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Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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40 h after transfer. In
contrast, DC that had been loaded with an MHC class I-binding peptide
disappeared from the lymph node with kinetics that parallel the known
kinetics of activation of CD8+ T cells to effector
function. In the presence of high numbers of specific CTL precursors,
as in TCR transgenic mice, DC numbers were significantly decreased by
72 h after injection. The rate of DC disappearance was extremely
rapid and efficient in recently immunized mice and was slower in
"memory" mice in which memory CD8+ cells needed to
reacquire effector function before mediating DC elimination. We also
show that CTL-mediated clearance of Ag-loaded DC has a notable effect
on immune responses in vivo. Ag-specific CD8+ T cells
failed to divide in response to Ag presented on a DC if the DC were
targets of a pre-existing CTL response. The induction of antitumor
immunity by tumor Ag-loaded DC was also impaired. Therefore,
CTL-mediated clearance of Ag-loaded DC may serve as a negative feedback
mechanism to limit the activity of DC within the lymph
node. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or
IL-1ß, DC migrate from the peripheral tissues to regional lymph nodes
(3, 4) and undergo a maturation process characterized by a
reduction in Ag capture function and up-regulation of MHC and
costimulatory molecules (5, 6). Final DC activation is
induced by Ag-specific Th cells via the interaction of CD40-ligand on
the Th cell with CD40 on the DC (7, 8). Activated DC can
prime naive CD8+ T cells to CTL
(9, 10, 11), which have the capacity to recognize and kill
cells that express specific Ag in the peripheral tissues. The fate of
DC after they have reached the lymph node is unknown. Because no cells
with the morphology of DC can be demonstrated in efferent lymph
(12), it has been proposed that DC die in situ, although
the mechanism remains unclear. Previous studies have shown that DC injected s.c. or i.v. have the capacity to migrate to the regional lymph nodes or the spleen, respectively (13). Fluorescent-labeled DC injected s.c. have been shown to migrate to draining lymph nodes (DLN) where they interact with Ag-specific CD4+ T cells to form clusters in the paracortex (14). DC that had not been loaded with specific Ag failed to form such clusters. Surprisingly, it was also observed that the numbers of Ag-loaded DC in the DLN had declined by 48 h, whereas the non-Ag-loaded DC persisted for longer periods of time. This suggested that the Ag-loaded DC may have been eliminated by an immune-mediated mechanism.
We wished to examine in more detail the fate of peripherally administered DC in a model of CTL-mediated immunity and to establish how the immune response affected the persistence of DC in the lymph node. Our results suggest that DC clearance occurs in the presence of previously activated CTL and also during the activation of naive Ag-specific CTL precursors. Furthermore, the rapid clearance of tumor Ag-loaded DC was associated with impaired capacity to induce tumor immunity. Therefore, CTL-mediated clearance of Ag-loaded DC may serve as a negative feedback mechanism to limit the activity of DC within the lymph node.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 mice were from breeding pairs originally obtained from The Jackson Laboratory (Bar Harbor, ME). Strain 318 mice (15), transgenic for a TCR specific for H-2 Db plus fragment 33–41 of the lymphocytic choriomeningitis virus glycoprotein (LCMV33–41),3 were kindly provided by Dr. H. Pircher (Institute of Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany). The B6Aa0/Aa0 MHC class II-/- mice (16) were supplied by Dr. H. Bluethmann (Hoffmann-LaRoche, Basel, Switzerland). All mice were maintained at the Biomedical Research Unit of the Wellington School of Medicine by brother x sister mating; in vivo experimental protocols were approved by the Wellington School of Medicine Animal Ethics Committee and were performed according to institutional guidelines.
Tumor cell line
LL-LCMV is a derivative of the Lewis lung carcinoma LLTC (C57BL/6, H-2b) that has been modified to express a minigene encoding LCMV33–41 under the control of a CMV promoter (17).
In vitro culture media and reagents
Unless otherwise stated, all cultures were maintained in complete medium (CM) comprising of IMDM with 2 mM glutamine, 1% penicillin-streptomycin, 5 x 10-5 M 2-ME, and 5% FBS (all from Life Technologies, Auckland, New Zealand). The synthetic peptides LCMV33–41 (KAVYNFATM) and OVA257–264 (SIINFEKL) were from Chiron Mimotopes (Clayton, Australia).
Culture of bone marrow-derived DC
Bone marrow cells from C57BL/6 mice or B6Aa0/Aa0 mice were cultured at 4 x 105 cells/ml in CM containing 20 ng/ml IL-4 and 20 ng/ml GM-CSF as described previously (18). Cultures were provided fresh CM and cytokines every 3 days and incubated at 37°C until the time of assay (6–8 days). Cultures typically contained 70–100% DC as determined by fluorescent staining with the anti-CD11c Ab N418. DC (1 x 106 cells/ml) were loaded with peptide Ag by incubation at 37°C in CM containing 10 µM synthetic peptide for 2 h and then were washed three times with IMDM to remove excess peptide.
