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*
Basel Institute for Immunology, Basel, Switzerland; and
Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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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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To date, two different lineages of mouse DCs have been proposed. The
majority of DCs, defined as myeloid-derived DCs, originate in the bone
marrow from a common myeloid cell precursor, and are widely distributed
in both lymphoid and nonlymphoid tissues (4). Furthermore,
DCs have been observed to develop also from two early T cell precursor
populations and have, therefore, been termed lymphoid-related DCs
(5, 6). In addition to the common DC surface markers
mentioned above, this DC subset is characterized by expression of the
CD8
homodimer. The majority of CD8+ DCs are
found in the thymus, but the subpopulation is also present in the
periphery (7).
In the skin, two types of DCs have been described: Langerhans cells (LCs) usually located in the suprabasal regions of epidermis, and dermal DCs located primarily in the perivascular areas of the superficial plexus in the dermis (8). The current knowledge about DCs in dermatology derives mainly from studies performed with epidermal LCs in normal and diseased skin (9, 10). Less is known about the function of dermal DCs, but the observation that LCs are able, but not absolutely required to induce contact sensitivity suggests the participation of this second skin-residing DC population in T cell-mediated immune responses in the skin (11).
A lot of experimental work has attempted to correlate the different DC subsets with distinct biological functions. Because thymic CD8+ DCs are involved in negative selection (12), it has been suggested that peripheral lymphoid-related CD8+ DCs may also play a critical role in tolerization of T cells to self Ags by inducing T cell anergy or deletion (13, 14, 15). However, two recent studies suggest that both DC subsets can prime CD4+ T cells and differentially regulate Th1/Th2 priming in vivo (16, 17). Moreover, CD8+ DCs are also able to prime protective CTL responses in vivo, indicating that CD8+ DCs are not a particular DC subset involved only in the maintenance of tolerance (18).
To further elucidate the DC heterogeneity, we compared DCs obtained
from different lymphoid organs in terms of surface marker expression,
migratory properties, in vivo turnover, and presenting capacities. The
staining with two mAbs, one specific for the integrin CD11c and the
second for the CD40 molecule, in combination with the CD8-specific
Ab, allowed us to demonstrate the presence of at least four putative DC
subsets in the peripheral lymph nodes (LNs), whereas in the other
organs analyzed (spleen, thymus, Peyer’s patches, and also
gut-associated LN), only two were detectable. In this study, we present
the detailed analysis of these subpopulations with respect to their in
vivo behavior as well as to their functional characteristics.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Except where indicated, all experiments were performed with BALB/c mice. BALB/c and C57BL/6 mice were provided by IFFA-Credo (Saint Germain-sur-l’Abresle, France). Transgenic mice expressing a MHC class I-restricted TCR specific for the peptide p33 derived from lymphocytic choriomeningitis virus (LCMV) (327), a MHC class II-restricted TCR specific for the OVA peptide323–339 (DO11.10), a MHC class II-restricted TCR specific for moth cytochrome c (AD10), and the transgenic mouse line 107.1 expressing an I-Ed transgene under the control of a segment of the I-E MHC class II promoter have been described previously (19, 20, 21, 22). Mice were bred under specific pathogen-free conditions according to Swiss federal law.
DC isolation and phenotypic characterization
DCs were isolated from spleens, thymus, Peyer’s patches, mesenteric LNs, and peripheral LNs (inguinal, popliteal, axillar, auricular) of BALB/c mice, as previously described (23). Briefly, tissues were digested twice for 30 min at 37°C in IMDM supplemented with 5% FCS and 100 µg/ml collagenase D (Boehringer Mannheim, Mannheim, Germany) in a shaking water bath. Cells were recovered, resuspended in a Optiprep gradient, and centrifuged at 600 x g for 15 min. Low density cells in the interface were harvested and incubated for 30 min on ice with PE-labeled anti-CD11c and Cy5-labeled anti-CD40, washed, and sorted with a FACStarPlus (Becton Dickinson, Mountain View, CA), or analyzed using a FACScalibur (Becton Dickinson) excluding propidium iodide-positive dead cells.
