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IMMUNOBIOLOGY
From the Walter and Eliza Hall Institute of Medical
Research, Melbourne, Victoria, Australia; and the Edward Jenner
Institute for Vaccine Research, Berkshire, United Kingdom.
The labeling kinetics of 5 dendritic cell (DC) subtypes within the
lymphoid organs of healthy laboratory mice during continuous administration of bromodeoxyuridine (BrdU) was determined to
investigate developmental relationships and determine turnover rates.
Individual DC subtypes behaved as products of separate developmental
streams, at least as far back as their dividing precursors. The rate of labeling varied with the lymphoid organ and the DC subtype. Labeling was faster overall in spleen and mesenteric lymph nodes (LNs) and
slower in thymus and skin-draining LNs. The CD8+ DC subtype
displayed the most rapid turnover, with a uniformly short (3-day)
lifespan in spleen but with distinct short-lived and longer-lived
subgroups in thymus. All the skin-derived DCs in LNs showed delayed and
slow BrdU labeling, indicating a long overall lifespan; however, this
was shown to reflect a long residence time in skin rather than a
long-duration presenting antigen in the draining LN.
Epidermal-derived Langerhans DCs displayed longer BrdU labeling lag and
slower overall turnover than the dermal-derived DCs, and the movement
of fluorescent Langerhans DC from skin to LN was slower than that of
dermal DCs following skin painting with a fluorescent dye. However,
once they arrived in lymphoid organs, all DCs present in healthy,
uninfected mice displayed a rapid turnover, and this turnover was even
faster after antigenic or microbial product stimulation.
(Blood. 2002;100:1734-1741) Dendritic cells (DCs) collect,
transport, and process antigens, finally presenting them to T
lymphocytes as peptide fragments on major histocompatibility complex
(MHC) molecules.1,2 All DC subtypes serve this basic
function but differ in antigen processing,3,4 in migratory
patterns,1,2,5-8 and in the nature of the response they
induce in T cells.9-14 The lifespan of different DC
subtypes within lymphoid organs, where they interact with T cells, is
therefore one determinant of how long an antigenic stimulus persists
and what type of immune response will result. In this study we use continuous bromodeoxyuridine (BrdU) labeling15,16 to
determine the lifespan of DC subtypes in the lymph nodes (LNs), thymus, and spleen of steady-state, uninfected adult laboratory mice. The rate
of labeling of the DCs, or rather the converse rate of loss of
unlabeled cells, serves as a measure of DC lifespan. Because mature DCs
are nondividing end-cells, the DNA precursor BrdU initially enters
dividing precursors, then flows into mature DCs. Accordingly, the
kinetics of labeling also provides information on the developmental history of the DC subtypes and on any precursor-product relationships between them.
We have already demonstrated that all 3 subtypes of mature
DCs in spleen have a remarkably short lifespan and are products of
independent streams of development.16,17 This limited
persistence in the spleen of individual antigen-presenting cells would
limit the duration of a splenic T-cell response and has implications for the maintenance of T-cell memory. However, it has been
claimed18 that certain skin-derived DCs survive for a long
time in LN, allowing persistent T-cell stimulation in LN following an
antigen pulse. Therefore, we extended our studies to LNs, where we
delineated 2 DC subtypes in addition to those found in spleen; these
arrive in LNs through the lymph and include the mature form of skin
Langerhans cells.8 We confirm the data of Ruedl et
al,18 who found that the skin-derived DCs in LNs display
slow labeling with BrdU. This led them to conclude that skin-derived
DCs have a long lifespan in LN. However, experiments on the potentially
migratory DCs in skin itself led us to a different interpretation. We
found the overall long lifespan of skin-derived DCs reflects a long
residence time in skin, not in LN. We found that the lifespan of DCs in normal laboratory mice varies, depending on the DC subtype and the
lymphoid organ, but in all cases the residence time of mature DCs
within the lymphoid organs themselves was short.
Mice
Antigen and adjuvant stimulation of mice
Lymphoid organs Organs used for DC isolation and analysis were spleen, thymus, and LN the latter were either mesenteric LNs, a pool of skin-draining LNs (axillary, brachial, and inguinal), or auricular LNs that drain
ear skin.
Isolation of mature DCs The procedure was as described recently.16,17,20 Briefly, spleen, thymus, or LN fragments were digested for 20 minutes at room temperature with collagenase-DNase, then were treated for 5 minutes with EDTA (ethylenediaminetetraacetic acid). All subsequent procedures were performed at 0°C to 4°C in a divalent metal-free medium. Light-density cells were selected by centrifugation at 4°C in a 310 mOsm Nycodenz medium, with the density optimized for each tissue at 1.082 g/cm3 for LN, 1.077 g/cm3 for spleen, and 1.075g/cm3 for thymus. Cells other than DCs were then depleted by an immunogenic bead procedure. For spleen and LNs, the depleting mAbs were anti-CD3 (KT3), anti-Thy1 (T24/31.7), anti-B220 (RA3-6B2), anti Gr-1 (RB6-8C5), and antierythrocyte (TER-119); for thymus, in which the CD4+CD8 DCs were absent,
the depleting mAb also included anti-CD4 (GK1.5), anti-F4/80 (F4/80),
and anti-CD11b (M1/70). This DC preparation, approximately 80% pure,
was then used for presorting.