DC migration assay
DC were labeled with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE; Molecular Probes, Eugene, OR) by incubation in PBS containing 1 µM CFSE for 10 min at 37°C before one wash in five volumes of ice-cold PBS and two washes with IMDM. Unless otherwise stated, mice were injected with 1 x 106 CFSE+ DC by s.c. injection in the distal forelimb (volar aspect). At the indicated times, both axillary and brachial lymph nodes were removed from immunized mice and incubated in 2.4 mg/ml collagenase type II (Life Technologies) and 1 mg/ml DNase I (Sigma, St. Louis, MO) for 90 min at 37°C. The tissue was then disrupted by aspiration through an 18-gauge needle. The cell suspension was sieved through gauze, washed in PBS, and resuspended for flow cytometric analysis in PBS containing 2% FBS and 0.01% sodium azide.
Lymph node suspensions were analyzed using a FACSort and CellQuest software (both from Becton Dickinson, Mountain View, CA). The region containing DC was identified on the basis of forward/side light scatter profile. No CFSE+ cells were found outside this region. In initial experiments, the total number of DC within the DLN was calculated as follows: % CFSE+ cells in the DC region x % of DLN cells in the DC region x number cells in DLN; data are expressed as average number of DC within DLN for each experimental group. Because it was observed over repeated experiments that the percentage of CFSE+ cells in the DC region was always proportional to the absolute number of CFSE+ cells across the experimental groups, data were expressed as average percentage of CFSE+ cells thereafter. Only events falling within the gated DC region were collected and stored (>250,000 events for each DLN suspension).
Frozen sections (8 µm) were prepared from the axillary lymph nodes of animals injected with CFSE+ DC 20 h earlier. The sections were stained with hematoxylin and eosin and analyzed by standard and fluorescence microscopy. CD8+ T cells are depleted by one i.v. injection of 500 µg purified 2.43 mAb 24 h before DC immunization.
Ab staining
Ab staining was in PBS containing 2% FBS and 0.01% sodium
azide. The anti-Fc
RII mAb 2.4G2 was used at 10 µg/ml to
inhibit nonspecific staining. Anti-MHC class II (3JP) and
anti-CD11c (N418) were affinity purified from culture supernatants
using protein G-Sepharose (Pharmacia Biotech, Uppsala, Sweden),
conjugated to biotin as described (19), and revealed using
streptavidin-PE (PharMingen, San Diego, CA). Instrument compensation
was set in each experiment using single color-stained samples.
Adoptive transfer and DC immunization
Pooled lymph node cell suspensions were prepared from strain 318
mice, and the percentage of T cells expressing the transgenic TCR was
determined on one sample of cells by staining with anti-V2 and
anti-Vß8.1, 8.2 Abs and by FACS analysis. The cells were then
labeled by incubation in 1.25 µM CFSE (Molecular Probes) in PBS for
10 min at room temperature at a cell concentration of 2 x
107 cells/ml. The cells were pelleted by
centrifugation in the presence of 50% FCS, washed two times in CM, and
then washed again in IMDM. Suspensions containing 5 x
106
V2+Vß8+ cells were
transferred into C57BL/6 recipients by i.v. injection into the tail
vein. One day after adoptive transfer, the mice were immunized s.c.
with 105 DC. After 66 h, the draining
axillary and brachial lymph nodes were removed, teased through gauze to
prepare single-cell suspensions, and analyzed by FACS.
Tumor immunity assay
Groups of C57BL/6 mice (n = 5) were immunized by s.c. injection into the left flank with 105 DC. Secondary immunizations were by s.c. injection into the contralateral flank 7 days later. One week after the last immunization, all animals were challenged with 106 LL-LCMV tumor cells injected s.c. into the left flank. Mice were monitored for tumor growth every 3–4 days, and tumor size for each group was calculated as the mean of the products of bisecting diameters (±SE). Measurements were terminated for each group when the first animal developed a tumor in excess of 200 mm2.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined the migration of injected DC to the secondary lymphoid
organs of mice. DC were cultured from bone marrow precursors in the
presence of GM-CSF and IL-4 for 7 days and labeled with CFSE, an
amine-reactive dye that can be retained in live cells for many
generations. DC were administered s.c. into the distal forelimb of mice
without any deliberate preincubation with Ag. As can be seen in Fig. 1
, 20 h after injection
CFSE+ cells could be detected in the DLN by
fluorescence microscopy on frozen tissue sections and were located in
the paracortical region of the lymph node. Analysis of DLN cell
preparations by flow cytometry also revealed the presence of
CFSE+ cells in the DLN (Fig. 2). No CFSE+ cells
could be detected in the non-DLN. In addition,
CFSE+ cells could not be detected in the DLN if
the DC were heat killed before injection. These results imply that the
CFSE+ cells had reached the DLN via an active
migratory process.
