IL-10)-treated immature DCs have been
reported to induce antigen-specific T-cell anergy.5-9 In addition, in vitro-generated human immature DCs have been demonstrated to induce the differentiation of Treg cells in vitro and in
vivo.9,10 Therefore, on the basis of these data, the
tolerogenic potential of DCs has been proposed to be correlated with an
immature DC state.1 On the other hand, DC-mediated
induction of murine T-cell tolerance has also been reported to be
exerted by specialized DCs, obtained from nonlymphoid organs such as
the liver11 or from mucosal locations such as the Peyer
patches12 and the lung.13
With regard to the characterization of physiological tolerogenic DCs,
splenic CD8 Murine DCs can be subdivided into 3 main subpopulations, based on
CD8 Mice
Isolation of B220+ DCs and B220 Flow cytometry Analysis of B220+ DCs in low-density cell fractions from C57BL/6 or BALB/c mouse thymus, spleen, lymph node, and bone marrow was performed after double staining with FITC-conjugated anti-CD11c (clone N418) and PE-conjugated anti-B220. Analysis of B220+ DCs from B-cell-deficient mice was performed after double staining with FITC-conjugated anti-B220 (clone RA3-6B2; Caltag, San Francisco, CA) and PE-conjugated anti-MHC class II (MHC class II; clone M5/114; PharMingen). Phenotypic analysis of B220+ DCs and B220 DCs was performed on DC-enriched cell fractions
after triple staining with FITC-conjugated anti-CD11c (clone N418),
PE-conjugated anti-B220, and biotin-conjugated anti-MHC class II
(clone FD11-54.3), anti-DEC-205 (clone NLDC-145), anti-CD24
(heat-stable antigen [HSA], clone M1/69), anti-CD11b (Mac-1, clone
M1/70), anti-macrophage antigen F4/80 (clone 31-A3-1), anti-CD4 (clone
GK1.5), anti-CD62L (clone Mel-14), anti-Ly-6C (clone ER-MP20),
anti-Ly-6G (Gr-1; clone RB6-8C5), anti-CD40 (clone FGK45), anti-CD86
(B7-2, clone GL1; PharMingen), anti-IL-3R (CD123, clone 5B11;
PharMingen), anti-CD19 (clone 1D3; PharMingen), or anti-CD8
(clone 53-6.72) followed by streptavidin-tricolor (Caltag).
Electron microscopy MACS-sorted thymic B220+ DCs were fixed with 1% glutaraldehyde and 1% paraformaldehyde in 0.1 M, pH 7.6, Sørensen phosphate buffer for 1 hour at 4°C, postfixed with 1% OsO4 in the same buffer for 1 hour at 4°C, dehydrated in graded acetone solutions, and embedded in Embed-812 (Electron Microscopy Sciences, Washington, PA). Ultrathin sections (70-80 nm) were counterstained with uranyl acetate and lead citrate and were examined with a JEOL 1010 electron microscope (JEOL, Tokyo, Japan).Treatment with CpG oligodeoxynucleotides MACS-sorted (or FACS-sorted for cytokine detection and RT-PCR analysis) thymic B220+ DCs, thymic B220 DCs,
and, in some experiments, peritoneal macrophages were cultured for 12 hours at 37°C in control conditions or in the presence of 6 µg/mL
CpG oligodeoxynucleotide-1826, TCC ATG ACG TTC CTG ACG TT19
(CpG). Culture medium was RPMI 1640 supplemented with 10% FCS, 10 mM
HEPES, 50 µM 2-mercaptoethanol, 100 U/mL penicillin-streptomycin. CpG-treated or untreated cells were subsequently assayed for the expression of DC maturation-related cell surface markers, for T-cell
stimulatory potential in mixed leukocyte reaction (MLR), for
the production of IL-10, IL-12, and interferon (IFN-), and for
the expression of the chemokine receptors CCR5, CCR6, and CCR7. The
effect of CpG on the expression of DC maturation-related markers was
compared with that of bacterial lipopolysaccharide (LPS) after 12-hour
culture in the presence of 1 µg/mL LPS from Salmonella
typhimurium (Sigma, St Louis, MO).
MLR assay MACS-sorted CpG-treated or -untreated thymic B220+ DCs and B220 DCs from C57BL/6 (H-2b) mice
were cultured with T cells purified from BALB/c (H-2d)
mesenteric lymph nodes in flat-bottomed, 96-well plates
(1 × 105 cells per well), at different
antigen-presenting cell (APC)/T cell ratios (1:10 to 1:100). T-cell
proliferation was assessed after 4 days by [3H] thymidine
(1 µCi/well) uptake in a 4-hour pulse.
Enzyme-linked immunosorbent assay for IL-10, IL-12, and
IFN- DCs, and peritoneal
macrophages, cultured (at 105 cells in 200 µL in 96-well
plates) in control medium or in the presence of CpG for 12 hours, were
tested for the presence of IL-10 and IL-12, using mouse IL-10 and IL-12
(p70) enzyme-linked immunosorbent assay (ELISA) kits (PharMingen), respectively.
