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*
Department of Medicine, Queen Elizabeth II Medical Center, University of Western Australia, Nedlands, Western Australia;
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and
Centre for Functional Genomics and Human Disease, Monash Institute of Reproduction and Development, Monash University, Clayton, Victoria, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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production, with no evidence of a partial or
nonresponsive phenotype among tetramer-positive cells. We also show
that CD4+ T cells are required for CD8+ T cell
infiltration of the tumor. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, it is clear that CD4+ T cells can also play an important role in facilitating an anti-tumor response (1). In some experiments in vivo depletion of CD4+ T cells has been shown to facilitate tumor progression; in others the cotransfer of CD4+ T cells improves tumor eradication. Moreover, studies using peptide immunization have demonstrated a requirement for coimmunization with both MHC class I- and class II-restricted peptides to ensure tumor eradication (2). The traditional explanation for these results is that CD4+ T cells provide IL-2 or help to the CD8+ T cells, an interpretation supported by studies in which IL-2 administration facilitates tumor eradication (3). More recently however, CD4+ T cells have been shown to have another role in the induction of CD8+ T cell responses via the modification of dendritic cells (DC),3 which, in turn, induce cytotoxic effector function in CD8+ T cells (4, 5, 6). Viruses or Abs to CD40 can also mediate this "licensing" of APCs by CD4+ T cells. It is also possible that CD4+ T cells are required in later phases of anti-tumor responses, as CD4+ T cells have been implicated in determining the magnitude and persistence of CTL responses in some chronic viral infections and models of autoimmune disease (7, 8, 9). Taken together these types of experiments provide a basis for the hypothesis that CD4+ T cells may play a broader role in anti-tumor responses than simply providing help for CTL induction. However, confirmation of this process, the mechanisms underlying it, and the role and subsequent fate of tumor-specific T cells are unknown.
To dissect out the role of tumor-specific T cells, we have developed a model system in which the influenza hemagglutinin (HA) gene is the model tumor Ag, and tumor-specific T cells are derived from HA-specific TCR transgenic mice. Two lines of TCR transgenic mice, one class I restricted (CL4 mice) (10) and the other class II-restricted (HNT mice) (11), both of which recognize HA in the context of H-2d, have been used. We have previously demonstrated in this model that tumor-specific CD4+ T cells act synergistically with limiting numbers of anti-tumor CD8+ T cells to prevent tumor growth (12). Here we examine the role that CD4+ T cells have in helping anti-tumor CD8+ T cells. Using MHC tetramers to directly identify the HA-specific CD8+ T cells, we show that the presence of CD4+ T cells not only correlates with the maintenance of specific CD8+ T cell numbers, but also with the maintenance of CTL function. In the absence of CD4+ T cells, CD8+ T cells cannot be found within the tumor mass. It is only in the presence of CD4+ T cells that other cells within the tumor exhibit up-regulation of MHC class II and ICAM expression. Together these data demonstrate that CD4+ T cells contribute to three major postlicensing events: maintenance of CD8 numbers, CD8 infiltration of tumors, and modulation of the tumor environment. These three events dramatically increase the efficacy of anti-tumor CTL effectors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c (H-2d) mice were obtained from the Animal Resources Center (Canning Vale, Australia) and maintained under standard conditions in the University Department of Medicine animal holding area. The anti-HA transgenic TCR mice (HNT, class II restricted; and CL4, class I restricted) were generated and screened as described previously (12). For all experiments female mice between 6 and 12 wk of age were used.
Tumor cell lines
The derivation and characterization of the AB1 murine MM cell
line and the generation of the AB1-HA transfectant (AB1 cells
transfected with the influenza HA gene) have been described previously
(12, 13). Cell lines were maintained in RPMI 1640 (Life
Technologies, Gaithersburg, MD) supplemented with 20 mM HEPES, 0.05 mM
2-ME, 60 µg/ml penicillin (CSL, Melbourne, Australia), 50 µg/ml
gentamicin (
West, Bentley, Australia), and 5% FCS (Life
Technologies). AB1-HA transfectants were selected by culture in medium
containing the neomycin analogue geneticin (Life Technologies) at a
final concentration of 400 µg/ml. The level of HA expression on
transfected cells was measured by FACS analysis, using the biotinylated
HA-specific mAb H18 (14) that was originally obtained from
Dr. Walter Gerhard (The Wistar Institute, Philadelphia, PA).