Presorting to eliminate autofluorescent cells DC preparations contained autofluorescent cells (5%-30%) that were not DCs but that could contaminate a DC sample.17 Such autofluorescent cells, together with dead cells, were eliminated before immunofluorescent labeling by high-speed presorting. Dead cells were labeled by including propidium iodide (PI; 1 µg/mL) in the suspension medium. Nonfluorescent cells were then selected, as described previously.17 Residual PI was removed by washing before cells were stained and fixed.DC migration from ear skin in culture The procedure was modified from that of Schuler and Steinman,21 with the exit of DCs from the skin enhanced by chemokine according to the approach of Kellermann et al.22 Ears were removed from 10 to 20 mice, cleared of hair, briefly washed in 70% ethanol, then placed ventral side down and split, removing the dorsal skin from the cartilage. Dorsal skin was placed split side down in 1 mL modified mouse osmolarity RPMI 1640 medium containing 10% fetal calf serum for 2 to 4 hours at 37°C in a 10% CO2 in-air incubator to eliminate the non-DCs initially released. The skin was then transferred to another 1 mL culture medium, this time containing 0.1 µg recombinant mouse 6Ckine (R&D Systems, Minneapolis, MN). After 24-hour incubation at 37°C, the cells that had migrated to the culture medium were harvested and kept in cold medium. The skin was transferred to fresh warm medium containing 6Ckine and then was incubated for another 24 hours. Cells that migrated from the skin over both incubations were pooled. The yield was 3 to 6 × 104 DCs per ear.Immunofluorescence labeling of DCs Monoclonal antibodies, fluorescence conjugates, and labeling procedures have been specified previously.8,16,17,20 To identify and sort all DCs, the pan-DC markers used were high levels of MHC class II or CD11c. Anti-CD11c (N418) was used as Cy5, phycoerythrin (PE), or Alexa594 conjugates. Anti-MHC class II (N22 or M5/114) was used as Cy5 or Alexa 594 conjugates; conjugation levels were less than maximal to ensure the strong staining for MHC class II did not cause inaccurate color compensation. Markers used to separate the DC subpopulations were CD8 , CD4, and DEC-205 (CD205). Anti-CD8
(YTS169.4), anti-CD4 (GK1.5), and anti-DEC-205 (NLDC-145) were used as
PE, Cy5, or Alexa 594 conjugates. The second-stage stain for
biotin-conjugated mAbs was Alexa594- or Cy5-streptavidin. Permeabilization and staining of cells for the cytoplasmic domain of
langerin using the HD24 mAb was as specified
previously.8
Bromodeoxyuridine administration and immunofluorescence labeling The procedure was similar to that developed for T cells.15 Groups of 4 to 8 mice were initially injected intraperitoneally with 1 mg bromodeoxyuridine (BrdU) (Sigma, St Louis, MO) in saline and then continuously given BrdU (0.8 mg/mL) in sterile drinking water that was changed daily. After various times, the DCs were isolated, presorted to remove autofluorescent cells, and stained as above. Control DCs from mice not given BrdU were isolated in parallel. Surface-stained DCs were washed, resuspended in cold 0.15 M NaCl, and fixed by drop-wise addition of cold 95% ethanol. They were incubated on ice for 30 minutes, washed with PBS, and incubated for 30 minutes at room temperature with PBS containing 1% paraformaldehyde and 0.01% Tween 20. Control DCs were then pelleted, incubated for 10 minutes at room temperature with 50 U DNase I (Boehringer Mannheim, Germany) in 0.15 M NaCl containing 4.2 mM MgCl2, and washed. They were then incubated for 30 minutes at room temperature with fluorescein isothiocyanate (FITC)-conjugated anti-BrdU mAb (Becton Dickinson, San Jose, CA), washed, and resuspended in PBS.Flow cytometric analysis of bromodeoxyuridine-labeled cells BrdU-stained and surface marker-stained DCs were analyzed on a FACStar Plus flow cytometer (Becton Dickinson). Data were gated for MHC class II+ DCs, and those gated DCs were divided into subsets based on the expression of CD8, CD4, and DEC-205, as
described elsewhere.8,17 The distinction between the
BrdU-positive and -negative FITC fluorescence made use of background
control DCs from mice not treated with BrdU but stained with anti-BrdU
antibody. A computational technique (described in
http://www.wehi.edu.au/cytometry/Abstracts/AFCGOOB.html) was used to
subtract the background histogram, enumerating the upper percentage of
cells in the fluorescence-positive cell population (Figure
1).
Fluorescence labeling of DCs in ear skin The approach was similar to that of Anjuère et al,23 as described previously,8 using tetramethylrhodamine-5(and 6)-isothiocyanate (TRITC) as the fluorescent dye.
Separating labeled from unlabeled DCs In our BrdU administration protocol, BrdU was injected intraperitoneally at the beginning to ensure dividing precursors had immediate access to the label, and continued availability was ensured by the inclusion of BrdU in the drinking water. It was important that all DCs that acquired BrdU-labeled DNA be registered as positive cells. This was readily attained for splenic DCs (Figure 1), in which BrdU-labeled DCs were clearly separated from the background fluorescence of unlabeled DCs; there was nevertheless a little overlap, which resulted in a completely labeled DC population only registering 97% positive. However, with LN DCs (Figure 1) and thymic DCs, the intensity of fluorescence per labeled DC was lower, indicating their immediate dividing precursors differed and had less access to the label. This resulted in more overlap between background and positive cell fluorescence. Rather than increase BrdU dose, which would produce toxic effects, we developed a computational technique that fitted the background histogram to the lower component of the positive sample fluorescence, then subtracted this, leaving the upper component of BrdU-positive cells to be enumerated. This allowed a more precise estimate of the percentage of labeled DCs than by making an arbitrary cutoff between positives and negatives.Labeling kinetics of different lymphoid organs BrdU-labeling kinetics and thus turnover times of the total DCs of different lymphoid organs were compared (Figure 2). A short (2-hour) pulse of BrdU gave only marginal labeling, indicating that the DCs were not themselves dividing. Splenic DCs showed the fastest input of labeled cells, without any detectable lag, indicating either immediate generation from dividing precursors in the spleen or rapid replenishment through the bloodstream. Most unlabeled splenic DCs disappeared rapidly, indicating a short half-life within the organ. However, a small proportion of splenic DCs showed a longer lifespan because some unlabeled cells persisted 9 to 12 days.
Thymic DCs showed a different labeling pattern (Figure 2). Initially, the accumulation of labeled DCs was as rapid as in spleen, but this reached a plateau and only 20% of the DC population had been replaced by day 3. After an apparent lag, the remaining 80% of the thymic DC population was labeled by day 10. This 2-phase labeling kinetics was consistent over several separate experiments and persisted even when BrdU was repetitively administered by intraperitoneal injection. Labeling kinetics of LN DCs was particularly interesting because the usual model of DC life history predicted that immature DCs would first spend time as "sentinels" in nonlymphoid tissue before entering the LN. The labeling pattern obtained varied with the LN studied (Figure 2). Mesenteric LN DCs showed rapid labeling with no evidence of a lag. In contrast, the total DCs in the LN draining cutaneous tissue showed some lag in the initial labeling and a more gradual replacement of unlabeled with labeled cells. Rate of BrdU labeling of different subtypes of thymic DCs The pronounced break in the thymic DC BrdU-labeling curve suggested heterogeneity in this population. Thymic DCs can be segregated into a major group showing bright staining for CD8 and
those showing only moderate staining; the latter do not produce CD8 themselves but pick up CD8 from the thymocytes.17
Both these DC populations are DEC-205+. On segregating
thymic DCs by CD8 staining, little difference was observed in BrdU
labeling; both populations showed the 2-phased labeling kinetics
(Figure 3). This reinforces the view that
they are related cells. Another possible segregation of thymic DCs is
into approximately 50% positive and 50% negative for the early B-cell
marker BP-1.24 However, at several time points, there was
no difference in the BrdU labeling of these 2 subsets.