Cryopreserved supernatants from FACS-sorted thymic B220+
DCs, cultured (at 105 cells in 200 µL in 96-well plates)
in control medium or in the presence of CpG for 12 hours or Sendai
virus for 18 hours, were tested for the presence of IFN- RT-PCR mRNA was purified from FACS-sorted cells with magnetic beads (mRNA direct micro kit; Dynal), reverse transcribed, and subjected to PCR amplification using the following primers: CCR5-forward, ACT TGG GTG GTG GCT GTG TTT; CCR5-reverse, TTG TCT TGC TGG AAA ATT GAA20; CCR6-forward, CTG CAG TTC GAA GTC ATC; CCR6-reverse, GTC ATC ACC ACC ATA ATG TTG; CCR7-forward, AGC ACC ATG GAC CCA GGG AAA CC; CCR7-reverse, CAG CAT CCA GAT GCC CAC A; IFN--forward, TGT CTG
ATG CAG CAG GTG G; IFN--reverse, AAG ACA GGG CTC TCC AGA C. PCR
conditions were: CCR5, 15 seconds at 94°C, 30 seconds at
57°C, 60 seconds at 72°C; CCR6, 15 seconds at 94°C, 15 seconds at
59°C, 45 seconds at 72°C; CCR7, 15 seconds at 94°C, 90 seconds at
68°C; IFN-, 40 seconds at 94°C, 40 seconds at 62°C, 60 seconds at 72°C. PCR products were: CCR5, 539 base pair (bp); CCR6, 320 bp;
CCR7, 561bp; IFN-, 166 bp. PCR was performed on a GeneAmp PCR System
9700, using 1.25 U AmpliTaq Gold polymerase per PCR reaction
(Perkin-Elmer, Foster City, CA). PCR products were analyzed on agarose
gels stained with ethidium bromide and photographed with a Nikon
Coolpix 950 digital camera (Nikon, Tokyo, Japan).
Induction of Treg cell differentiation by B220+ DCs As summarized in Figure 7, this assay included 3 independent culture phases. During the first phase, OVA-specific TCR transgenic T cells (OVA-TCR TCs) were cultured for 72 hours with either thymic B220+ DCs or B220
DCs isolated from BALB/c mice, at 3:1 or 6:1 T cell-APC ratios, at
105 cells per well, in 96-well plates, in the presence or
absence of 10 µg/mL OVA. Cell proliferation was assessed by
[3H] thymidine (1 µCi/well) uptake in a 16-hour pulse.
In the second phase, OVA-TCR TCs, which were precultured during the
first phase with either thymic B220+ DCs
(OVA-TCs[+B220+ DCs]) or B220 DCs
(OVA-TCs[+DCs]), at a 3:1 T cell-APC ratio, were then washed twice
to remove remaining OVA, transferred to 24-well plates, and cultured at
5 × 105 cells per well for an additional 72 hours,
without OVA, in the presence of 1 ng/mL mouse IL-2 (Peprotech, London,
United Kingdom). After this second phase, precultured OVA-TCR TCs were
used to assess whether OVA-TCs[+B220+ DCs] were anergic T
cells or Treg cells. For the anergy reversal assay,
OVA-TCs[+B220+ DCs] or OVA-TCs[+DCs] (105
per well) were cultured with BALB/c splenocytes (5 × 104
per well) in 96-well plates, with 10 µg/mL OVA, in the presence or
absence of 5 ng/mL mouse IL-2. Cell proliferation was assessed after 48 hours by [3H] thymidine (1 µCi/well) uptake in a
16-hour pulse. The Treg cell assay was performed according
to a protocol modified from Thorstenson and Khoruts21 by
culturing OVA-TCR TCs (105 per well) with BALB/c
splenocytes (105 per well) in 96-well plates, with 10 µg/mL OVA, in the presence or absence of OVA-TCs[+B220+
DCs] or OVA-TCs[+DCs] (105 per well). Cell proliferation
was assessed after 36 hours by [3H] thymidine (1 µCi/well) uptake in a 16-hour pulse.
Identification of B220+ DCs Preliminary studies of thymic DC CD11c expression (not shown) revealed the existence of CD11cint and CD11chi subpopulations. This differential CD11c expression level in fact corresponded to 2 discrete cell subsets that could be precisely defined by correlating CD11c with the expression of the B-cell marker B220 (Figure 1A). B220 DCs with
high levels of CD11c corresponded to the cell population considered
conventional DCs, whereas CD11cint cells expressed B220 and
will be named hereafter B220+ DCs, for B220+
regulatory DCs. CD11c B220+ cells
corresponded to thymic B cells.22 B220 DCs
and B220+ DCs were present in the thymus at approximately a
1:1 ratio. As a consequence, in numerous reports B220+ DCs
were inadvertently included in thymic DC preparations, unless the
isolation method used involved the elimination of cells expressing CD4,
Ly-6C, Ly-6G (Gr-1) (Figure 2A) or
nonadherent cells because B220+ DCs had a low adherence
potential (not shown). Thymic B220 DCs had a slightly
higher forward-scatter profile than thymic B220+ DCs; the
latter displayed significantly lower side scatter, reflecting less
complex cytoplasmic and cell surface characteristics, in agreement with
electron microscopic studies. As shown in Figure 1B, thymic
B220+ DCs displayed an oval or irregularly shaped nucleus,
short microvilli at the cell surface, numerous rough
endoplasmic reticulum cisternae, and a clearly defined perinuclear area
containing a well-developed Golgi apparatus and numerous mitochondria.