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B, MHC class II expression could
be demonstrated on CFSE+ cells obtained from mice
that had received C57BL/6 DC. In contrast, no expression of MHC class
II was found on CFSE+ cells from mice that
received MHC class II-/- DC. We conclude that
the CFSE+ cells detected in the DLN were the same
DC that had been injected peripherally and that these cells had
actively migrated from the site of injection to the DLN.
The proportion of CFSE+ DC that reached the DLN
and their kinetics of appearance were also examined. As shown in Fig. 3A, the absolute number of
CFSE+ DC found within the DLN represented only a
small proportion (0.1%) of the original number of DC injected. The
injected DC appeared in the DLN within 12 h of injection, reaching
maximum numbers before 48 h. Considerable numbers of
CFSE+ DC could still be demonstrated in the DLN
at 172 h postinjection (Fig. 3B), the latest time point
examined.
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DC loaded with MHC class I-binding peptide Ag are cleared from the DLN
Next, we sought to determine the fate of Ag-loaded DC after s.c.
injection into mice. CFSE+ DC were loaded with
LCMV33–41, an MHC class I-binding peptide from
the LCMV glycoprotein, and injected into the forelimbs of C57BL/6
recipients. The numbers of Ag-loaded DC in the DLN were compared with
the numbers in the DLN of mice that received DC not loaded with Ag. As
can be seen in Fig. 4A,
loading with Ag had no effect on the number of
CFSE+ DC recovered from the DLN at 16 h
after injection. By 72 h, a small reduction in the number of DC in
the DLN was observed in the experiment shown, but this reduction was
not always observed in repeated experiments. In contrast, when the
number of CD8+ T cells specific for the Ag
presented on DC was increased as in TCR transgenic recipients, a
significant and highly reproducible reduction in the number of
Ag-loaded DC in the DLN was observed 72 h after injection. No
reduction was apparent at 16 h. Depletion of
CD8+ T cells from TCR transgenic recipients
before DC injection prevented the reduction in number of Ag-loaded DC
in the DLN (Fig. 4B). These results suggest that activation
of TCR transgenic CD8+ T cells to cytotoxic
effector cells is associated with the disappearance of DC expressing
specific Ag from the DLN. DC clearance occurs between 16 and 72 h
after injection, a period consistent with the acquisition of effector
function by CD8+ T cells as reported by other
investigators (20, 21). The minimal clearance of Ag-loaded
DC demonstrated in the DLN of naive, non-TCR transgenic mice probably
reflects the smaller number of Ag-specific T cells that become
activated in these mice and hence the lower number of interactions that
result in DC clearance.
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Next, we next investigated the fate of Ag-loaded DC in the context
of an ongoing immune response. To this end, CFSE+
DC loaded with the MHC class I-binding peptide
LCMV33–41 were administered to mice that had
been injected s.c. in the flank 7 days before with
105 DC alone or with 105 DC
loaded with the same LCMV33–41 peptide. The
7-day interval was chosen because our previous studies have shown that
Ag-specific T cell expansion is maximal at this time (22);
also, resistance to challenge with
LCMV33–41-expressing tumors can be demonstrated
(17). In addition, "memory" recipients were also used.
These animals had received LCMV33–41-loaded DC 6
mo before and had subsequently rejected a challenge with tumor cells
expressing the LCMV33–41 epitope. All mice
received the LCMV33–41-loaded,
CFSE+ DC by s.c. injection into the anterior
forelimb. As can be seen in Fig. 5,
similar numbers of CFSE+ DC were observed in the
DLN of mice that were either previously immunized with DC without Ag or
in those of mice that had received no previous treatment. In contrast,
a large reduction in the number of CFSE+ DC was
observed in the DLN of animals immunized with
LCMV33–41 peptide-loaded DC 7 days earlier. The
reduction was clearly detectable as early as 20 h after injection,
suggesting that it was related to the presence of peptide-specific
effector cells in the recipient mice. Similar results were also
obtained with MHC class II-/- DC (data not
shown), indicating that CD4+ T cells were not
involved in DC elimination. A decrease in the number of
CFSE+ DC was also observed in the DLN of mice
from the "memory" group. However, in this latter case the decrease
in CFSE+ DC was observed only at 72 h and
not at 20 h after in vivo injection. This result suggests that the
reduction in the number of CFSE+ DC was related
to the acquisition of effector activity by pre-existing memory
CD8+ T cells in the recipient mice.