Sorted DC subsets were immobilized for 5 min onto poly(L-lysine)-coated coverslips and subsequently processed according to standard protocols. Briefly, the specimens were fixed with glutaraldehyde (2.5% v/v in 0.1 M sodium cacodylate buffer, pH 7.4) for 2 h at 25°C, incubated with osmium-tetroxide (1% w/v in double-distilled water) for another 1 h at 4°C, and dehydrated with acetone. Epon sections (80 nm) were poststained with aqueous uranyl-acetate and lead citrate (30 and 3 min, respectively) and examined with a transmission electron microscope at 60 kV (JEM 1200 EX, JEOL, Tokyo, Japan).
Skin organ culture
Ear skin from BALB/c mice was split in dorsal and ventral halves and cultured in 24-well culture plates (one ear/well), as previously described. Purified skin DCs were obtained by collecting the cells emigrating from these skin explants into the culture medium during 3 consecutive days and by sorting MHC class II-positive cells using a FACStarPlus.
Three-color FACS analysis
To determine the phenotype of the different LN DC subsets, DC
were isolated as described above, and stained for 30 min on ice with
FITC-labeled anti-CD11c, Cy5-labeled anti-CD40, and PE-labeled
anti-B7-1, anti-B7-2, anti-I-A, anti-F4/80,
anti-CD4, and anti-CD8. For the detection of E-cadherin and
mannose-like receptor, DCs were stained with PE-labeled anti-CD11c,
Cy5-labeled anti-CD40, and FITC-labeled anti-NLDC145 or
purified rat anti-E-cadherin (Sigma, St. Louis, MO). After washing,
FITC-labeled goat anti-rat was added and cells were incubated for
another 30 min on ice. Cells were washed, resuspended, and analyzed
using a FACScalibur flow cytometer excluding propidium iodide-positive
cells.
Kinetics of DC subsets in peripheral LN and in skin
Mice were injected i.p. with 1 mg bromodeoxyuridine (BrdU) (Sigma) dissolved in PBS and were fed thereafter with drinking water containing 1 mg/ml BrdU. DCs were isolated from peripheral LNs and skin explants and sorted, as described above. The purified cells were fixed subsequently overnight with 70% ethanol, washed with PBS, and resuspended in 0.5 ml 3 N HCl/0.5% Tween 20. After 20 min at room temperature, cells were collected by centrifugation and neutralized by resuspension in 0.2 ml 0.1 M borate buffer, pH 8.5. After two following washings, DC were stained with FITC-labeled anti-BrdU (Becton Dickinson) and analyzed on a FACScalibur.
In vitro immunostimulation assays
For the MLR, the MHC class II- and class I-restricted presentation assays, DCs were sorted using a FACStarPlus, as described above, obtaining a purity >97%. For the MLR, different numbers of sorted DCs (H-2d, 20 x 104-1.25 x 103) were added to 1 x 105 purified T cells obtained from spleen of H-2b C57BL/6. For the MHC class II-restricted presentation assay, different number of DCs (2 x 104-1.25 x 103/well) obtained from BALB/c mice were pulsed for 1 h with 100 nM OVA323–339 peptide, washed, and cocultured with OVA-specific CD4+ T cells. For the MHC class I-restricted presentation assay, different number of DCs (2 x 10 4-1.25 x 103/well) obtained from C57BL/6 were pulsed for 1 h with 10-8 M LCMV-derived peptide p33, washed five times, and cocultured with purified CD8+ T cells obtained from LCMV-specific TCR-transgenic mouse. T cell proliferation was assessed by [3H]thymidine (1 µCi/well) uptake in a 16-h pulse after 4 days for the MLR and 2 days for MHC class II- and class I-restricted presentation assay.