Thymic B220+ DCs had lower viability on culture than
B220 DCs (approximately 20% versus 60% viable cells,
after 12-hour incubation in RPMI medium with 5% FCS, in the absence of
exogenous cytokines; data not shown). Although this result could
reflect that B220+ DCs represented a final differentiation
stage of a B220 DC subset, this appeared to be unlikely
because B220+ DC and B220 DC subpopulations
were generated simultaneously after the reconstitution of irradiated
mice with bone marrow precursors (C.A., unpublished data).
B220+ DCs were also found in the spleen, peripheral and
mesenteric lymph nodes, and bone marrow (Figure 1C), but not in the blood. The B220 Phenotypic analysis of B220+ DCs The phenotype of thymic B220+ DCs performed in DC-enriched cell fractions is presented in Figure 2A. B220+ DCs displayed lower CD11c and MHC class II expression levels than B220 DCs. In addition B220+ DCs shared CD8
and CD24 (HSA) expression and nonexpression of CD11b, F4/80, and CD62L
with thymic B220 DCs, but, in contrast to the latter,
they were negative for DEC-205 and for the costimulatory molecules CD40
and CD86. Interestingly, thymic B220+ DCs, but not
B220 DCs, expressed Ly-6C and Ly-6G (Gr-1). The phenotype
of B220+ DCs located in the spleen, lymph nodes, and bone
marrow did not differ significantly from that of thymic
B220+ DCs except for the expression of CD8. This
molecule has allowed the definition of CD8,
CD8int, and CD8+ DC subsets (not
expressing B220), with differential distribution among lymphoid and
hemopoietic organs.15 Regarding B220+ DCs,
their CD8 expression differed depending on their location (Figure
2B). In the thymus and lymph nodes, approximately 50% of
B220+ DCs expressed high CD8 levels, and 50% displayed
from low to intermediate levels. Within the spleen, 50% had
intermediate to high CD8 levels, whereas the rest were
CD8. Finally, bone marrow B220+ DCs did
not express CD8. Whether CD8 level expression by
B220+ DCs reflects the existence of different
B220+ DC subsets has to be defined. Alternatively, CD8
expression by a unique B220+ DC population may be subjected
to a differential regulation depending on location. In this sense, high
CD8 levels could correlate with their location in relation to T-cell
areas. According to this hypothesis, most B220+ DCs from
thymus and bone marrow are CD8+ and
CD8, respectively. Similarly, CD8 expression by
B220 DCs could be subjected to environmental regulation.
In this regard, it has been recently reported that splenic
CD8+ DCs originate from the CD8 subset
by a maturation process involving CD8, DEC-205, and CD24 up-regulation.24 Regulation of CD8 expression by
B220+ DCs and B220 DCs is under investigation
in our laboratory.
CpG-induced maturation and T-cell stimulatory potential of B220+ DCs The low or null MHCII, CD40, and CD86 levels expressed by B220+ DCs most likely revealed an immature DC-like state; therefore, it could be hypothesized that up-regulation of these molecules by B220+ DCs could occur on culture in the presence of compounds known to induce a mature DC state. To test this hypothesis MACS-purified thymic B220+ DCs were treated with CpG or bacterial LPS, each of which efficiently promotes DC maturation.25 As illustrated in Figure 3A, 12-hour culture of B220+ DCs in the presence of CpG determined a strong MHCII up-regulation and the expression of high levels of CD40 and CD86. Comparison of the effect of CpG on thymic B220+ DCs and thymic B220 DCs that express CD8 (CD8+ DCs),
revealed that this DC maturation inducer had a comparable effect on the
CD8+ DC subset (Figure 3B). CD8 expression by
B220+ DCs was not significantly influenced by CpG
treatment, but a slight CD8 down-regulation was noticed for
CD8+ DCs. A similar effect was produced by LPS, though
under the experimental conditions considered in our assay, CpG promoted
a stronger CD86 up-regulation by B220+ DCs than LPS
(Figure 3A).