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CTL-mediated clearance of DC from the lymph node impairs induction of further immune responses
We wished to establish whether elimination of Ag-loaded DC during
an immune response impacts upon T cell activation initiated by the same
DC. As an in vivo readout of T cell activation, we examined the
proliferation of CFSE-labeled,
LCMV33–41-specific CD8+ T
cells adoptively transferred into syngeneic recipients. Proliferation
of CFSE+ T cells can be monitored in the DLN of
immunized mice by flow cytometry and is detected as progressive halving
of cellular fluorescence with every cell division completed
(23). Thus, we examined the specific proliferation induced
by DC that were or were not the targets of a pre-existing immune
response. Mice were preimmunized s.c. in the flank with DC +
OVA257–264 peptide to elicit an OVA-specific CTL
immune response or with DC only as a control. One week later, both
groups of mice received an adoptive transfer of
CFSE+ LCMV33–41-specific T
cells and were immunized s.c. in the forelimb with DC loaded with both
the OVA257–264 and
LCMV33–41 peptides. These mice were used to
examine the proliferation of LCMV33–41-specific
T cells. In addition, separate mice that had also been immunized in the
flank with DC + OVA257–264 or with DC only
received CFSE+ DC that had been loaded with both
the OVA257–264 and
LCMV33–41 peptides by s.c. injection in the
forelimb. These latter mice were used to evaluate the numbers of
CFSE+ DC in the DLN. As shown in Fig. 6, OVA257–264 +
LCMV33–41-loaded DC were rapidly eliminated in
mice that had previously been immunized with DC +
OVA257–264, most likely due to the induced
OVA-specific CTL response. In contrast, a considerable proportion of
OVA257–264 +
LCMV33–41-loaded DC could be demonstrated in the
DLN of mice previously immunized with DC only. Fig. 6 also shows the
proliferative response of LCMV33–41-specific T
cells in mice that had received the same DC immunizations. In mice in
which DC could be demonstrated in the DLN,
LCMV33–41-specific T cells underwent several
cycles of cell division, indicating the onset of an active immune
response. In contrast, in mice in which DC had disappeared from the
DLN, only limited proliferation of
LCMV33–41-specific T cells could be
demonstrated. We conclude from these results that CTL-mediated
elimination of DC may have a profound impact on T cell immune responses
and may prevent the initiation of immune responses to other Ags that
are simultaneously presented on the same DC.
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We wished to extend our findings by examining whether elimination
of Ag-loaded DC during the induction of an antitumor immune response
has a significant negative impact on antitumor immunity. For these
studies we used the tumor cell line LL-LCMV, a Lewis lung carcinoma
expressing the LCMV33–41 epitope
(17). All mice were preimmunized s.c. in the flank with DC
loaded with OVA257–264 to induce
OVA257–264-specific CTL responses. One week
later, mice received a second s.c. immunization in the opposite flank
with MHC class II-/- DC that were loaded with
both OVA257–264 and the "tumor Ag"
LCMV33–41 or with MHC class
II-/- DC loaded with the "tumor Ag"
LCMV33–41 only. MHC class
II-/- DC were used in this experiment to rule
out any effects mediated by CD4+ T cells. Similar
results were obtained when MHC class II+/+ DC
were used (data not shown), because DC are eliminated by pre-existing
CTL responses regardless of MHC class II expression. DC presenting
OVA257–264 and tumor Ag became targets of the
anti-OVA257–264 CTL response and were
eliminated (data not shown). In contrast, DC presenting tumor Ag alone
remained unaffected. One week after the second DC immunization, mice
were challenged with LL-LCMV, and tumor size was measured. In Fig. 7, we show that DC presenting both
OVA257–264 and
LCMV33–41 were less effective at inducing
antitumor immunity than DC presenting the
LCMV33–41 Ag alone were. This reduction in
efficacy was most likely due to the rapid clearance of
OVA257–264-loaded DC by
OVA257–264-specific CTL, which prevented the
productive initiation of an LCMV33–41-specific
immune response. However, a limited degree of antitumor immunity was
reproducibly induced by OVA257–264-loaded DC in
these experiments, suggesting that the DC were able to induce some
degree of T cell activation before being eliminated. Alternatively,
DC-associated Ag had been released and taken up by other APC, allowing
a specific immune response to be initiated.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this paper we have monitored the migration of CFSE+ DC injected s.c. into mice. The effect of Ag presented on MHC class I on DC survival in the DLN was also examined. We show that Ag-loaded DC disappear from the lymph node during the course of a CD8+ T cell response, with kinetics that parallel the known kinetics of activation of CD8+ T cells to effector function (20, 25). Ag-loaded DC were immediately cleared in recently immunized mice with a reduction in DC numbers observed in the DLN within 20 h of injection, suggesting that some DC may have been eliminated before reaching the lymph node. The kinetics of clearance were somewhat slower in "memory" mice, in which labeled DC were clearly demonstrated in the DLN at 20 h after injection but not at 72 h after injection. Memory CD8+ cells presumably would need to reacquire effector function before mediating elimination of DC in these mice (21). Lastly, Ag-loaded DC were cleared from the DLN between 16 h and 72 h after s.c. injection into naive, TCR transgenic mice. This indicates that Ag-loaded DC may be eliminated as a consequence of a primary CD8+ T cell immune response, perhaps as a mechanism to allow turnover of DC within the lymph node. This process may contribute to the restriction of the number of T cell specificities generated in a given immune response, a phenomenon that has been reported for viral infections (26, 27, 28). High-avidity T cells that become successfully activated in response to Ag on a given DC may eliminate that DC, thereby preventing the full activation of lower-avidity T cells that recognize different antigenic epitopes presented on the same DC.