Preparation of cells for in vivo CTL
Detection of in vivo CTL was performed as described previously (15). Erythrocytes were removed from BALB/c spleens by resuspending cells in RBC lysis buffer for 5 min, followed by three washes in PBS and resuspending at 5 x 106 cells/ml. Cells were divided into two populations, one of which was pulsed with 1 µg/ml of CL4 peptide for 90 min at 37°C. Cells were then labeled with CFSE (Molecular Probes, Eugene, OR) for 10 min at room temperature. For CFSE fluorescence intensities, peptide-pulsed cells were labeled at a final concentration of 5 µM (CFSEhigh) and unpulsed cells at 0.5 µM (CFSElow). Cells were washed with FCS four times and then with PBS before i.v. injecting CFSE-labeled cells into recipients. In all experiments cells were recovered 20 h after transfer and analyzed by FACS for fluorescence intensity using CellQuest software (Becton Dickinson Immunocytometry Systems, San Jose, CA).
HA tetramer preparation
Recombinant protein was prepared as previously described by Garboczi and colleagues (16). The plasmid encoding Kd (provided by Dr. Jon Yewdell, National Institute of Allergy and Infectious Disease, National Institutes of Health, and Dr. Altman, Emory College of Medicine, Atlanta, GA) was modified to encode a BirA recognition sequence at the C terminus (17). In some experiments the tetramers were further purified by size exclusion chromatography.
HA tetramer staining and FACS analysis
For analysis, 5 x 105 lymphocytes
were treated with purified anti-mouse CD16/CD32 (Fc-III/II
receptor, PharMingen, San Diego, CA), then stained with the HA tetramer
for 2 h at room temperature. Abs to CD8 coupled with fluorescein
were then added for an additional 20 min. Propidium iodide (1 µg/ml)
was added in the final wash to exclude nonviable cells. Events were
acquired on a FACScan flow cytometer, and the data were analyzed using
CellQuest software (Becton Dickinson).
IFN- enzyme-linked immunospot (ELISPOT) assay
Cells secreting IFN- in an Ag-specific manner were detected
using a standard ELISPOT assay (18, 19). Ninety-six-well
multiscreen HA plates (Millipore, Bedford, MA) were coated with rat
anti-mouse IFN- Ab (clone R4-6A2; PharMingen) overnight at
4°C, washed with PBS, then incubated with 200 µl of RPMI 1640
medium supplemented with 10% FCS for 1 h at room temperature.
Two-fold dilutions of lymph node (LN) cells from animals previously
inoculated s.c. with 2 x 105 AB1-HA cells
and i.v. with 1 x 107 CL4 LN cells with or
without 1 x 107 HNT LN cells were added to
wells starting at 106/well in the presence of
4 x 105 gamma-irradiated (1200 rad)
syngeneic spleen cells. Cells were incubated for 26 h with or
without CL4 peptide stimulation (1 µg/ml, final concentration). Wells
were sequentially washed three times each with
ddH20, PBS, and PBS containing 0.05% Tween 20
and then incubated for 20 h at 4°C with biotinylated
anti-mouse IFN- Ab (4 µg/ml, clone XMG1.2, PharMingen). Wells
were washed and incubated with peroxidase-labeled anti-biotin Ab (2
µg/ml; Vector, Burlingame, CA) for 20 h at 4°C. Wells were
then washed and spots were developed using freshly prepared substrate
(3-amino-9-ethyl-carbazole; Sigma, St. Louis, MO) dissolved in
dimethyformamide, diluted in 0.1 M sodium acetate (pH 4.8), and
filtered, and 0.015% H2O2
(final concentration) was added to give a 0.3 mg/ml solution. After 30
min the substrate solution was discarded, and plates were washed under
running water and air-dried. Colored spots were counted using a
stereomicroscope.