When tested in an MLR assay for their ability to stimulate T-cell
proliferation, thymic B220+ DCs displayed a low T-cell
stimulatory capacity when compared with thymic CD8+ DCs
(Figure 4A). This could be related to
their low MHCII and costimulatory molecule expression levels, and it
could be hypothesized that up-regulation of these molecules on
B220+ DCs could endow them with a higher ability to induce
T-cell activation and proliferation. According to this view, when
thymic B220+ DCs preincubated with CpG were tested in MLR,
they displayed a T-cell stimulatory capacity comparable to that of
control CD8+ DCs, indicating that their low stimulatory
potential in control conditions could be attributed, according to our
hypothesis, to a low MHC and costimulatory molecule expression. As
expected, CpG-treated CD8+ DCs induced stronger T-cell
stimulation than their control counterparts. Therefore,
B220+ DCs could be driven to acquire a strong APC potential
on maturation. More interestingly, analysis of MHCII, CD40, and CD86
expression by B220+ DCs cultured for 12 hours in the
absence of CpG revealed that a remarkable up-regulation of these
molecules occurred (Figure 3A), though it was lower than after CpG or
LPS treatment. This result revealed that the low T-cell stimulation
potential displayed by control, non-CpG-treated B220+ DCs
most likely reflected the stimulatory capacity of cultured B220+ DCs acquired as the consequence of the up-regulation
of MHCII and costimulation molecules during the first hours of the
4-day MLR assay. Hence, these data suggest that, in fact, under
physiological conditions, B220+ DCs have a null or an
extremely reduced T-cell stimulatory capacity. In relation to their APC
ability, no IL-12 was detected after 12-hour culture of thymic
B220+ DCs in control medium, but large amounts of this
cytokine were produced after CpG stimulation (Figure 4B).
Interestingly, production of IL-12 after CpG stimulation was 2- to
3-fold higher for thymic B220+ DCs than for
CD8+ DCs. On the other hand, low but significant amounts of
IL-10 were produced by CpG-treated B220+ DCs, though the
production level was lower than that detected for peritoneal
macrophages used as positive controls for IL-10 secretion (Figure 4C).
Expression of CCR5, CCR6, and CCR7 by B220+ DCs With regard to DC-related chemokine receptors, the expression of CCR5, CCR6, and CCR7 by control or CpG-treated thymic B220+ DCs was analyzed by RT-PCR using specific primers. Thymic CD8+ DCs, B cells, and anti-CD40-matured Langerhans cells were used as positive controls for the expression of CCR5,26 CCR6,27 and CCR7,28 respectively. Thymic B220+ DCs expressed CCR5 at levels comparable to those of CD8+ DCs, but they expressed significantly lower levels of CCR6 than B cells and lower levels of CCR7-specific mRNA than mature Langerhans cells (Figure 5). Interestingly, CpG treatment did not significantly influence CCR5 or CCR6 expression, but it induced the up-regulation of CCR7, reaching expression levels similar to those detected in Langerhans cells stimulated with anti-CD40.
In conclusion, with CpG treatment, B220+ DCs can be driven to acquire the capacity to induce T-cell proliferation, produce IL-12, and up-regulate CCR7, endowing them with the potential to migrate to T-cell areas of peripheral lymphoid organs.28 Production of IFN- . Although CpG induced the secretion of
IFN- by B220+ DCs, viral stimulation induced a much
stronger production of this cytokine, and consequently the production
of IFN- by B220+ DCs after incubation with Sendai virus
was 6-fold higher than after CpG stimulation (Figure
6).
T-cell tolerogenic potential of B220+ DCs: induction of Treg cell differentiation Considered globally, the data presented above dealing with the function of B220+ DCs indicate that this subset of DCs could be induced to play an important defense role against microbial pathogens by fulfilling antigen-presenting and cytokine secretion functions. However, in steady state when not subjected to bacterial or
viral stimulationB220+ DCs appear to be inefficient APCs
because of their low MHC and costimulatory molecule expression levels.
This fact, together with their capacity to produce IL-10, prompted us
to investigate whether B220+ DCs could be endowed with a
tolerogenic potential by inducing T-cell unresponsiveness and the
differentiation of Treg cells. The experimental system used
for this purpose is described in "Materials and methods" and in
Figure 7. In brief, OVA-TCR TCs were
first cultured with thymic B220+ DCs or B220
DCs in the presence of OVA. After this first phase, OVA-TCR TCs, precultured with B220+ DCs (OVA-TCs[+B220+
DCs]) or B220 DCs (OVA-TCs[+DCs]), were cultured with
IL-2 in the absence of OVA and APCs. Importantly, less than 5% of
B220+ DCs or B220 DCs survived after the
first phase, and they were not detectable after the second culture
phase (data not shown). Following this second phase,
OVA-TCs[+B220+ DCs] were tested for the capacity of IL-2
to revert their nonresponsive state and for their Treg cell
potential. As shown in Figure 7A, B220+ DCs displayed a
reduced capacity to induce the proliferation of OVA-TCR TCs in the
presence of OVA, according to our previous data from MLR assays (Figure
4A). As expected, no cell proliferation was detected in the absence of
OVA. When OVA-TCs[+DCs] were restimulated after the second phase with
BALB/c splenocytes plus OVA, a strong cell proliferation was induced,
and this response was further increased by exogenous IL-2 (Figure 7B).