The close parallel of the kinetics of DC clearance with the development
of a CTL response suggests that the failure to demonstrate
CFSE+ DC in the DLN is most likely due to active
elimination of labeled DC rather than to their migration to another
site or to selective loss of the CFSE label from otherwise viable DC.
This hypothesis is also supported by the observation that DC
elimination was inhibited by anti-CD8 Ab treatment and did not
require MHC class II expression by the DC. Elimination of DC was
clearly a systemic event in that it was observed at sites distant from
the site of original immunization, as would be expected on the basis of
the CTL’s ability to recirculate to different sites. However, the
mechanism of DC clearance, although clearly Ag-specific, is as yet
undefined. We cannot exclude the possibility that there was a constant
rapid turnover of DC in the DLN and that the clearance observed
represented a failure of DC to migrate to the DLN in the presence of
activated CTL. However, the fact that Ag-loaded DC were present in the
DLN of naive TCR transgenic mice at 16 h and then were lost by
72 h is highly suggestive of a cytolytic mechanism operating
within the node. Furthermore, the kinetics of DC clearance in naive
animals are consistent with the reported time required for CTL to gain
cytolytic function upon activation (20, 25). Preliminary
experiments indicated that DC clearance is not impaired in
IFN--deficient mice (data not shown), suggesting that this cytokine
is not critical to the clearance process and that other effector
mechanisms, presumably cytotoxicity, have a greater role. Other authors
have also reported a decrease in the number of Ag-loaded DC in the
lymph node during a CD4+ T cell immune response
(14). That decrease appeared less profound than the one we
describe here, probably reflecting different mechanisms of DC
elimination during CD4+ T cell responses compared
with CD8+ T cell responses. DC elimination has
also been demonstrated by histological means in mice exposed to viruses
that induce strong CTL immune responses (29).
We also show here that CTL-mediated clearance of Ag-loaded DC can have significant consequences on immune responses. Ag-specific T cell activation and proliferation, and induction of antitumor immunity were severely impaired when the DC were cleared by an existing CTL response. However, it should be noted that a limited degree of T cell proliferation and antitumor immunity was reproducibly demonstrated in these experiments, suggesting that some T cell activation was occurring despite the rapid clearance of DC. This weakened T cell response may have resulted from suboptimal stimulation by DC in the process of being eliminated or may have been induced by a low number of healthy DC that had escaped elimination.
It has been reported that Ag from short-lived migratory DC can be processed and presented by recipient DC within the lymph node (30). If DC are cleared from the DLN by a cytolytic mechanism, these dying cells may provide a ready source of Ag for lymph node-resident DC. The recipient DC may be of the "lymphoid" subclass that has been proposed to serve a regulatory, tolerogenic function (31, 32). This process could account for the reduced antitumor responses observed when the DC were "cleared" by an existing CTL response. Alternatively, it is possible that transfer of Ag from migratory DC to lymph node-resident DC, in fact, may be stimulatory but that this process was inefficient in our experimental system.
One surprising finding in our study is that a proportion of the injected DC appeared to persist in the DLN for a long time (in excess of 7 days from the in vivo transfer). This suggests that DC may have the ability to "wait" for T cells of the appropriate specificity to migrate through the lymph node and to recognize Ag on their surface. The prolonged survival of some DC may be simply a stochastic process or alternatively may reflect heterogeneity in the degree of activation of our DC before injection in vivo. It is also possible that the DC become activated in vivo by host CD4+ T cells to become the "temporal bridge" hypothesized by Ridge et al. (10), thereby becoming "conditioned" to stimulate further immune responses. Our experiments do not distinguish among these possibilities. In addition, we cannot exclude the possibility that this apparent prolonged persistence of DC in the DLN may in fact represent a slow turnover of DC that are continuously replaced by fresh DC migrating from the site of injection. We find this possibility less attractive in that it would appear that the lymph node should offer a more favorable environment for DC survival compared with that of the periphery. However, additional experiments are required to clarify this issue.
The process of DC clearance has implications for the design of DC-based immunotherapy regimes. From our results it can be concluded that repeated immunizations at short intervals with DC loaded with a given MHC class I-binding peptide may not be effective at enhancing responses to this Ag because the DC used in the secondary injections would be rapidly cleared by existing CTL. Indeed, our own experiments have suggested that repeated immunization with LCMV33–41-loaded DC does not lead to enhanced CTL responses against LL-LCMV challenge (data not shown). However, repeated DC injections may be effective in maintaining effector function in "memory" CD8+ T cells that may have lost activity due to suboptimal presentation of Ag in the context of tumor tissue.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Franca Ronchese, Malaghan Institute of Medical Research, P.O. Box 7060, Wellington South, New Zealand. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell; DLN, draining lymph node; LCMV, lymphocytic choriomeningitis virus; CM, complete medium; CFSE, carboxyfluorescein succinimidyl ester.