In vivo skin sensitization
Green fluorescent Cell Tracker (Molecular Probes, Leiden, The Netherlands) was dissolved 1:20 in a 50/50 (v/v) acetone-butyl phtalate mixture just before application. Mice were painted with 400 µl on the shaved abdomen or with 50 µl on the dorsal site of the ears. At different time points (1–4 days), draining LNs were collected and DC were isolated as described above. Cells were double stained with PE-labeled anti-CD11c and Cy5-labeled anti-CD40 and analyzed using a FACScalibur excluding propidium iodide-positive cells.
LCMV-derived peptide p33 or moth cytochrome c peptides (1 mg/ml DMSO) were dissolved 1:10 in a 50/50 (v/v) acetone-dibutyl phtalate mixture just before application. C57BL/6 and 107.1 mice, respectively, were painted with 50 µl on the dorsal site of the ears. One, two, and three days after treatment, DC were isolated from draining LNs, as described above, stained with and sorted on the basis of different CD11c and CD40 expression patterns obtaining a purity of >97%. The same DC subsets were isolated and sorted from peripheral LNs of untreated mice. Purified DC (104/well) were cocultured with purified CD8+ T cells obtained from LCMV-specific TCR-transgenic mouse or with purified CD4+ T cells obtained from moth cytochrome c-specific TCR-transgenic mouse (AD10), respectively, for 2 days and [3H]thymidine (1 µCi/well) for 16 h prior harvesting.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Differential CD11c/CD40 expression pattern of gradient-enriched
DCs revealed at least three potential DC subpopulations in the
peripheral LNs:
CD11chighCD40int (I;
18% of total DC population),
CD11cintCD40high (II;
40% of total DC population), and
CD11chighCD40high (III;
15% of total DC population) subsets with different cell size and
granularity (not shown). Because the
CD11cintCD40negative subset
does not share the morphological and functional properties of the other
three DC subsets (I–III) (data not shown), we excluded that these
cells belong to classical DCs and were not further characterized in
this study.
When other lymphoid tissues were analyzed, such as spleen, Peyer’s
patches, thymus, and gut-associated mesenteric LNs, both
CD11cintCD40high (II) and
CD11chighCD40high (III)
subsets were missing (Fig. 1
B), suggesting that these two
subsets might be skin-derived DCs. Only some scattered cells were found
in the area of gates II and III, but they represent less than
2–3%.
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, NLDC145, and F4/80
(Fig. 2). All three subpopulations were
positive for MHC class II and for both costimulatory molecules, B7-1
and B7-2, although with varying intensity. CD8, a marker found
on lymphoid-related DCs, was highly expressed on more than 50%
of CD11chighCD40int (I)
cells, whereas the other two
CD11cintCD40high (II)
and CD11chighCD40high (III)
subsets were negative for this molecule. In addition, in disagreement
with recently published data, we were never able to detect an
up-regulation of the CD8 molecule on fractions II and III upon skin
irritation (see below) (24). The CD4 molecule, known to be
expressed on a subset of myeloid DC, was detectable only on about 30%
of cells from the fraction I, whereas subsets II and III were
clearly negative. Expression of NLDC145 correlated with that of CD8
in the CD11chighCD40int (I)
subset, although expression was also detectable in the CD8-negative
CD11cintCD40high (II) and
CD11chighCD40high (III)
subsets. The macrophage-related surface marker F4/80, a marker found on
myeloid-related DCs, was expressed at high levels only in a fraction of
the CD11chighCD40int(I) and
all CD11chighCD40high (III)
cells.
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A). Ultrastructurally, LCs
are characterized by unique cytoplasmatic organelles, the so-called
Birbeck granules. For this reason, we analyzed the presence of
these structures by transmission electron microscopy. As expected, all
cells of populations
CD11chighCD40int (I),
CD11cintCD40high (II), and
CD11chighCD40high (III)
showed typical dendritic morphology (Fig. 3B); however,
structures resembling Birbeck granules were very rare and strictly
confined to population
CD11chighCD40high (III)
(see insert).