Immunohistochemical staining
Surface Ags were detected using the streptavidin-biotin labeling
immunoperoxidase staining technique. Tissues from various sites were
removed, placed in compound-embedding medium (OCT; Miles, Elkhart, IN),
snap-frozen using dry ice, and stored at -80°C. Ten-micrometer
sections were cut, collected on poly-L-lysine-coated
slides, and allowed to air-dry. Slides were stored at 4°C (for a
maximum of 2 days) before staining. Before immunostaining, sections
were fixed with cold ethanol (15 min) and blocked with 1% (v/v)
H2O2 (5 min) followed by
avidin/biotin block (10 min each). Sections were incubated with the
appropriate dilutions of rat anti-mouse mAbs against CD8 (53-6.7,
Lyt2), CD4 (RM4-5, L3T4), CD54 (3E2, ICAM-1), and isotype controls rat
IgG2a,
(R35-95) and rat IgG2b, (A95-1; all from PharMingen) and
rat anti-mouse mAb against class II (TIB-120, M5/114.15.2, provided
by P. Holt, TVW Telethon Institute for Child Health and Research,
Perth, Australia) for 1 h followed by incubation with a
biotinylated secondary Ab for 30 min (mouse anti-rat IgG
F(ab')2; Jackson ImmunoResearch, West Grove, PA).
Immunostaining was detected by incubating with streptavidin-HRP (Dako,
Copenhagen, Denmark) for 30 min and with
diaminobenzidine-H2O2
(Sigma) for 5–10 min. Slides were washed three times for 5 min each
time in PBS between each incubation step, counterstained with
hematoxylin, and mounted in aqueous mounting medium.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Both CD4+ and CD8+
Ag-specific T cells are required for eradication of the AB1-HA MHC
class I+, class II- tumor
(Fig. 1
A) (12).
To determine the minimum number of cells that protect from tumor
growth, AB1-HA-inoculated mice were adoptively transferred either with
1 x 107 LN cells from HA-specific, MHC
class I-restricted TCR transgenic mice (CL4 mice,
CD8+ T cells) plus LN cells from HA-specific, MHC
class II-restricted TCR transgenic mice (HNT mice,
CD4+ T cells; titrated over a range of
104 to 5 x 106 cells;
Fig. 1B) or with 1 x 107
CD4+ T cells and a titration of
CD8+ T cells (Fig. 1C). When
<107 cells of either subpopulation were
transferred, the level of protection was markedly reduced. This
reduction correlated with the number of titrated cells.
CD8+ plus CD4+ T cells were
then adoptively transferred into BALB/c mice 7 or 14 days after AB1-HA
inoculation, when tumor in control mice is not palpable. Delaying the
cotransfer of CD4+ plus
CD8+ T cells until day 7 or 14 after tumor
inoculation resulted in no protection from tumor growth (Fig. 2). In fact, there was no protection even
if these cells were transferred as early as 4 days after tumor
inoculation (data not shown). To determine whether delaying the
administration of either T cell subpopulation would affect tumor
growth, BALB/c mice were inoculated with AB1-HA and concomitantly
transferred with either CD4+ or
CD8+ T cells. At 7 (Fig. 2A) or 14
(Fig. 2B) days after tumor inoculation, mice were given the
reciprocal population. The efficacy of tumor eradication was reduced in
all experimental groups, with no significant difference between
delaying transfer of the second reciprocal cell population from day 7
to day 14, although the kinetics of tumor growth were somewhat delayed
compared with those in the control animals that received tumor only.
Mice that received CD4+ T cells concurrently with
tumor inoculation showed a small, but reproducible, degree of
protection compared with those given CD8+ T cells
at the time of tumor inoculation (40% tumor-free animals compared with
0%; Fig. 2).