Received for publication July 6, 1999. Accepted for publication January 13, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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I. A. Cockburn, S. Chakravarty, M. G. Overstreet, A. Garcia-Sastre, and F. Zavala Memory CD8+ T Cell Responses Expand When Antigen Presentation Overcomes T Cell Self-Regulation J. Immunol., January 1, 2008; 180(1): 64 - 71. [Abstract] [Full Text] [PDF]
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K. E. Matthews, J. S. Qin, J. Yang, I. F. Hermans, M. J. Palmowski, V. Cerundolo, and F. Ronchese Increasing the Survival of Dendritic Cells In Vivo Does Not Replace the Requirement for CD4+ T Cell Help during Primary CD8+ T Cell Responses J. Immunol., November 1, 2007; 179(9): 5738 - 5747. [Abstract] [Full Text] [PDF]
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 Y. Nakamura, P. Watchmaker, J. Urban, B. Sheridan, A. Giermasz, F. Nishimura, K. Sasaki, R. Cumberland, R. Muthuswamy, R. B. Mailliard, et al. Helper Function of Memory CD8+ T Cells: Heterologous CD8+ T Cells Support the Induction of Therapeutic Cancer Immunity Cancer Res., October 15, 2007; 67(20): 10012 - 10018. [Abstract] [Full Text] [PDF]
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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]
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 A. Sapoznikov, J. A.A. Fischer, T. Zaft, R. Krauthgamer, A. Dzionek, and S. Jung Organ-dependent in vivo priming of naive CD4+,but not CD8+,T cells by plasmacytoid dendritic cells J. Exp. Med., August 6, 2007; 204(8): 1923 - 1933. [Abstract] [Full Text] [PDF]
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M. Matter, V. Pavelic, D. D. Pinschewer, S. Mumprecht, B. Eschli, T. Giroglou, D. von Laer, and A. F. Ochsenbein Decreased Tumor Surveillance after Adoptive T-Cell Therapy Cancer Res., August 1, 2007; 67(15): 7467 - 7476. [Abstract] [Full Text] [PDF]
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D. M. Jelley-Gibbs, J. P. Dibble, D. M. Brown, T. M. Strutt, K. K. McKinstry, and S. L. Swain Persistent Depots of Influenza Antigen Fail To Induce a Cytotoxic CD8 T Cell Response J. Immunol., June 15, 2007; 178(12): 7563 - 7570. [Abstract] [Full Text] [PDF]
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 T. Burster, T. Giffon, M. E. Dahl, P. Bjorck, M. Bogyo, E. Weber, K. Mahmood, D. B. Lewis, and E. D. Mellins Influenza A virus elevates active cathepsin B in primary murine DC Int. Immunol., May 1, 2007; 19(5): 645 - 655. [Abstract] [Full Text] [PDF]
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 K. E. Matthews, A. Karabeg, J. M. Roberts, S. Saeland, G. Dekan, M. M. Epstein, and F. Ronchese Long-Term Deposition of Inhaled Antigen in Lung Resident CD11b-CD11c+ Cells Am. J. Respir. Cell Mol. Biol., April 1, 2007; 36(4): 435 - 441. [Abstract] [Full Text] [PDF]
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 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]
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S. Laffont, J. D. Coudert, L. Garidou, L. Delpy, A. Wiedemann, C. Demur, C. Coureau, and J.-C. Guery CD8+ T-cell-mediated killing of donor dendritic cells prevents alloreactive T helper type-2 responses in vivo Blood, October 1, 2006; 108(7): 2257 - 2264. [Abstract] [Full Text] [PDF]
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D. Xia, S. Hao, and J. Xiang CD8+ Cytotoxic T-APC Stimulate Central Memory CD8+ T Cell Responses via Acquired Peptide-MHC Class I Complexes and CD80 Costimulation, and IL-2 Secretion. J. Immunol., September 1, 2006; 177(5): 2976 - 2984. [Abstract] [Full Text] [PDF]
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S. N. Mueller, C. M. Jones, A. T. Stock, M. Suter, W. R. Heath, and F. R. Carbone CD4+ T Cells Can Protect APC from CTL-Mediated Elimination. J. Immunol., June 15, 2006; 176(12): 7379 - 7384. [Abstract] [Full Text] [PDF]
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D. Mayerova, L. Wang, L. S. Bursch, and K. A. Hogquist Conditioning of langerhans cells induced by a primary CD8 T cell response to self-antigen in vivo. J. Immunol., April 15, 2006; 176(8): 4658 - 4665. [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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K. Yamaoka, B. Min, Y.-J. Zhou, W. E. Paul, and J. J. O'Shea Jak3 negatively regulates dendritic-cell cytokine production and survival Blood, November 1, 2005; 106(9): 3227 - 3233. [Abstract] [Full Text] [PDF]