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We next analyzed the stimulatory activity in vitro of sorted DC
subsets in allogeneic MLR and in peptide MHC class I and II
presentation assays, as illustrated in Fig. 4. In all three assays, all DC subsets
were highly efficient to prime allogeneic T cells (Fig. 4A),
OVA-specific CD4+ T cells (Fig. 4B),
and p33-specific CD8+ T cells (Fig. 4C), respectively.
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To estimate how quickly DC subpopulations turn over in the
peripheral LN, unimmunized BALB/c mice were fed with BrdU for up to 28
days. At different time points over this period, BrdU incorporation was
monitored by FACS analysis and the percentage of
BrdU+ cells was calculated (Fig. 5A). More than 80% (plateau
level) of CD11chighCD40int
(I) cells were BrdU+ after 10 days of continuous
labeling, indicating that this DC subset turns over in about 10 days
with an influx of DCs, probably directly derived from the bone marrow,
of more than 10% a day. When CD8+ and
CD8- DCs in fraction I were sorted and analyzed
separately, the lymphoid-related CD8+ subset had
about 30% faster turnover kinetics when compared with the
myeloid-related DCs (Fig. 5B).
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1 mo (Fig. 5
A). To determine the
turnover dynamics of skin resident DCs, we performed skin organ
cultures from groups of mice treated over a period of 28 days with
BrdU. At various time points, ears were collected and treated for
primary skin culture. Cells emigrating from the skin explants into the
culture medium during 3 consecutive days were collected, sorted for MHC
class II-positive cells, and stained with anti-BrdU Ab, as
described above. As shown in Fig. 5C, the MHC class
II+ cells obtained from skin explants show a
turnover of about 1 mo, because at day 28 more than 75% of the cells
were labeled with BrdU. In vivo skin sensitization drives two distinct DC populations into the draining LN
To induce migration of skin-residing DC subpopulations, mice were
painted with a skin irritant, a mixture of butyl phtalate and acetone
(1:1), and DCs of the draining LN were monitored over a period of 4
days. Green fluorescent Cell Tracker was added to the irritant mixture
to assess the skin origin of different DC subsets by analyzing the
presence of green fluorescent cells in the draining LN using the
FACS, as shown in Fig. 6. One day after
skin painting, the majority of green cells were detectable in the
CD11chighCD40high (III)
subset (70%), whereas the
CD11cintCD40high (II)
subpopulation reached the peak 1 day later. The presence of
fluorescence cells was clearly still detectable at day 3 (about 30% of
both subsets), but rapidly declined by day 4. No green fluorescent
cells were detectable in the remaining fraction I.
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The in situ ability of skin-derived DCs to take up immunogenic
peptides and present them in vitro to Ag-specific T cells was measured
by isolating DCs from draining LNs at various times after cutaneous
application of peptides in the appropriate solvent (1–3 days after
treatment). As expected, only the
CD11cintCD40high (II) and
CD11chighCD40high (III)
subsets carried the peptide information, because they were the only DCs
capable of stimulating peptide-specific CD4+ and
CD8+ T cells, whereas
CD11chighCD40int (I)
subpopulation was unable to present the skin-applied peptides (Fig. 7). In the case of p33, the MHC class
I-binding peptide, maximum T cell proliferation was induced using DCs
obtained from the draining LN 24 h after skin painting.