Another explanation for a discontinuous labeling curve would be discontinuity in the maturation process of a single DC lineage. As label flows into nondividing DCs, the upstream MHC class IIlo DCs should label ahead of the more mature downstream MHC class IIhi DCs. Accordingly, thymic DCs were divided into those showing the lowest level of expression of surface MHC class II versus those showing the highest level of expression. This was an arbitrary division because the fluorescence distribution was continuous. As predicted, label flowed more rapidly into the thymic DCs with the lowest surface MHC class II than into those with the highest. However, this did not explain the biphasic labeling curve because both subgroups showed biphasic labeling (Figure 3). Similar results were obtained regardless of the gate set between high and low MHC class II fluorescence. This labeling of less mature DCs a little ahead of more mature DCs, but without a definite discontinuity between the 2, was also seen for splenic DCs overall and for less mature versus more mature forms of all individual subsets of splenic DCs (data not shown). Labeling kinetics of individual DC subtypes in spleen A key issue was whether DC lifespan was dictated by the environment of the individual lymphoid organ or whether DC subtypes showed independent behavior. Spleen DCs can be segregated into 3 subtypesCD4+8DEC-205,
CD4CD8DEC-205, and
CD4CD8+DEC-205+.17
Of the 3.7 ± 0.5 × 106 DCs recovered per spleen,
these subtypes constituted 56% ± 3%, 19% ± 4%, and
23% ± 1%, respectively. As we demonstrated
previously16 and confirm in Figure
4, the individual DC subtypes in spleen showed distinct labeling patterns. All labeled continuously from the
beginning without any evidence of a lag. The
CD4CD8+DEC-205+ DCs showed the
fastest turnover in spleen (half-life, 1.5 days) with a linear "first
in-first out" labeling pattern. The
CD4+CD8 DCs showed the slowest turnover
(half-life, 2.9 days), with some DCs persisting longer than others,
suggesting a stochastic process. We used these data for comparison with
the DC subtypes in other lymphoid organs.
Comparison of the labeling kinetics of the common DC subtypes in LN, spleen, and thymus The 3 populations of DCs found in spleen can also be distinguished in LN, though in LN there is low (less than 5%) representation of the CD4+CD8 DCs.8 Accordingly, for
the LN DC-labeling data in Figure 4, this population is omitted. Of the
1.6 ± 0.5 × 105 total DCs recovered from mesenteric
LNs, CD8+DEC-205+ DCs constituted
19% ± 7%, and CD8DEC-205 DCs
constituted 41% ± 3%; of the 3.7 ± 0.9 × 105
total DCs recovered from pooled cutaneous-draining LN, they constituted 17% ± 6% and 21% ± 2%, respectively. In LN, as in spleen, the CD8+DEC-205+ DCs labeled faster, and hence had
a shorter lifespan, than the CD8DEC-205
DCs. In LN, as in spleen, there was no evidence of an initial labeling
lag in either of these DC subtypes. However, the rate of labeling of
both DC subtypes varied with the LN studied. It was more rapid in
mesenteric LN than in cutaneous-draining LNs. The labeling pattern of
the CD8+DEC-205+ DCs in particular differed
between the LNs and was almost as rapid as spleen in mesenteric LNs but
was similar to thymus, with a biphasic labeling curve, in
cutaneous-draining LNs. The total time for most of the
CD8+DEC-205+ DCs to be replaced was
approximately 3 days in spleen, 4 days in mesenteric LN, and 9 days in
thymus and cutaneous-draining LN.
Lifespan of DCs derived from skin Several groups, using different combinations of markers, have identified in cutaneous-draining LNs the mature forms of the DCs that migrated from the skin.18,23,25 We have segregated in cutaneous-draining LNs 2 skin-derived DC subtypes.8 One is CD4CD8 but expresses a moderate level of
DEC-205, in contrast to the CD4CD8 DCs in
spleen; this we identified as a dermal-derived population, probably
similar to other interstitial DCs. It represents 20% ± 5% of the
DCs in the cutaneous-draining LNs. A population equivalent to this is
found in mesenteric LN,8 where it represents 26% ± 6%
of the DCs. A second DC subtype, only found in cutaneous-draining LN,
is CD4CD8loDEC-205hi and
expresses the Langerhans cell marker langerin8; we
identified this DC as epidermal derived, the mature form of skin
Langerhans cells. It represents 33% ± 11% of the DCs in
cutaneous-draining LNs. We have found DCs corresponding to both these
LN DC subtypes in approximately equal numbers in the cells that migrate
out of skin on culture and have shown that they can be separated based on the level of expression of DEC-205 or of langerin.8 The BrdU-labeling kinetics of these LN-restricted DC subtypes is shown in
Figure 4.
Both LN-specific DC subtypes in cutaneous-draining LNs showed a
pronounced initial lag and a slower labeling rate than the DCs common
to LN and spleen. However, the
CD4 Comparison of the labeling kinetics of potential migratory skin DCs with the skin-derived DCs in LNs Does the slow labeling of skin-derived DCs in LN mean these DCs persist longer in the LN after migration? To test this, we compared the BrdU-labeling kinetics of the LN DCs with that of the DCs migrating out of cultured ear skin. Note that the ears were taken from mice that had received BrdU administration for various times before culture, so this procedure simply sampled the pre-existent labeling behavior of potentially migratory DCs within the skin under steady-state conditions. As shown in Figure 5, the DEC-205lo and especially the DEC-205hi DC subsets exiting the skin showed a marked initial lag in labeling, explaining much of the lag in the labeling of their counterparts in cutaneous-draining LN.
DEC-205int DCs (putative dermal-derived DCs) obtained from the skin by culture showed a moderate rate of labeling after the initial lag, similar to counterpart DEC-205int DCs in cutaneous-draining LNs but preceding them by 2 to 3 days (Figure 5). For more direct comparison, the DCs of the small ear-skin draining auricular LNs were also isolated. These showed 67% labeled DEC-205int DCs at 10 days and 77% ± 1% labeling at 14 days, values close to those of the pooled cutaneous LN DEC-205int DCs. These comparisons suggest the lifespan of the dermal-derived DCs, once having exited the skin and entered the draining LN, is short (approximately 2-3 days). The DEC-205hi DC (putative epidermal-derived Langerhans cells) obtained from the skin by culture showed exceptionally slow and puzzling labeling kinetics (Figure 5). After an initial 3- to 5-day lag, there was a brief increase in labeling rate, then a distinct slow labeling phase. Only 27% of these potentially migratory DCs were labeled by 14 days, well below the 60% labeling achieved by the corresponding DCs in the pooled cutaneous-draining LN. To check this discrepancy, the DEC-205hiCD8lo in the small ear skin draining auricular LN were isolated, providing more direct comparison. These DCs showed 47% labeling at 10 days and 55% ± 2% labeling at 14 days, values similar to those for equivalent DC subsets in the pooled cutaneous LN. Accordingly, it appears the lifespan of the potentially migratory Langerhans cells in the epidermis itself is long but variable and can last much longer than 2 weeks. Langerhans cells that, under steady state, exit the epidermis to seed the skin-draining LN thus appear to be shorter-lived than most of those that exit cultured ear skin under the influence of 6-Ckine. Because the 2 approaches did not sample the same population, the actual residence time of the DEC-205hiCD8lo DCs within the draining LN could not be determined. However, it appears to be much shorter than the average residence time of Langerhans cells within the skin. Tracking DCs from skin to LN To verify our identification of cutaneous-draining LN CD4CD8loDEC-205hi and
CD4CD8DEC-205int as
skinderived epidermal Langerhans DCs and dermal DCs, respectively, the ear skin was first painted with TRITC. One to 4 days later, the
TRITC-positive cells in the draining auricular LN were then characterized with the use of an intracellular stain for langerin as an
additional marker to positively identify progeny of Langerhans cells.8,26 A discrete population of TRITC+
DCs, representing approximately 20% of the total DCs, was obtained (Figure 6). Their phenotype was identical
whether all TRITC+ cells, or only those with the highest
TRITC fluorescence, were characterized. At early time points these
cells were DEC-205int langerin, suggesting a
preponderance of dermal DCs. After 3 days, DEC-205hi
langerin+ cells appeared in the TRITC+
population, and they dominated by 4 days, indicating that the labeled
epidermal Langerhans DC were the slowest to migrate to the auricular
LN. This delay in movement of TRITC-labeled epidermal Langerhans DCs
from skin to LN, compared with dermal DCs, is consistent with their
greater lag in the BrdU-labeling curves of Figure 5. The rate of BrdU
labeling of the TRITC-marked DCs in the auricular LN was then assessed
after 14 days of continuous BrdU administration and 4 days after the
ear skin was painted with TRITC. These TRITC+ DCs were
48% ± 10% positive for BrdU, a value close to that of the total
CD4CD8loDEC-205hi putative
epidermal-derived Langerhans DC subset in normal steady-state mice not
painted with TRITC.