In contrast, no proliferation of OVA-TCs[+B220+ DCs]
occurred after restimulation with BALB/c splenocytes plus OVA, and this
effect could not be reverted in the presence of IL-2. This result
suggests that the nonresponsiveness induced by B220+ DCs on
OVA-TCR TCs (ie, the nonresponsiveness of OVA-TCs[+B220+
DCs]) did not correspond to an anergic state because the reversal of
anergic T cells can be achieved by exogenous IL-2.32 Based on this result, we then tested whether OVA-TCs[+B220+
DCs] were endowed with a Treg cell potential by analyzing
their capacity to inhibit the proliferation of OVA-TCR TCs cultured with syngeneic splenocytes plus OVA but not previously stimulated (Figure 7C). Interestingly, OVA-TCs[+B220+ DCs] strongly
reduced the proliferation of OVA-TCR TCs when compared with that
obtained in control conditions (ie, OVA-TCR TCs + splenocytes + OVA). In contrast, when OVA-TCs[+DCs] were used in this assay, thymidine incorporation was almost 2-fold higher than in control conditions as a result of the sum of the proliferation of
OVA-TCs[+DCs] and OVA-TCR TCs not previously stimulated.
To exclude that the inhibition of OVA-TCR TC proliferation
induced by OVA-TCs[+B220+ DCs] was only the consequence
of a dilution effect resulting from the presence of OVA-nonresponding
T cells (in this case OVA-TCs[+B220+ DCs]) among OVA-TCR
TCs and splenocytes, an additional control condition was considered.
For this purpose, OVA-TCR TCs were cultured with splenocytes plus OVA
in the presence of genuine OVA-nonresponding T cells
B220+ DCs, described in this report, constitute a new
subset of mouse DCs that, when in steady state, display characteristics of immaturelike DCs, including very low levels of MHC expression and
costimulatory molecules and a markedly reduced T-cell stimulation potential compared with conventional murine DCs not expressing B220. As
demonstrated by recent data from our laboratory, B220+ DCs
could be generated along with CD8 On stimulation with bacterial agents known to promote DC activation and
maturation, such as CpG,25 B220+ DCs acquire a
high T-cell stimulation potential, paralleled by a strong up-regulation
of MHC and costimulatory molecules, IL-12 production, and expression of
the chemokine receptor CCR7, involved in DC migration to lymphoid organ
T-cell areas.28 Globally, these functional changes in
B220+ DCs endow them with a T-cell stimulatory capacity
comparable to that of conventional stimulatory B220 Interestingly, our data demonstrate that this reduced T-cell stimulatory capacity of B220+ DCs is paralleled by their potential to induce a nonresponsive state in T cells that does not correspond to T-cell anergy because anergic T cells, but not T cells precultured with B220+ DCs, can be rescued in vitro by the addition of exogenous IL-2.32 More important, our data suggest that nonresponsive T cells generated on culture with B220+ DCs function as Treg cells, as demonstrated by their capacity to exert an inhibitory effect on T-cell proliferation (reviewed in Read and Powrie38). Therefore, our data indicate that B220+ DCs could represent a physiological subset of DCs with tolerogenic potential, not previously described, involved in the generation of Treg cells and thus in the control of autoreactive T-cell clones. Consequently, B220+ DCs could be involved in the maintenance of peripheral tolerance by the induction of Treg cells. On the other hand, given that within the thymus B220+ DCs are as numerous as conventional thymic DCs, indicating that they probably fulfill an important role in T-cell development, it can be hypothesized that thymic B220+ DCs could be involved in intrathymic Treg cell differentiation. In this sense, the CD4+ CD25+ murine Treg cell subset has been claimed to develop in the thymus.4 A great deal of controversy exists regarding the origin, heterogeneity, and mechanism of action of Treg cells, partly because different experimental models have been used in their characterization. Additional experiments are in progress in our laboratory to define the molecular mechanisms controlling the induction of intrathymic and peripheral Treg cell differentiation by B220+ DCs and the suppressive effects exerted by these Treg cells. Interestingly, as previously discussed, our phenotypic and functional data support the view that under physiological conditions B220+ DCs constitute a subset of DCs in an immature state that could underlie their possible tolerogenic potential. Experiments carried out in humans and mice have demonstrated the capacity of in vitro-generated immature DCs to induce the differentiation of T anergic and Treg cells (reviewed in Jonuleit et al4). In conclusion, B220+ DCs represent a specialized subset of constitutively immature DCs that could be involved in intrathymic Treg cell development and in the differentiation of peripheral Treg cells and, consequently, in the control of peripheral T-cell tolerance. On the other hand, on encounter with microbial pathogens, B220+ DCs can function as potent APCs and promote the induction of T-cell defense responses.
We thank Dr A. Rolink for the anti-CD40 hybridoma FGK45 and Dr G. Márquez for the CCR6 and CCR7 primers.
Submitted August 29, 2001; accepted March 26, 2002.
Supported by grants from the European Commission (QLRT-1999-00276), the Comunidad de Madrid of Spain (08.1/0076/2000), and the Ministerio de Ciencia y Tecnología of Spain (BOS 2000-0558).
P.M. and G.M.d.H. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Carlos Ardavín, Department of Cell Biology, Faculty of Biology, Complutense University, 28040 Madrid, Spain; e-mail: ardavin{at}bio.ucm.es.