Stimulatory capacity dramatically declined 2 and 3 days after treatment
(Fig. 7A). Skin painting with a MHC class II-binding peptide
revealed a more prolonged presentation capacity of the immigrated
DCs. In fact, the cutaneously applied peptide was presented by
CD11cintCD40high (II) and
CD11chighCD40high (III) 1
and 2 days after skin treatment, while at day 3 the presentation
ability was markedly reduced (Fig. 7B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several observations strongly suggest that two of these populations, II and III, are derived from skin. First, they are only present in LNs that drain skin and not, e.g., in thymus, spleen, Peyer’s patches, and mesenteric LNs. Second, only cells of subsets II and III carry the cutaneously applied Ag or cellular dye. Interestingly, the cells in subset III occasionally carry Birbeck granules and express E-cadherin, both markers of epidermal LCs, thereby making them most likely direct descendants of LCs (25, 26). The cells in subset II are derived most likely from dermis, as suggested by kinetic analysis (see later). These conclusions are supported by earlier observations, which have established the presence of two different DC compartments in the skin: LC restricted to the epidermis (27) and dermal DC localized in the perivascular area of the dermis (28, 29). The observation that LCs are able (30), but not essential, to induce contact hypersensitivity suggested also the participation of dermal DCs in the regulation of skin immune reactions (31). Unfortunately, the phenotypic characterization of mouse dermal DCs has been hampered to date by the lack of unique serological markers, unlike in human system, in which CD36 can be used as a typical marker for these cells (29).
The third subset (I) contains cells that belong to both the classical myeloid- and lymphoid-related DCs in about equal proportions. Continuous BrdU-labeling experiments showed that this subset in toto turned over rapidly in about 10 days. When analyzed separately, the lymphoid-related CD8+ subset had about 30% faster turnover kinetics than the myeloid-related DCs, and this was the case not only in peripheral LNs, but also in the spleen and mesenteric LNs, in which corresponding subsets followed identical kinetics (data not shown). If DCs do not divide in periphery as is commonly argued (32), it is most likely the case that BrdU+ cells are direct migrants from the bone marrow.
The skin-derived subsets II and III turned over much slower and they required about 30 days to do so. Interestingly, both of these subsets showed a clear lag period of 3 days before the BrdU+ cells started to accumulate in the LNs. Therefore, it seems that these cells had a minimum of 3 days of transit time in the skin during their journey from the bone marrow to peripheral LNs. If all DCs that were seeded from the bone marrow to the skin behaved as a homogenous cohort of cells in transit to LNs, we would expect that DCs in the skin were fully labeled in about 3 days (= lag period). This was, however, clearly not the case. DCs in the skin turned over very slowly (about 30 days) and, therefore, we want to postulate that only a fraction of skin DCs are mobile. Indeed, earlier observations have indicated that a large portion of skin DCs are in fact sessile, and hence need long periods (several weeks) to become labeled and to migrate out from the skin (33).
Our results about LN DCs showing different origins and dynamics are in agreement with recent published data from Salomon et al. (34). In fact, they identified three distinct populations of lymph node DCs (a myeloid- and a lymphoid-related DC subset, but only one skin-derived DC subset) that can be distinguished on the basis of phenotype, morphology, turnover, and Ag-uptake characteristics. However, we extended these observations by measuring the turnover kinetics over a long time period for all identified DC subpopulations under normal homeostasis and, in addition, we also determined the inflammatory triggered superkinetics for both skin-derived DC subsets.
In fact, it is well known that exposure to inflammatory cytokines
(e.g., TNF- and IL-1) (35), as well as bacterial
components (e.g., LPS) (36), induces a rapid DC
mobilization from peripheral nonlymphoid tissues to the draining LN.
When contact sensitizers, such as FITC, were cutaneously applied on
shaved mouse skin, many green fluorescent DC could be isolated from
draining LNs (37). In our hands, skin irritation increased
dramatically the turnover rate of cells in subsets II and III with
characteristic differences. When irritant was applied together with a
cellular dye, it could be observed that already 1 day after application
the representation of subset III sharply increased (from about 6 to
22% of all DCs) (data not shown), and at the same time the proportion
of dye-positive cells within subset III enhanced to about 70%
corresponding to 6- to 7-fold increase of normal influx rates. Skin
painting triggered similar drastic changes in kinetics of cells in
fraction II, but with 1-day delay of the peak influx. We attribute this
delay of kinetics to the anatomical location of the skin precursor of
these cells. Mobile epidermal LCs, future fraction III, have faster
access to the irritant/dye mixture than deeper residing dermal DCs,
which would then give rise to fraction II. The possibility that cells
in fraction III would differentiate to cells in subset II is made
unlikely by the fact that II compartment is about 3-fold larger than
III in normal and irritated LNs, and hence cellular division would have
to be invoked, of which there is no evidence. In addition, if the
putative differentiation step occurred, we would expect to observe
delayed onset of accumulation of BrdU+ cells into
fraction II as compared with fraction III in continuous labeling
analysis, but this was not the case.