Effect of T-cell, antigen, and microbial stimuli on DC turnover All the preceding results were with normal mice not subject to deliberate antigenic or microbial stimuli. It was notable that although most DCs turned over rapidly in spleen and mesenteric LN, a proportion appeared to have a longer lifespan because some DCs remained unlabeled beyond 1 week. This might have resulted from a few DCs having received life-prolonging signals during an immune response. The possibility of microbial products or antigen-activated T cells prolonging the lifespan of the DCs already present in the animal was tested in several ways, in each case evaluating changes in splenic DC turnover by measuring the labeling rate around the crucial 2-day time point. In the first experiment, the DCs of RAG-1 null mice were studied because these mice lack T cells. This absence of T cells (and B cells) had only a small effect on the apparent DC turnover rate as measured by BrdU labeling at 2.5 daysfor total DCs, it was 60% in the control mice and 69% in
the RAG-1 null mice. In the second experiments, antigenic and microbial
stimuli were applied to TCR-transgenic, OVA-specific OT-II mice, and
the turnover of the splenic DCs was studied. As shown in Table
1, injection of the specific antigen OVA
into OT-II mice did not prolong the apparent lifespan of any of the DC
subtypes; rather, it increased the labeling rate and, hence, the
turnover compared to the controls. As we found
previously,16 bacterial LPS also increased DC turnover
(Table 1). Combined antigen-LPS stimulation gave results similar to
that of LPS alone. These conclusions also applied to the individual
splenic DC subtypes. Therefore, these aspects of an active immune
response to infection seem unlikely to extend the lifespan of the
resident DCs but seem likely to increase their rate of
turnover.
The kinetics of BrdU labeling by the different DC subtypes provides basic information on 2 aspects of their biologic nature, namely turnover rates and developmental relationships. Regarding possible precursor-product relationships, a slow-labeling subtype cannot be the direct precursor of a rapidly labeling subtype of similar incidence unless division intervenes, and the DCs we isolated did not divide. In addition, provided the subtypes show a clear discontinuity in the expression of markers used to segregate them, an upstream subtype of a single lineage should show an immediate accumulation of labeled cells, whereas a downstream subtype should show a labeling lag. However, as emphasized previously,17 there was no sign of a lag or any precursor-product relationship in the labeling kinetics of the 3 major DC subtypes in spleen, and each behaved as the product of a separate developmental stream. Even though the 2 DC subtypes in cutaneous-draining LNs did show a marked lag in accumulation of BrdU-labeled cells, it did not imply they were the downstream products of the faster labeling DCs within the LN itself. Rather, it reflected their independent origin in the dermis and epidermis of the skin, with their immediate upstream precursors responsible for the labeling lag to be found in these tissues. Thus, the different DC subtypes we have segregated all appear to derive from different developmental streams, at least as far back as their dividing precursors. The stages of hemopoietic development at which these streams diverge remain to be established. In the spleen the differences in BrdU-labeling kinetics correlates well
with the DC subtypes segregated by surface phenotype. However, in the
thymus, marked discontinuity in the overall BrdU-labeling kinetics
could not be correlated with any DC subsets defined by surface
phenotype, at least using our current markers. Even though the thymic
DCs showing lower surface levels of MHC class II did label a little
ahead of those showing higher levels, as expected, this appeared to be
a rapid and continuous transit and did not explain the 2-phase labeling
kinetics. One group of approximately 20% thymic DCs showed the same
rapid 3-day turnover as splenic DCs, whereas the remainder showed a
labeling lag. It took approximately 9 days for these unlabeled thymic
DCs to disappear. We have not established the basis of this
heterogeneity in turnover rates. However, its persistence with
different routes and levels of BrdU administration suggests it is not a
technical artifact of the labeling procedure. The more slowly labeled
major population might derive from endogenous precursors, with a
nondividing immature intermediate accounting for the labeling lag. The
more rapidly labeled major population might derive from dividing or
rapidly labeled DC precursors entering through the bloodstream, as we propose for spleen. Whatever the explanation, similar labeling discontinuity occurs among the CD8 The DC subtype with the fastest turnover in all organs is the DC
expressing high levels of CD8 In addition to the differences in the rate of turnover between different DC subtypes, it is clear that the environment associated with the individual lymphoid organs influences DC lifespan. DC turnover for all individual DC subtypes is faster in spleen than in mesenteric LN and faster in mesenteric LN than in cutaneous-draining LN. The higher rate of DC turnover in the mesenteric compared to cutaneous-draining LN might reflect a higher level of stimuli in the normal gut compared to the normal skin of a clean, noninfected laboratory mouse. However, our results indicate that in steady state there is a continual transit of DCs into the skin-draining LNs from the dermis and the epidermis, even when there is no obvious stimulus inducing an exit from skin. These results on turnover rate in steady state are generally in accordance with the earlier studies of Salomon et al25 and Ruedl et al,18 in showing that the DCs that migrate from the skin, and particularly the DCs of the Langerhans cell lineage, have an exceptionally long lifespan as measured from the last dividing precursor to loss, presumably by death, from the draining LN. Despite this agreement on the long overall lifespan of skin-derived DCs, we disagree with the conclusion of Ruedl et al18 that these DCs have a long lifespan in the LN. This is an important issue because this conclusion would imply that mature Langerhans cells and dermal-derived DCs in LN could persist and present antigen for much longer periods than other DC types, thereby prolonging T-cell responses. To check this we compared in some detail the BrdU-labeling kinetics of the DCs within cutaneous-draining LN with that of the potentially migratory DCs in skin, sampling these by inducing their exit from ear skin on culture and segregating the dermal-derived DCs from the