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S. L. Bailey-Bucktrout, S. C. Caulkins, G. Goings, J. A. A. Fischer, A. Dzionek, and S. D. Miller Cutting Edge: Central Nervous System Plasmacytoid Dendritic Cells Regulate the Severity of Relapsing Experimental Autoimmune Encephalomyelitis J. Immunol., May 15, 2008; 180(10): 6457 - 6461. [Abstract] [Full Text] [PDF]
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L. Chen, E. Calomeni, J. Wen, K. Ozato, R. Shen, and J.-X. Gao Natural killer dendritic cells are an intermediate of developing dendritic cells J. Leukoc. Biol., June 1, 2007; 81(6): 1422 - 1433. [Abstract] [Full Text] [PDF]
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M. Bros, F. Jahrling, A. Renzing, N. Wiechmann, N.-A. Dang, A. Sutter, R. Ross, J. Knop, S. Sudowe, and A. B. Reske-Kunz A newly established murine immature dendritic cell line can be differentiated into a mature state, but exerts tolerogenic function upon maturation in the presence of glucocorticoid Blood, May 1, 2007; 109(9): 3820 - 3829. [Abstract] [Full Text] [PDF]
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Y. Lou, C. Liu, G. J. Kim, Y.-J. Liu, P. Hwu, and G. Wang Plasmacytoid Dendritic Cells Synergize with Myeloid Dendritic Cells in the Induction of Antigen-Specific Antitumor Immune Responses J. Immunol., February 1, 2007; 178(3): 1534 - 1541. [Abstract] [Full Text] [PDF]
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G. Penna, S. Amuchastegui, N. Giarratana, K. C. Daniel, M. Vulcano, S. Sozzani, and L. Adorini 1,25-Dihydroxyvitamin D3 Selectively Modulates Tolerogenic Properties in Myeloid but Not Plasmacytoid Dendritic Cells J. Immunol., January 1, 2007; 178(1): 145 - 153. [Abstract] [Full Text] [PDF]
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D. Allman, M. Dalod, C. Asselin-Paturel, T. Delale, S. H. Robbins, G. Trinchieri, C. A. Biron, P. Kastner, and S. Chan Ikaros is required for plasmacytoid dendritic cell differentiation Blood, December 15, 2006; 108(13): 4025 - 4034. [Abstract] [Full Text] [PDF]
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L. Gabriele, A. Fragale, P. Borghi, P. Sestili, E. Stellacci, M. Venditti, G. Schiavoni, M. Sanchez, F. Belardelli, and A. Battistini IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features J. Leukoc. Biol., December 1, 2006; 80(6): 1500 - 1511. [Abstract] [Full Text] [PDF]
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U. Yrlid, V. Cerovic, S. Milling, C. D. Jenkins, J. Zhang, P. R. Crocker, L. S. Klavinskis, and G. G. MacPherson Plasmacytoid Dendritic Cells Do Not Migrate in Intestinal or Hepatic Lymph J. Immunol., November 1, 2006; 177(9): 6115 - 6121. [Abstract] [Full Text] [PDF]
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Y. Matsumura, S. N. Byrne, D. X. Nghiem, Y. Miyahara, and S. E. Ullrich A Role for Inflammatory Mediators in the Induction of Immunoregulatory B Cells J. Immunol., October 1, 2006; 177(7): 4810 - 4817. [Abstract] [Full Text] [PDF]
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H. Sjolin, S. H. Robbins, G. Bessou, A. Hidmark, E. Tomasello, M. Johansson, H. Hall, F. Charifi, G. B. K. Hedestam, C. A. Biron, et al. DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection. J. Immunol., September 1, 2006; 177(5): 2908 - 2916. [Abstract] [Full Text] [PDF]
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A. L. Blasius, E. Giurisato, M. Cella, R. D. Schreiber, A. S. Shaw, and M. Colonna Bone Marrow Stromal Cell Antigen 2 Is a Specific Marker of Type I IFN-Producing Cells in the Naive Mouse, but a Promiscuous Cell Surface Antigen following IFN Stimulation. J. Immunol., September 1, 2006; 177(5): 3260 - 3265. [Abstract] [Full Text] [PDF]
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B. C. Harman, J. P. Miller, N. Nikbakht, R. Gerstein, and D. Allman Mouse plasmacytoid dendritic cells derive exclusively from estrogen-resistant myeloid progenitors Blood, August 1, 2006; 108(3): 878 - 885. [Abstract] [Full Text] [PDF]
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M. Foti, F. Granucci, M. Pelizzola, O. Beretta, and P. Ricciardi-Castagnoli Dendritic cells in pathogen recognition and induction of immune responses: a functional genomics approach J. Leukoc. Biol., May 1, 2006; 79(5): 913 - 916. [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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J. Zhang-Hoover, P. Finn, and J. Stein-Streilein Modulation of Ovalbumin-Induced Airway Inflammation and Hyperreactivity by Tolerogenic APC J. Immunol., December 1, 2005; 175(11): 7117 - 7124. [Abstract] [Full Text] [PDF]