Rapid influx of DCs into LNs after skin irritation was followed by an almost as quick disappearance of the labeled cells. After 3 days of the peak immigration, Cell Tracker+ DCs in both II and III fractions were hardly detectable. Most likely these DCs died in the LNs during this 3-day period (vs 30 days during normal homeostasis) because no DCs have been observed to leave LNs via efferent lymphatics (38).
Thus, it seems that T cells have a 3-day window in peripheral LNs to encounter and screen DCs for their antigenic cargo taken in inflammatory skin lesions. To test this directly, we applied defined MHC class I- and II-binding peptides on the skin in the presence of the irritant solvent and then measured in vitro the Ag-presenting activity of different DC subsets from draining LNs various times after application. Consistent with our Cell Tracker analyses, only cells in fractions II and III showed activity with characteristic kinetic biases. Interestingly, a class I peptide was presented only for 1 day, while a class II peptide could be detected at least for 2 days. Most likely class I/peptide complexes have shorter t1/2 than corresponding class II complexes (39). In fact, it is a hallmark of a mature DC that their MHC class II molecules show increased stability (40, 41). It is not clear, in the case of class II, whether the loss of presentation is due to the loss of class II/peptide complexes or to the loss by death of the actual presenting cells. In this respect, it would be interesting to study the issue whether the Ag-specific T cells in vivo can rescue DCs or prolong their life span because two previous reports seem to be contradictory (42, 43).
Having been able to identify clear subsets of DCs in peripheral LNs, it is now important to study how these subpopulations are regulated and how do they contribute functionally to the immune system.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: DC, dendritic cell; BrdU, bromodeoxyuridine; int, intermediate; LC, Langerhans cell; LCMV, lymphocytic choriomeningitis virus; LN, lymph node.
Received for publication May 17, 2000. Accepted for publication August 2, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+ and CD8- dendritic cells in the induction of primary immune responses in vivo. J. Leukocyte Biol. 66:242.[Abstract]
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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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J. Yang, S. P. Huck, R. S. McHugh, I. F. Hermans, and F. Ronchese Perforin-dependent elimination of dendritic cells regulates the expansion of antigen-specific CD8+ T cells in vivo PNAS, January 3, 2006; 103(1): 147 - 152. [Abstract] [Full Text] [PDF]
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B. Abel, S. Freigang, M. F. Bachmann, U. Boschert, and M. Kopf Osteopontin Is Not Required for the Development of Th1 Responses and Viral Immunity J. Immunol., November 1, 2005; 175(9): 6006 - 6013. [Abstract] [Full Text] [PDF]
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 B. G. Molenkamp, R. J.C.L.M. Vuylsteke, P. A.M. van Leeuwen, S. Meijer, W. Vos, P. G.J.T.B. Wijnands, R. J. Scheper, and T. D. de Gruijl Matched Skin and Sentinel Lymph Node Samples of Melanoma Patients Reveal Exclusive Migration of Mature Dendritic Cells Am. J. Pathol., November 1, 2005; 167(5): 1301 - 1307. [Abstract] [Full Text] [PDF]
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J. Xiang, H. Huang, and Y. Liu A New Dynamic Model of CD8+ T Effector Cell Responses via CD4+ T Helper-Antigen-Presenting Cells J. Immunol., June 15, 2005; 174(12): 7497 - 7505. [Abstract] [Full Text] [PDF]