epidermal-derived Langerhans cell DCs. The first point was that the DCs sampled from skin displayed an initial labeling lag similar to that of their corresponding subtypes in the LN, indicating that most of this lag represented the time for the label to transit from the dividing precursors to nondividing precursors to potentially migratory DCs with the skin itself and did not represent developmental changes within the LN. The labeling lag was greater for the epidermal Langerhans cell DCs than for the dermal DCs. This fits well with the studies of DC dynamics following painting the ear skin with fluorescent marker dye. These showed that for the bulk of the marked cells in the skin, which included a range of developmental states, the dermal DCs migrated from skin to LN more rapidly than the epidermal Langerhans DC, which showed a 3-day lag. Particular stimuli might reduce this lag and hasten the exit of Langerhans DCs. After the initial BrdU-labeling lag, the rate of labeling of potentially migratory dermal and epidermal DCs in ear skin was slow, indicating that most of the overall long lifespan of these DC subtypes was spent within the skin itself. The slow entry of labeled cells into the LN did not reflect a slow turnover of DCs in the LN. Rather, it reflected the fact that the DCs arriving in the LN contained only a small proportion of labeled cells because of slow turnover in the skin of a large pool of immature cells. In the case of the DEC-205int putative dermal DCs, the labeling curve of potentially migratory cells in ear skin was similar in form to that of their counterparts in the LN, but they labeled 2 to 3 days earlier. This suggested that once they entered LNs, their remaining lifespan was short, approximately 2 to 3 days. In the case of DEC-205hi putative epidermal Langerhans DCs, the labeling rate of the potentially migratory cells in the ear skin was, surprisingly, much lower than that of their counterparts in the LN, including the draining auricular LN. Evidently the population of Langerhans cells induced to leave the epidermis in the 6Ckine-containing cultures included a much higher proportion of older, slow-turnover, or sessile cells than the population seeding the LN in steady state. Because of this evident difference in sampling, the lifespan of an epidermal-derived Langerhans cell, once it arrives in the LN, could not be accurately determined. However, given the very slow labeling rate of this DC population overall in the skin, it is clear that most of the slow entry of BrdU cells into the mature LN forms can be attributed to a slow turnover in the epidermis. Their remaining lifespan once they enter the LN is likely to be short, perhaps very short. Our overall conclusion is that for the steady-state uninfected laboratory mouse, the residence time of a DC once it arrives in a lymphoid organ varies from short (9 days) to very short (1-2 days). The impact of T-cell or microbial stimuli did not prolong the lifespan of such pre-existent DCs but appeared to shorten their residence time in lymphoid organs (Table 1). This should place limits on the duration of a T-cell-mediated immune response, unless there is a continual input of antigen from another source. However, there is one important caveat to this conclusion. We have emphasized elsewhere28 that certain DC subtypes are only generated from precursors as a result of microbial stimuli, and such DCs would not have been sampled in this study of uninfected laboratory mice. One such DC subtype is the progeny of the type 1 interferon-producing, plasmacytoid DC precursor, a precursor that transforms into a DC only on viral or bacterial product stimulation.29 Systematic study of the lifespan of the novel DC populations induced by microbial invasion is now needed to determine whether these could provide a long-lived, antigen-presenting, T-cell stimulus.
Submitted September 7, 2001; accepted April 8, 2002.
Supported by the World Health Organization Special Program for Research and Training in Tropical Diseases. The Wellcome Trust provided the funds for the MoFlo cell sorter.
A.T.K. and S.H. contributed equally to the study.
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: Ken Shortman, Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Post Office Royal Melbourne Hospital, Victoria, 3050, Australia.
1. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271-296[CrossRef][Medline] [Order article via Infotrieve].
2.
Hart DN.
Dendritic cells: unique leukocyte populations which control the primary immune response.
Blood.
1997;90:3245-3287
3.
den Haan JMM, Lehar SM, Bevan MJ.
CD8+ but not CD8
4.
Pooley JL, Heath WR, Shortman K.
Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8 5. Wolff K, Stingl G. The Langerhans cell. J Invest Dermatol. 1983;80(suppl):17-21[CrossRef]. 6. Holt PG, Haining S, Nelson DJ, Sedgwick JD. Origin and steady-state turnover of MHC class II-bearing dendritic cells in the epithelium of the conducting airways. J Immunol. 1994;153:256-261[Abstract].
7.
Liu L, Zhang M, Jenkins C, MacPherson GG.
Dendritic cell heterogeneity in vivo: two functionally different dendritic cell populations in rat intestinal lymph can be distinguished by CD4 expression.
J Immunol.
1998;161:1146-1155
8.
Henri S, Vremec D, Kamath A, et al.
The dendritic cell populations of mouse lymph nodes.
J Immunol.
2001;167:741-748
9.
Süss G, Shortman K.
A subclass of dendritic cells kills CD4 T cells via Fas/Fas-ligand-induced apoptosis.
J Exp Med.
1996;183:1789-1796 10. Kronin V, Winkel K, Süss G, et al. A subclass of dendritic cells regulates the response of naive CD8 T cells by limiting their IL-2 production. J Immunol. 1996;157:3819-3827[Abstract].
11.
Rissoan MC, Soumelis V, Kadowski N, et al.
Reciprocal control of T helper and dendritic cell differentiation.
Science.
1999;283:1183-1186
12.
Maldonado-López R, De Smedt T, Michel P, et al.
CD8
13.
Pulendran B, Smith JL, Caspary G, et al.
Distinct dendritic cell subsets differentially regulate the class of immune response in vivo.
Proc Natl Acad Sci U S A.
1999;96:1036-1041
14.
Hochrein H, Shortman K, Vremec D, Scott B, Hertzog P, O'Keeffe M.
Differential production of IL-12, IFN-
15.
Tough DF, Sprent J.
Turnover of naive- and memory-phenotype T cells.
J Exp Med.
1994;179:1127-1135
16.
Kamath A, Pooley J, O'Keeffe M, et al.
The development, maturation and turnover rate of mouse spleen dendritic cell populations.
J Immunol.
2000;165:6762-6770
17.
Vremec D, Pooley J, Hochrein H, Wu L, Shortman K.
CD4 and CD8 expression by dendritic cell subtypes in mouse thymus and spleen.
J Immunol.
2000;164:2978-2986
18.
Ruedl C, Koebel P, Bachmann M, Hess M, Karjalainen K.
Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes.
J Immunol.