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N. Bendriss-Vermare, S. Burg, H. Kanzler, L. Chaperot, T. Duhen, O. de Bouteiller, M. D'agostini, J.-M. Bridon, I. Durand, J. M. Sederstrom, et al. Virus overrides the propensity of human CD40L-activated plasmacytoid dendritic cells to produce Th2 mediators through synergistic induction of IFN-{gamma} and Th1 chemokine production J. Leukoc. Biol., October 1, 2005; 78(4): 954 - 966. [Abstract] [Full Text] [PDF]
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S. Kojo, K.-i. Seino, M. Harada, H. Watarai, H. Wakao, T. Uchida, T. Nakayama, and M. Taniguchi Induction of Regulatory Properties in Dendritic Cells by V{alpha}14 NKT Cells J. Immunol., September 15, 2005; 175(6): 3648 - 3655. [Abstract] [Full Text] [PDF]
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J. K. H. Tan and H. C. O'Neill Maturation requirements for dendritic cells in T cell stimulation leading to tolerance versus immunity J. Leukoc. Biol., August 1, 2005; 78(2): 319 - 324. [Abstract] [Full Text] [PDF]
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G. S. Angelov, M. Tomkowiak, A. Marcais, Y. Leverrier, and J. Marvel Flt3 Ligand-Generated Murine Plasmacytoid and Conventional Dendritic Cells Differ in Their Capacity to Prime Naive CD8 T Cells and to Generate Memory Cells In Vivo J. Immunol., July 1, 2005; 175(1): 189 - 195. [Abstract] [Full Text] [PDF]
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B. Baban, A. M. Hansen, P. R. Chandler, A. Manlapat, A. Bingaman, D. J. Kahler, D. H. Munn, and A. L. Mellor A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation Int. Immunol., July 1, 2005; 17(7): 909 - 919. [Abstract] [Full Text] [PDF]
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Y. Omatsu, T. Iyoda, Y. Kimura, A. Maki, M. Ishimori, N. Toyama-Sorimachi, and K. Inaba Development of Murine Plasmacytoid Dendritic Cells Defined by Increased Expression of an Inhibitory NK Receptor, Ly49Q J. Immunol., June 1, 2005; 174(11): 6657 - 6662. [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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V. Gillan, R. A. Lawrence, and E. Devaney B cells play a regulatory role in mice infected with the L3 of Brugia pahangi Int. Immunol., April 1, 2005; 17(4): 373 - 382. [Abstract] [Full Text] [PDF]
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S. Uematsu, S. Sato, M. Yamamoto, T. Hirotani, H. Kato, F. Takeshita, M. Matsuda, C. Coban, K. J. Ishii, T. Kawai, et al. Interleukin-1 receptor-associated kinase-1 plays an essential role for Toll-like receptor (TLR)7- and TLR9-mediated interferon-{alpha} induction J. Exp. Med., March 21, 2005; 201(6): 915 - 923. [Abstract] [Full Text] [PDF]
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F. Okano, M. Merad, K. Furumoto, and E. G. Engleman In Vivo Manipulation of Dendritic Cells Overcomes Tolerance to Unmodified Tumor-Associated Self Antigens and Induces Potent Antitumor Immunity J. Immunol., March 1, 2005; 174(5): 2645 - 2652. [Abstract] [Full Text] [PDF]
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I. J. Fugier-Vivier, F. Rezzoug, Y. Huang, A. J. Graul-Layman, C. L. Schanie, H. Xu, P. M. Chilton, and S. T. Ildstad Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment J. Exp. Med., February 7, 2005; 201(3): 373 - 383. [Abstract] [Full Text] [PDF]
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C. J. Workman and D. A. A. Vignali Negative Regulation of T Cell Homeostasis by Lymphocyte Activation Gene-3 (CD223) J. Immunol., January 15, 2005; 174(2): 688 - 695. [Abstract] [Full Text] [PDF]
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T. B. Oriss, M. Ostroukhova, C. Seguin-Devaux, B. Dixon-McCarthy, D. B. Stolz, S. C. Watkins, B. Pillemer, P. Ray, and A. Ray Dynamics of Dendritic Cell Phenotype and Interactions with CD4+ T Cells in Airway Inflammation and Tolerance J. Immunol., January 15, 2005; 174(2): 854 - 863. [Abstract] [Full Text] [PDF]
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K. A. Swanson, Y. Zheng, K. M. Heidler, Z.-D. Zhang, T. J. Webb, and D. S. Wilkes Flt3-Ligand, IL-4, GM-CSF, and Adherence-Mediated Isolation of Murine Lung Dendritic Cells: Assessment of Isolation Technique on Phenotype and Function J. Immunol., October 15, 2004; 173(8): 4875 - 4881. [Abstract] [Full Text] [PDF]
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A. L. Mellor, P. Chandler, B. Baban, A. M. Hansen, B. Marshall, J. Pihkala, H. Waldmann, S. Cobbold, E. Adams, and D. H. Munn Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase Int. Immunol., October 1, 2004; 16(10): 1391 - 1401. [Abstract] [Full Text] [PDF]