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D. M. Jelley-Gibbs, D. M. Brown, J. P. Dibble, L. Haynes, S. M. Eaton, and S. L. Swain Unexpected prolonged presentation of influenza antigens promotes CD4 T cell memory generation J. Exp. Med., September 6, 2005; 202(5): 697 - 706. [Abstract] [Full Text] [PDF]
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R. Obst, H.-M. van Santen, D. Mathis, and C. Benoist Antigen persistence is required throughout the expansion phase of a CD4+ T cell response J. Exp. Med., May 16, 2005; 201(10): 1555 - 1565. [Abstract] [Full Text] [PDF]
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D. M. Jelley-Gibbs, J. P. Dibble, S. Filipson, L. Haynes, R. A. Kemp, and S. L. Swain Repeated stimulation of CD4 effector T cells can limit their protective function J. Exp. Med., April 4, 2005; 201(7): 1101 - 1112. [Abstract] [Full Text] [PDF]
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T. W. Kim, J.-H. Lee, L. He, D. A.K. Boyd, J. M. Hardwick, C.-F. Hung, and T-C. Wu Modification of Professional Antigen-Presenting Cells with Small Interfering RNA In vivo to Enhance Cancer Vaccine Potency Cancer Res., January 1, 2005; 65(1): 309 - 316. [Abstract] [Full Text] [PDF]
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S. J. Prasad, K. J. Farrand, S. A. Matthews, J. H. Chang, R. S. McHugh, and F. Ronchese Dendritic Cells Loaded with Stressed Tumor Cells Elicit Long-Lasting Protective Tumor Immunity in Mice Depleted of CD4+CD25+ Regulatory T Cells J. Immunol., January 1, 2005; 174(1): 90 - 98. [Abstract] [Full Text] [PDF]
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E. Vassiliou, V. Sharma, H. Jing, F. Sheibanie, and D. Ganea Prostaglandin E2 Promotes the Survival of Bone Marrow-Derived Dendritic Cells J. Immunol., December 1, 2004; 173(11): 6955 - 6964. [Abstract] [Full Text] [PDF]
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S. B. J. Wong, C. B. Buck, X. Shen, and R. F. Siliciano An Evaluation of Enforced Rapid Proteasomal Degradation as a Means of Enhancing Vaccine-Induced CTL Responses J. Immunol., September 1, 2004; 173(5): 3073 - 3083. [Abstract] [Full Text] [PDF]
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J. Karman, C. Ling, M. Sandor, and Z. Fabry Initiation of Immune Responses in Brain Is Promoted by Local Dendritic Cells J. Immunol., August 15, 2004; 173(4): 2353 - 2361. [Abstract] [Full Text] [PDF]
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M. B. Jordan, D. Hildeman, J. Kappler, and P. Marrack An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder Blood, August 1, 2004; 104(3): 735 - 743. [Abstract] [Full Text] [PDF]
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B. Wang, H. Chen, X. Jiang, M. Zhang, T. Wan, N. Li, X. Zhou, Y. Wu, F. Yang, Y. Yu, et al. Identification of an HLA-A*0201-restricted CD8+ T-cell epitope SSp-1 of SARS-CoV spike protein Blood, July 1, 2004; 104(1): 200 - 206. [Abstract] [Full Text] [PDF]
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P. Wolint, M. R. Betts, R. A. Koup, and A. Oxenius Immediate Cytotoxicity But Not Degranulation Distinguishes Effector and Memory Subsets of CD8+ T Cells J. Exp. Med., April 5, 2004; 199(7): 925 - 936. [Abstract] [Full Text] [PDF]
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A. V. Gorbachev and R. L. Fairchild CD4+ T Cells Regulate CD8+ T Cell-Mediated Cutaneous Immune Responses by Restricting Effector T Cell Development through a Fas Ligand-Dependent Mechanism J. Immunol., February 15, 2004; 172(4): 2286 - 2295. [Abstract] [Full Text] [PDF]
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H. Matsuyoshi, S. Senju, S. Hirata, Y. Yoshitake, Y. Uemura, and Y. Nishimura Enhanced Priming of Antigen-Specific CTLs In Vivo by Embryonic Stem Cell-Derived Dendritic Cells Expressing Chemokine Along with Antigenic Protein: Application to Antitumor Vaccination J. Immunol., January 15, 2004; 172(2): 776 - 786. [Abstract] [Full Text] [PDF]
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A. Martin-Fontecha, S. Sebastiani, U. E. Hopken, M. Uguccioni, M. Lipp, A. Lanzavecchia, and F. Sallusto Regulation of Dendritic Cell Migration to the Draining Lymph Node: Impact on T Lymphocyte Traffic and Priming J. Exp. Med., August 18, 2003; 198(4): 615 - 621. [Abstract] [Full Text] [PDF]