2000;165:4910-4916 19. Barnden MJ, Allison J, Heath WR, Carbone FR. Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol. 1998;76:34-40[CrossRef][Medline] [Order article via Infotrieve]. 20. Vremec D, Shortman K. Dendritic cell subtypes in mouse lymphoid organs: cross-correlation of surface markers, changes with incubation, and differences among thymus, spleen, and lymph nodes. J Immunol. 1997;159:565-573[Abstract].
21.
Schuler G, Steinman RM.
Murine epidermal Langerhans cells mature into potent immuno-stimulatory dendritic cells in vitro.
J Exp Med.
1985;161:526-546
22.
Kellermann SA, Hudak S, Oldham ER, Liu YJ, McEvoy LM.
The CC chemokine receptor-7 ligands 6Ckine and macrophage inflammatory protein-3
23.
Anjuère F, Martin P, Ferrero I, et al.
Definition of dendritic cell subpopulations present in the spleen, Peyer's patches, lymph nodes, and skin of the mouse.
Blood.
1999;93:590-598 24. Wu L, Vremec D, Ardavin C, et al. Mouse thymus dendritic cells: kinetics of development and changes in surface markers during maturation. Eur J Immunol. 1995;25:418-425[Medline] [Order article via Infotrieve].
25.
Salomon B, Cohen JL, Masurier C, Klatzmann D.
Three populations of mouse lymph node dendritic cells with different origins and dynamics.
J Immunol.
1998;160:708-717 26. Valladeau J, Ravel O, Dezutter-Dambuyant C, et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity. 2000;12:71-81[CrossRef][Medline] [Order article via Infotrieve]. 27. Anjuere F, Martinez del Hoyo G, Martin P, Ardavin C. Langerhans cells acquire a CD8+ dendritic cell phenotype on maturation by CD40 ligation. J Leukoc Biol. 2000;67:206-209[Abstract]. 28. Shortman K, Liu Y-J. Mouse and human dendritic cell subtypes. Nat Rev Immunol. 2002;2:153-163. 29. Asselin-Paturel C, Boonstra A, Dalod M, et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol. 2001;2:1144-1150[CrossRef][Medline] [Order article via Infotrieve].
© 2002 by The American Society of Hematology.
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|
 |
|
  Y. Chen, S. Khanna, C. S. Goodyear, Y. B. Park, E. Raz, S. Thiel, C. Gronwall, J. Vas, D. L. Boyle, M. Corr, et al. Regulation of Dendritic Cells and Macrophages by an Anti-Apoptotic Cell Natural Antibody that Suppresses TLR Responses and Inhibits Inflammatory Arthritis J. Immunol., July 15, 2009; 183(2): 1346 - 1359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Tripp, F. Sparber, I. F. Hermans, N. Romani, and P. Stoitzner Glycolipids Injected into the Skin Are Presented to NKT Cells in the Draining Lymph Node Independently of Migratory Skin Dendritic Cells J. Immunol., June 15, 2009; 182(12): 7644 - 7654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Gautier, T. Huby, F. Saint-Charles, B. Ouzilleau, J. Pirault, V. Deswaerte, F. Ginhoux, E. R. Miller, J. L. Witztum, M. J. Chapman, et al. Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis Circulation, May 5, 2009; 119(17): 2367 - 2375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. K. Vogt, A. Link, J. Perrin, D. Finke, and S. A. Luther Novel function for interleukin-7 in dendritic cell development Blood, April 23, 2009; 113(17): 3961 - 3968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Merad and M. G. Manz Dendritic cell homeostasis Blood, April 9, 2009; 113(15): 3418 - 3427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wang, Q. Jiang, C. Chan, K. S. Gorski, E. McCadden, D. Kardian, D. Pardoll, and K. A. Whartenby Inhibition of activation-induced death of dendritic cells and enhancement of vaccine efficacy via blockade of MINOR Blood, March 26, 2009; 113(13): 2906 - 2913. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Lee, M. Zamora, M. M. Linehan, N. Iijima, D. Gonzalez, A. Haberman, and A. Iwasaki Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection J. Exp. Med., February 16, 2009; 206(2): 359 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sundquist and M. J. Wick Salmonella induces death of CD8{alpha}+ dendritic cells but not CD11cintCD11b+ inflammatory cells in vivo via MyD88 and TNFR1 J. Leukoc. Biol., February 1, 2009; 85(2): 225 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. H. Lay, L. Zhang, R. M. Ribeiro, S. N. Mueller, G. T. Belz, and M. P. Davenport Kinetics of Major Histocompatibility Class I Antigen Presentation in Acute Infection J. Immunol., January 15, 2009; 182(2): 902 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Jakubzick, M. Bogunovic, A. J. Bonito, E. L. Kuan, M. Merad, and G. J. Randolph Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes J. Exp. Med., November 24, 2008; 205(12): 2839 - 2850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-B. O. Barbaroux, M. Beleut, C. Brisken, C. G. Mueller, and R. W. Groves Epidermal Receptor Activator of NF-{kappa}B Ligand Controls Langerhans Cells Numbers and Proliferation J. Immunol., July 15, 2008; 181(2): 1103 - 1108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Shklovskaya, B. Roediger, and B. Fazekas de St. Groth Epidermal and Dermal Dendritic Cells Display Differential Activation and Migratory Behavior While Sharing the Ability to Stimulate CD4+ T Cell Proliferation In Vivo J. Immunol., July 1, 2008; 181(1): 418 - 430. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lorenzo, M. Horowitz, and Y. Choi Osteoimmunology: Interactions of the Bone and Immune System Endocr. Rev., June 1, 2008; 29(4): 403 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Varas, C. Hernandez-Lopez, J. Valencia, S. Mattavelli, V. G. Martinez, L. Hidalgo, C. Gutierrez-Frias, A. G. Zapata, R. Sacedon, and A. Vicente Survival and function of human thymic dendritic cells are dependent on autocrine Hedgehog signaling J. Leukoc. Biol., June 1, 2008; 83(6): 1476 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Marleau, K. L. Summers, and B. Singh Differential Contributions of APC Subsets to T Cell Activation in Nonobese Diabetic Mice J. Immunol., April 15, 2008; 180(8): 5235 - 5249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. F. Poulin, S. Henri, B. de Bovis, E. Devilard, A. Kissenpfennig, and B. Malissen The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells J. Exp. Med., December 24, 2007; 204(13): 3119 - 3131. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Ginhoux, M. P. Collin, M. Bogunovic, M. Abel, M. Leboeuf, J. Helft, J. Ochando, A. Kissenpfennig, B. Malissen, M. Grisotto, et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state J. Exp. Med., December 24, 2007; 204(13): 3133 - 3146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Singh, M. Cox, and R. H. Schwartz TLR Ligands Differentially Modulate T Cell Responses to Acute and Chronic Antigen Presentation J. Immunol., December 15, 2007; 179(12): 7999 - 8008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Iijima, M. M. Linehan, S. Saeland, and A. Iwasaki Vaginal epithelial dendritic cells renew from bone marrow precursors PNAS, November 27, 2007; 104(48): 19061 - 19066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Bennett, M. Noordegraaf, C. A. E. Martina, and B. E. Clausen Langerhans Cells Are Required for Efficient Presentation of Topically Applied Hapten to T Cells J. Immunol., November 15, 2007; 179(10): 6830 - 6835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Czeloth, A. Schippers, N. Wagner, W. Muller, B. Kuster, G. Bernhardt, and R. Forster Sphingosine-1 Phosphate Signaling Regulates Positioning of Dendritic Cells within the Spleen J. Immunol., November 1, 2007; 179(9): 5855 - 5863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. McCaughtry, M. S. Wilken, and K. A. Hogquist Thymic emigration revisited J. Exp. Med., October 29, 2007; 204(11): 2513 - 2520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Luketic, J. Delanghe, P. T. Sobol, P. Yang, E. Frotten, K. L. Mossman, J. Gauldie, J. Bramson, and Y. Wan Antigen Presentation by Exosomes Released from Peptide-Pulsed Dendritic Cells Is not Suppressed by the Presence of Active CTL J. Immunol., October 15, 2007; 179(8): 5024 - 5032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Waithman, R. S. Allan, H. Kosaka, H. Azukizawa, K. Shortman, M. B. Lutz, W. R. Heath, F. R. Carbone, and G. T. Belz Skin-Derived Dendritic Cells Can Mediate Deletional Tolerance of Class I-Restricted Self-Reactive T Cells J. Immunol., October 1, 2007; 179(7): 4535 - 4541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. John and P. J. Nelson Dendritic Cells in the Kidney J. Am. Soc. Nephrol., October 1, 2007; 18(10): 2628 - 2635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Obst, H.-M. van Santen, R. Melamed, A. O. Kamphorst, C. Benoist, and D. Mathis Sustained antigen presentation can promote an immunogenic T cell response, like dendritic cell activation PNAS, September 25, 2007; 104(39): 15460 - 15465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Diao, E. Winter, W. Chen, F. Xu, and M. S. Cattral Antigen Transmission by Replicating Antigen-Bearing Dendritic Cells J. Immunol., September 1, 2007; 179(5): 2713 - 2721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Chen, L. Huang, and J. Wang Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity Blood, May 15, 2007; 109(10): 4360 - 4367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Qian, H. An, Y. Yu, S. Liu, and X. Cao TLR agonists induce regulatory dendritic cells to recruit Th1 cells via preferential IP-10 secretion and inhibit Th1 proliferation Blood, April 15, 2007; 109(8): 3308 - 3315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Fiorina, M. Jurewicz, K. Tanaka, N. Behazin, A. Augello, A. Vergani, U. Von Adrian, N. R. Smith, M. H. Sayegh, and R. Abdi Characterization of Donor Dendritic Cells and Enhancement of Dendritic Cell Efflux With cc-Chemokine Ligand 21: A Novel Strategy to Prolong Islet Allograft Survival Diabetes, April 1, 2007; 56(4): 912 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Maeda, H. Matsuyuki, K. Shimano, H. Kataoka, K. Sugahara, and K. Chiba Migration of CD4 T Cells and Dendritic Cells toward Sphingosine 1-Phosphate (S1P) Is Mediated by Different Receptor Subtypes: S1P Regulates the Functions of Murine Mature Dendritic Cells via S1P Receptor Type 3 J. Immunol., March 15, 2007; 178(6): 3437 - 3446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Turner, L. S. Cauley, K. M. Khanna, and L. Lefrancois Persistent Antigen Presentation after Acute Vesicular Stomatitis Virus Infection J. Virol., February 15, 2007; 81(4): 2039 - 2046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Varol, L. Landsman, D. K. Fogg, L. Greenshtein, B. Gildor, R. Margalit, V. Kalchenko, F. Geissmann, and S. Jung Monocytes give rise to mucosal, but not splenic, conventional dendritic cells J. Exp. Med., January 22, 2007; 204(1): 171 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Liu, B. A. Foster, T. Chen, G. Zheng, and A. Chen Modifying Dendritic Cells via Protein Transfer for Antitumor Therapeutics Clin. Cancer Res., January 1, 2007; 13(1): 283 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bogunovic, F. Ginhoux, A. Wagers, M. Loubeau, L. M. Isola, L. Lubrano, V. Najfeld, R. G. Phelps, C. Grosskreutz, E. Scigliano, et al. Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men J. Exp. Med., November 27, 2006; 203(12): 2627 - 2638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pradhan, J. Genebriera, W. L. Denning, K. Felix, C. A. Elmets, and L. Timares CD4 T Cell-Induced, Bid-Dependent Apoptosis of Cutaneous Dendritic Cells Regulates T Cell Expansion and Immune Responses J. Immunol., November 1, 2006; 177(9): 5956 - 5967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Durakovic, K. B. Bezak, M. Skarica, V. Radojcic, E. J. Fuchs, G. F. Murphy, and L. Luznik Host-Derived Langerhans Cells Persist after MHC-Matched Allografting Independent of Donor T Cells and Critically Influence the Alloresponses Mediated by Donor Lymphocyte Infusions J. Immunol., October 1, 2006; 177(7): 4414 - 4425. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Liao and N. H. Ruddle Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J. Immunol., September 1, 2006; 177(5): 3369 - 3379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Ceredig, M. Rauch, G. Balciunaite, and A. G. Rolink Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment Blood, August 15, 2006; 108(4): 1216 - 1222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Reinhardt, S. Hong, S.-J. Kang, Z.-e. Wang, and R. M. Locksley Visualization of IL-12/23p40 In Vivo Reveals Immunostimulatory Dendritic Cell Migrants that Promote Th1 Differentiation J. Immunol., August 1, 2006; 177(3): 1618 - 1627. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Diao, E. Winter, C. Cantin, W. Chen, L. Xu, D. Kelvin, J. Phillips, and M. S. Cattral In Situ Replication of Immediate Dendritic Cell (DC) Precursors Contributes to Conventional DC Homeostasis in Lymphoid Tissue. J. Immunol., June 15, 2006; 176(12): 7196 - 7206. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Sanchez-Sanchez, L. Riol-Blanco, and J. L. Rodriguez-Fernandez The Multiple Personalities of the Chemokine Receptor CCR7 in Dendritic Cells J. Immunol., May 1, 2006; 176(9): 5153 - 5159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. B. Flohe, H. Agrawal, D. Schmitz, M. Gertz, S. Flohe, and F. U. Schade Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response J. Leukoc. Biol., March 1, 2006; 79(3): 473 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Fogg, C. Sibon, C. Miled, S. Jung, P. Aucouturier, D. R. Littman, A. Cumano, and F. Geissmann A Clonogenic Bone Marrow Progenitor Specific for Macrophages and Dendritic Cells Science, January 6, 2006; 311(5757): 83 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 C. H. Schimmelpfennig, S. Schulz, C. Arber, J. Baker, I. Tarner, J. McBride, C. H. Contag, and R. S. Negrin Ex Vivo Expanded Dendritic Cells Home to T-Cell Zones of Lymphoid Organs and Survive in Vivo after Allogeneic Bone Marrow Transplantation Am. J. Pathol., November 1, 2005; 167(5): 1321 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tussiwand, N. Onai, L. Mazzucchelli, and M. G. Manz Inhibition of Natural Type I IFN-Producing and Dendritic Cell Development by a Small Molecule Receptor Tyrosine Kinase Inhibitor with Flt3 Affinity J. Immunol., September 15, 2005; 175(6): 3674 - 3680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ordway, M. Henao-Tamayo, I. M. Orme, and M. Gonzalez-Juarrero Foamy Macrophages within Lung Granulomas of Mice Infected with Mycobacterium tuberculosis Express Molecules Characteristic of Dendritic Cells and Antiapoptotic Markers of the TNF Receptor-Associated Factor Family J. Immunol., September 15, 2005; 175(6): 3873 - 3881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. G. Diacovo, A. L. Blasius, T. W. Mak, M. Cella, and M. Colonna Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes J. Exp. Med., September 6, 2005; 202(5): 687 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-L. Hahn, H. A. Schenkein, and J. G. Tew Endocarditis-Associated Oral Streptococci Promote Rapid Differentiation of Monocytes into Mature Dendritic Cells Infect. Immun., August 1, 2005; 73(8): 5015 - 5021. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 M. O'Keeffe, T. C. Brodnicki, B. Fancke, D. Vremec, G. Morahan, E. Maraskovsky, R. Steptoe, L. C. Harrison, and K. Shortman Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development Int. Immunol., March 1, 2005; 17(3): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tamura, P. Tailor, K. Yamaoka, H. J. Kong, H. Tsujimura, J. J. O'Shea, H. Singh, and K. Ozato IFN Regulatory Factor-4 and -8 Govern Dendritic Cell Subset Development and Their Functional Diversity J. Immunol., March 1, 2005; 174(5): 2573 - 2581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Montoya, M. J. Edwards, D. M. Reid, and P. Borrow Rapid Activation of Spleen Dendritic Cell Subsets following Lymphocytic Choriomeningitis Virus Infection of Mice: Analysis of the Involvement of Type 1 IFN J. Immunol., February 15, 2005; 174(4): 1851 - 1861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Llodra, V. Angeli, J. Liu, E. Trogan, E. A. Fisher, and G. J. Randolph From the Cover: Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques PNAS, August 10, 2004; 101(32): 11779 - 11784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
N. Sanchez-Sanchez, L. Riol-Blanco, G. de la Rosa, A. Puig-Kroger, J. Garcia-Bordas, D. Martin, N. Longo, A. Cuadrado, C. Cabanas, A. L. Corbi, et al. Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells Blood, August 1, 2004; 104(3): 619 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Fleeton, N. Contractor, F. Leon, J. D. Wetzel, T. S. Dermody, and B. L. Kelsall Peyer's Patch Dendritic Cells Process Viral Antigen from Apoptotic Epithelial Cells in the Intestine of Reovirus-infected Mice J. Exp. Med., July 19, 2004; 200(2): 235 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Burnett, E. J. Kershen, J. Zhang, L. Zeng, S. C. Straley, A. M. Kaplan, and D. A. Cohen Conditional macrophage ablation in transgenic mice expressing a Fas-based suicide gene J. Leukoc. Biol., April 1, 2004; 75(4): 612 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
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L. C. Bonifaz, D. P. Bonnyay, A. Charalambous, D. I. Darguste, S.-I. Fujii, H. Soares, M. K. Brimnes, B. Moltedo, T. M. Moran, and R. M. Steinman In Vivo Targeting of Antigens to Maturing Dendritic Cells via the DEC-205 Receptor Improves T Cell Vaccination J. Exp. Med., March 15, 2004; 199(6): 815 - 824. [Abstract] [Full Text] [PDF]
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N. S. Wilson, D. El-Sukkari, and J. A. Villadangos Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis Blood, March 15, 2004; 103(6): 2187 - 2195. [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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C. De Trez, M. Brait, O. Leo, T. Aebischer, F. A. Torrentera, Y. Carlier, and E. Muraille Myd88-Dependent In Vivo Maturation of Splenic Dendritic Cells Induced by Leishmania donovani and Other Leishmania Species Infect. Immun., February 1, 2004; 72(2): 824 - 832. [Abstract] [Full Text] [PDF]
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M. J. Miller, A. S. Hejazi, S. H. Wei, M. D. Cahalan, and I. Parker T cell repertoire scanning is promoted by dynamic dendritic cell behavior and random T cell motility in the lymph node PNAS, January 27, 2004; 101(4): 998 - 1003. [Abstract] [Full Text] [PDF]
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N. S. Wilson, D. El-Sukkari, G. T. Belz, C. M. Smith, R. J. Steptoe, W. R. Heath, K. Shortman, and J. A. Villadangos Most lymphoid organ dendritic cell types are phenotypically and functionally immature Blood, September 15, 2003; 102(6): 2187 - 2194. [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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I.-J. Kim, E. Flano, D. L. Woodland, F. E. Lund, T. D. Randall, and M. A. Blackman Maintenance of Long Term {gamma}-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells J. Immunol., July 15, 2003; 171(2): 886 - 892. [Abstract] [Full Text] [PDF]
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A. D. Edwards, D. Chaussabel, S. Tomlinson, O. Schulz, A. Sher, and C. Reis e Sousa Relationships Among Murine CD11chigh Dendritic Cell Subsets as Revealed by Baseline Gene Expression Patterns J. Immunol., July 1, 2003; 171(1): 47 - 60. [Abstract] [Full Text] [PDF]
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L. Corcoran, I. Ferrero, D. Vremec, K. Lucas, J. Waithman, M. O'Keeffe, L. Wu, A. Wilson, and K. Shortman The Lymphoid Past of Mouse Plasmacytoid Cells and Thymic Dendritic Cells J. Immunol., May 15, 2003; 170(10): 4926 - 4932. [Abstract] [Full Text] [PDF]
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E. Donskoy and I. Goldschneider Two Developmentally Distinct Populations of Dendritic Cells Inhabit the Adult Mouse Thymus: Demonstration by Differential Importation of Hematogenous Precursors Under Steady State Conditions J. Immunol., April 1, 2003; 170(7): 3514 - 3521. [Abstract] [Full Text] [PDF]
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E. Flano, I.-J. Kim, J. Moore, D. L. Woodland, and M. A. Blackman Differential {gamma}-Herpesvirus Distribution in Distinct Anatomical Locations and Cell Subsets During Persistent Infection in Mice J. Immunol., April 1, 2003; 170(7): 3828 - 3834. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
by mouse dendritic cell subsets.
J Immunol.
2001;166:5448-5455