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 C. L. Bennett, E. van Rijn, S. Jung, K. Inaba, R. M. Steinman, M. L. Kapsenberg, and B. E. Clausen Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity J. Cell Biol., May 23, 2005; 169(4): 569 - 576. [Abstract] [Full Text] [PDF]
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J. Machen, J. Harnaha, R. Lakomy, A. Styche, M. Trucco, and N. Giannoukakis Antisense Oligonucleotides Down-Regulating Costimulation Confer Diabetes-Preventive Properties to Nonobese Diabetic Mouse Dendritic Cells J. Immunol., October 1, 2004; 173(7): 4331 - 4341. [Abstract] [Full Text] [PDF]
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J. Diao, E. Winter, W. Chen, C. Cantin, and M. S. Cattral Characterization of Distinct Conventional and Plasmacytoid Dendritic Cell-Committed Precursors in Murine Bone Marrow J. Immunol., August 1, 2004; 173(3): 1826 - 1833. [Abstract] [Full Text] [PDF]
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G. Schiavoni, F. Mattei, P. Borghi, P. Sestili, M. Venditti, H. C. Morse III, F. Belardelli, and L. Gabriele ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells Blood, March 15, 2004; 103(6): 2221 - 2228. [Abstract] [Full Text] [PDF]
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J. T. Pribila, A. A. Itano, K. L. Mueller, and Y. Shimizu The {alpha}1{beta}1 and {alpha}E{beta}7 Integrins Define a Subset of Dendritic Cells in Peripheral Lymph Nodes with Unique Adhesive and Antigen Uptake Properties J. Immunol., January 1, 2004; 172(1): 282 - 291. [Abstract] [Full Text] [PDF]
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P. Saint-Mezard, C. Chavagnac, S. Bosset, M. Ionescu, E. Peyron, D. Kaiserlian, J.-F. Nicolas, and F. Berard Psychological Stress Exerts an Adjuvant Effect on Skin Dendritic Cell Functions In Vivo J. Immunol., October 15, 2003; 171(8): 4073 - 4080. [Abstract] [Full Text] [PDF]
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 A J Stagg, A L Hart, S C Knight, and M A Kamm The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria Gut, October 1, 2003; 52(10): 1522 - 1529. [Abstract] [Full Text] [PDF]
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 P. Hamrah, Y. Liu, Q. Zhang, and M. R. Dana Alterations in Corneal Stromal Dendritic Cell Phenotype and Distribution in Inflammation Arch Ophthalmol, August 1, 2003; 121(8): 1132 - 1140. [Abstract] [Full Text] [PDF]
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A. Iwasaki The Importance of CD11b+ Dendritic Cells in CD4+ T Cell Activation In Vivo: With Help from Interleukin 1 J. Exp. Med., July 21, 2003; 198(2): 185 - 190. [Full Text] [PDF]
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M. Yoshino, H. Yamazaki, H. Nakano, T. Kakiuchi, K. Ryoke, T. Kunisada, and S.-I. Hayashi Distinct antigen trafficking from skin in the steady and active states Int. Immunol., June 1, 2003; 15(6): 773 - 779. [Abstract] [Full Text] [PDF]
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J. Alferink, I. Lieberam, W. Reindl, A. Behrens, S. Weiss, N. Huser, K. Gerauer, R. Ross, A. B. Reske-Kunz, P. Ahmad-Nejad, et al. Compartmentalized Production of CCL17 In Vivo: Strong Inducibility in Peripheral Dendritic Cells Contrasts Selective Absence from the Spleen J. Exp. Med., March 3, 2003; 197(5): 585 - 599. [Abstract] [Full Text] [PDF]
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A. Boonstra, C. Asselin-Paturel, M. Gilliet, C. Crain, G. Trinchieri, Y.-J. Liu, and A. O'Garra Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development: Dependency on Antigen Dose and Differential Toll-like Receptor Ligation J. Exp. Med., January 6, 2003; 197(1): 101 - 109. [Abstract] [Full Text] [PDF]