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M. Leverkus, A. D. McLellan, M. Heldmann, A. O. Eggert, E.-B. Brocker, N. Koch, and E. Kampgen MHC class II-mediated apoptosis in dendritic cells: a role for membrane-associated and mitochondrial signaling pathways Int. Immunol., August 1, 2003; 15(8): 993 - 1006. [Abstract] [Full Text] [PDF]
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J. C. R. Hafalla, A. Morrot, G.-i. Sano, G. Milon, J. J. Lafaille, and F. Zavala Early Self-Regulatory Mechanisms Control the Magnitude of CD8+ T Cell Responses Against Liver Stages of Murine Malaria J. Immunol., July 15, 2003; 171(2): 964 - 970. [Abstract] [Full Text] [PDF]
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I. Hwang, X. Shen, and J. Sprent Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: Distinct roles for CD54 and B7 molecules PNAS, May 27, 2003; 100(11): 6670 - 6675. [Abstract] [Full Text] [PDF]
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C. E. Hirst, M. S. Buzza, C. H. Bird, H. S. Warren, P. U. Cameron, M. Zhang, P. G. Ashton-Rickardt, and P. I. Bird The Intracellular Granzyme B Inhibitor, Proteinase Inhibitor 9, Is Up-Regulated During Accessory Cell Maturation and Effector Cell Degranulation, and Its Overexpression Enhances CTL Potency J. Immunol., January 15, 2003; 170(2): 805 - 815. [Abstract] [Full Text] [PDF]
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A. Nopora and T. Brocker Bcl-2 Controls Dendritic Cell Longevity In Vivo J. Immunol., September 15, 2002; 169(6): 3006 - 3014. [Abstract] [Full Text] [PDF]
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M. C. Wolkers, M. Toebes, M. Okabe, J. B. A. G. Haanen, and T. N. M. Schumacher Optimizing the Efficacy of Epitope-Directed DNA Vaccination J. Immunol., May 15, 2002; 168(10): 4998 - 5004. [Abstract] [Full Text] [PDF]
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M. J. Palmowski, E. M.-L. Choi, I. F. Hermans, S. C. Gilbert, J.-L. Chen, U. Gileadi, M. Salio, A. Van Pel, S. Man, E. Bonin, et al. Competition Between CTL Narrows the Immune Response Induced by Prime-Boost Vaccination Protocols J. Immunol., May 1, 2002; 168(9): 4391 - 4398. [Abstract] [Full Text] [PDF]
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H. P. Jones, L. Tabor, X. Sun, M. D. Woolard, and J. W. Simecka Depletion of CD8+ T Cells Exacerbates CD4+ Th Cell-Associated Inflammatory Lesions During Murine Mycoplasma Respiratory Disease J. Immunol., April 1, 2002; 168(7): 3493 - 3501. [Abstract] [Full Text] [PDF]
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S. Gardella, C. Andrei, L. V. Lotti, A. Poggi, M. R. Torrisi, M. R. Zocchi, and A. Rubartelli CD8+ T lymphocytes induce polarized exocytosis of secretory lysosomes by dendritic cells with release of interleukin-1{beta} and cathepsin D Blood, October 1, 2001; 98(7): 2152 - 2159. [Abstract] [Full Text] [PDF]
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J. P. Medema, D. H. Schuurhuis, D. Rea, J. van Tongeren, J. de Jong, S. A. Bres, S. Laban, R. E.M. Toes, M. Toebes, T. N.M. Schumacher, et al. Expression of the Serpin Serine Protease Inhibitor 6 Protects Dendritic Cells from Cytotoxic T Lymphocyte-Induced Apoptosis: Differential Modulation by T Helper Type 1 and Type 2 Cells J. Exp. Med., September 3, 2001; 194(5): 657 - 668. [Abstract] [Full Text] [PDF]
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F. Ronchese and I. F. Hermans Killing of Dendritic Cells: A Life Cut Short or a Purposeful Death? J. Exp. Med., September 3, 2001; 194(5): f23 - f26. [Full Text] [PDF]
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O. T. M. Chan, V. Paliwal, J. M. McNiff, S.-H. Park, A. Bendelac, and M. J. Shlomchik Deficiency in {beta}2-Microglobulin, But Not CD1, Accelerates Spontaneous Lupus Skin Disease While Inhibiting Nephritis in MRL-Faslpr Mice: An Example of Disease Regulation at the Organ Level J. Immunol., September 1, 2001; 167(5): 2985 - 2990. [Abstract] [Full Text] [PDF]
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D. J. Nelson, S. Mukherjee, C. Bundell, S. Fisher, D. van Hagen, and B. Robinson Tumor Progression Despite Efficient Tumor Antigen Cross-Presentation and Effective "Arming" of Tumor Antigen-Specific CTL J. Immunol., May 1, 2001; 166(9): 5557 - 5566. [Abstract] [Full Text] [PDF]
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S. Corinti, C. Albanesi, A. la Sala, S. Pastore, and G. Girolomoni Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions J. Immunol., April 1, 2001; 166(7): 4312 - 4318. [Abstract] [Full Text] [PDF]
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