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G. Schlecht, S. Garcia, N. Escriou, A. A. Freitas, C. Leclerc, and G. Dadaglio Murine plasmacytoid dendritic cells induce effector/memory CD8+ T-cell responses in vivo after viral stimulation Blood, September 15, 2004; 104(6): 1808 - 1815. [Abstract] [Full Text] [PDF]
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M. Epardaud, M. Bonneau, F. Payot, C. Cordier, J. Megret, C. Howard, and I. Schwartz-Cornil Enrichment for a CD26hi SIRP- subset in lymph dendritic cells from the upper aero-digestive tract J. Leukoc. Biol., September 1, 2004; 76(3): 553 - 561. [Abstract] [Full Text] [PDF]
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F. Palamara, S. Meindl, M. Holcmann, P. Luhrs, G. Stingl, and M. Sibilia Identification and Characterization of pDC-Like Cells in Normal Mouse Skin and Melanomas Treated with Imiquimod J. Immunol., September 1, 2004; 173(5): 3051 - 3061. [Abstract] [Full Text] [PDF]
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H. J. de Heer, H. Hammad, T. Soullie, D. Hijdra, N. Vos, M. A.M. Willart, H. C. Hoogsteden, and B. N. Lambrecht Essential Role of Lung Plasmacytoid Dendritic Cells in Preventing Asthmatic Reactions to Harmless Inhaled Antigen J. Exp. Med., July 6, 2004; 200(1): 89 - 98. [Abstract] [Full Text] [PDF]
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B. Quah, K. Ni, and H. C. O'Neill In vitro hematopoiesis produces a distinct class of immature dendritic cells from spleen progenitors with limited T cell stimulation capacity Int. Immunol., April 1, 2004; 16(4): 567 - 577. [Abstract] [Full Text] [PDF]
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B. Leon, G. Martinez del Hoyo, V. Parrillas, H. H. Vargas, P. Sanchez-Mateos, N. Longo, M. Lopez-Bravo, and C. Ardavin Dendritic cell differentiation potential of mouse monocytes: monocytes represent immediate precursors of CD8- and CD8+ splenic dendritic cells Blood, April 1, 2004; 103(7): 2668 - 2676. [Abstract] [Full Text] [PDF]
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L. Li, H.-C. Hsu, C. R. Stockard, P. Yang, J. Zhou, Q. Wu, W. E. Grizzle, and J. D. Mountz IL-12 Inhibits Thymic Involution by Enhancing IL-7- and IL-2-Induced Thymocyte Proliferation J. Immunol., March 1, 2004; 172(5): 2909 - 2916. [Abstract] [Full Text] [PDF]
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M. Salio, M. J. Palmowski, A. Atzberger, I. F. Hermans, and V. Cerundolo CpG-matured Murine Plasmacytoid Dendritic Cells Are Capable of In Vivo Priming of Functional CD8 T Cell Responses to Endogenous but Not Exogenous Antigens J. Exp. Med., February 17, 2004; 199(4): 567 - 579. [Abstract] [Full Text] [PDF]
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V. G. Pillarisetty, A. B. Shah, G. Miller, J. I. Bleier, and R. P. DeMatteo Liver Dendritic Cells Are Less Immunogenic Than Spleen Dendritic Cells because of Differences in Subtype Composition J. Immunol., January 15, 2004; 172(2): 1009 - 1017. [Abstract] [Full Text] [PDF]
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A. M. Woltman and C. van Kooten Functional modulation of dendritic cells to suppress adaptive immune responses J. Leukoc. Biol., April 1, 2003; 73(4): 428 - 441. [Abstract] [Full Text] [PDF]
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G. Miller, V. G. Pillarisetty, A. B. Shah, S. Lahrs, and R. P. DeMatteo Murine Flt3 Ligand Expands Distinct Dendritic Cells with Both Tolerogenic and Immunogenic Properties J. Immunol., April 1, 2003; 170(7): 3554 - 3564. [Abstract] [Full Text] [PDF]
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H. Hemmi, T. Kaisho, K. Takeda, and S. Akira The Roles of Toll-Like Receptor 9, MyD88, and DNA-Dependent Protein Kinase Catalytic Subunit in the Effects of Two Distinct CpG DNAs on Dendritic Cell Subsets J. Immunol., March 15, 2003; 170(6): 3059 - 3064. [Abstract] [Full Text] [PDF]
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P. Brawand, D. R. Fitzpatrick, B. W. Greenfield, K. Brasel, C. R. Maliszewski, and T. De Smedt Murine Plasmacytoid Pre-Dendritic Cells Generated from Flt3 Ligand-Supplemented Bone Marrow Cultures Are Immature APCs J. Immunol., December 15, 2002; 169(12): 6711 - 6719. [Abstract] [Full Text] [PDF]
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
+ B220+ dendritic cells endowed with type
1 interferon production capacity and tolerogenic potential
Top
Abstract
Introduction
) after culture
in control medium or in the presence of CpG, determined by ELISA
(mean ± SD of 3 independent experiments). (C) IL-10 production by
FACS-sorted thymic B220+ DCs, thymic CD8+ DCs,
and peritoneal macrophages (M
-Actin mRNA levels are shown to control
for the relative expression of each cytokine receptor mRNA in the
different populations considered.