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I. Cremer, M.-C. Dieu-Nosjean, S. Marechal, C. Dezutter-Dambuyant, S. Goddard, D. Adams, N. Winter, C. Menetrier-Caux, C. Sautes-Fridman, W. H. Fridman, et al. Long-lived immature dendritic cells mediated by TRANCE-RANK interaction Blood, November 15, 2002; 100(10): 3646 - 3655. [Abstract] [Full Text] [PDF]
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 X. Zhang, L. M. Hillyer, and B. D. Woodward The Capacity of Noninflammatory (Steady-State) Dendritic Cells to Present Antigen in the Primary Response Is Preserved in Acutely Protein- or Energy-Deficient Weanling Mice J. Nutr., September 1, 2002; 132(9): 2748 - 2756. [Abstract] [Full Text] [PDF]
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G. J. Randolph Is Maturation Required for Langerhans Cell Migration? J. Exp. Med., August 19, 2002; 196(4): 413 - 416. [Full Text] [PDF]
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A. T. Kamath, S. Henri, F. Battye, D. F. Tough, and K. Shortman Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs Blood, August 13, 2002; 100(5): 1734 - 1741. [Abstract] [Full Text] [PDF]
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C. D. Richters, I. Mayen, C. E. G. Havenith, R. H. J. Beelen, and E. W. A. Kamperdijk Rat monocyte-derived dendritic cells function and migrate in the same way as isolated tissue dendritic cells J. Leukoc. Biol., April 1, 2002; 71(4): 582 - 587. [Abstract] [Full Text] [PDF]
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T. Storni, F. Lechner, I. Erdmann, T. Bachi, A. Jegerlehner, T. Dumrese, T. M. Kundig, C. Ruedl, and M. F. Bachmann Critical Role for Activation of Antigen-Presenting Cells in Priming of Cytotoxic T Cell Responses After Vaccination with Virus-Like Particles J. Immunol., March 15, 2002; 168(6): 2880 - 2886. [Abstract] [Full Text] [PDF]
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A. D. McLellan, M. Kapp, A. Eggert, C. Linden, U. Bommhardt, E.-B. Brocker, U. Kammerer, and E. Kampgen Anatomic location and T-cell stimulatory functions of mouse dendritic cell subsets defined by CD4 and CD8 expression Blood, March 15, 2002; 99(6): 2084 - 2093. [Abstract] [Full Text] [PDF]
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M. Menges, S. Ro{beta}ner, C. Voigtlander, H. Schindler, N. A. Kukutsch, C. Bogdan, K. Erb, G. Schuler, and M. B. Lutz Repetitive Injections of Dendritic Cells Matured with Tumor Necrosis Factor {alpha} Induce Antigen-specific Protection of Mice from Autoimmunity J. Exp. Med., December 31, 2001; 195(1): 15 - 22. [Abstract] [Full Text] [PDF]
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Y. Kawarada, R. Ganss, N. Garbi, T. Sacher, B. Arnold, and G. J. Hammerling NK- and CD8+ T Cell-Mediated Eradication of Established Tumors by Peritumoral Injection of CpG-Containing Oligodeoxynucleotides J. Immunol., November 1, 2001; 167(9): 5247 - 5253. [Abstract] [Full Text] [PDF]
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S. Henri, D. Vremec, A. Kamath, J. Waithman, S. Williams, C. Benoist, K. Burnham, S. Saeland, E. Handman, and K. Shortman The Dendritic Cell Populations of Mouse Lymph Nodes J. Immunol., July 15, 2001; 167(2): 741 - 748. [Abstract] [Full Text] [PDF]
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C. Ruedl, P. Koebel, and K. Karjalainen In Vivo-Matured Langerhans Cells Continue to Take Up and Process Native Proteins Unlike In Vitro-Matured Counterparts J. Immunol., June 15, 2001; 166(12): 7178 - 7182. [Abstract] [Full Text] [PDF]
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, CD11chighCD40int (I);
•, CD11cintCD40high (II); 
,
CD11chighCD40high (III). B, 
,
CD11chighCD40intCD8-.
C, MHC class II+ cells obtained from the
organ skin culture. Results are representative for three independent
experiments.