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We have already shown that the cotransfer of tumor-specific
CD4+ T cells increases the proliferation of HA
peptide-reactive CD8+ T cells recovered from
AB1-HA-inoculated animals (12). However, the direct
enumeration of these CD8+ T cells was not
possible, as there is neither a clonotypic nor a V
Ab for this
transgenic TCR. The V
-chain of the transgenic receptor,
V8.2, is relatively widely expressed in
wild-type animals and therefore cannot be used as a surrogate marker
for transferred cells. To overcome this problem, MHC class I tetramers
were produced that consisted of the H-2Kd
molecule and the HA peptide IYSTVASSL. To demonstrate that the
tetramers bind the appropriate receptors, LN cells from CL4 TCR
transgenic mice were stained. Tetramer-positive cells represented
>80% of the transgenic CD8+ T cells (49% of
the total cells analyzed; Fig. 3A), but did not stain T cells
from nontransgenic animals (Fig. 3B). Examples of tetramer
staining in the LN of animals that received adoptively transferred
cells are shown in Fig. 3, C–F. Animals that received
CD8+ T cells (Fig. 3, C and
D), showed consistently fewer tetramer-positive cells than
those that received both CD4+ and
CD8+ T cells (Fig. 3, E and
F). The summary of results from individual animals in which
the number of tetramer-positive cells in lymphoid organs was determined
14 and 28 days after tumor inoculation is shown in Fig. 4. Animals in both experimental groups
had similar numbers of tetramer-positive cells on day 14, i.e.,
0.22 ± 0.02% (SEM) of the total cells for the CD8 only group and
0.27 ± 0.02% of the total cells for the CD8 plus CD4 group (Fig. 4). However, by day 28 the number of tetramer-positive cells in the CD8
plus CD4 group remained similar to day 14 values (0.22 ± 0.02%),
but was significantly reduced to 0.10 ± 0.01% of the total cells
in animals given CD8 cells only (p = 0.000009).
This reduction in tetramer-positive cells in peripheral lymphoid tissue
was not the result of tetramer-positive cells trafficking to the tumor
(data not shown). Tetramer-positive cells were never detected in
animals inoculated with the AB1-HA tumor only (data not shown).
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, where
the r value, i.e., the ratio of the percentage of total cells in the
CFSElow (control) peak to that in the
CFSEhigh (target) peak represents the relative
cytotoxic capacity of the CD8+ T cells. This
assay was performed on days 14 and 28 after tumor inoculation. The
expression of a HA Ag by the tumor is not sufficient to induce a
specific CTL response (Fig. 5, A and B). The
variation seen between AB1-HA-inoculated animals on different days was
the same as that observed when CSFE-labeled splenocytes were
transferred into unmanipulated syngeneic recipients (data not shown).
Transferred CD8+ T cells were able to eradicate
the peptide-pulsed splenocytes up to 14 days after tumor inoculation
(Fig. 5C), but this capacity was reduced to that seen in
control mice by day 28 (Fig. 5D). In contrast, CTL function
was maintained in animals that had received both T cell subpopulations
(Fig. 5, E and F). The results from individual
animals for days 14 and 28 after tumor inoculation are shown in Fig. 6. Together these results demonstrate
that on day 14 there is little discernible difference in the capacity
of either experimental group to kill the peptide-pulsed targets (CD8
only: r = 48.6 ± 1.34;
CD8+CD4: r = 49.6 ± 1.24;
±SEM). However, by day 28 animals that received only
CD8+ T cells at the time of tumor inoculation
demonstrated reduced lytic capacity (r = 27.3 ±
2.5) compared with the day 14 results as well as with those exhibited
by the CD8 plus CD4 group on day 28 (r = 46.4
± 1.7).
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-secreting cells
after CL4 peptide stimulation of LN cells from animals that were
inoculated 14 days earlier with tumor and that received either
CD8+ T cells or both CD8+
and CD4+ T cells was comparable (51 ± 6 and
60 ± 16 IFN--secreting cells, respectively; Fig. 7). However, those animals that received
both CD8+ and CD4+ T cells
28 days after tumor inoculation demonstrated a significant increase in
the number of IFN--secreting cells (185 ± 43). In contrast,
the number of IFN--secreting cells in those animals that had
received only CD8+ T cells by day 28 had a
decreased number of IFN--secreting cells (18 ± 8).
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BALB/c mice were inoculated with either AB1-HA or the
nontransfected parental line AB1 and then injected i.v. with
CD8+, CD4+, or
CD8+ plus CD4+ T cells. To
investigate infiltration of the tumor, the site of inoculation was
excised at 5 days after tumor inoculation and examined by
immunohistochemistry. This time point was chosen because the adoptive
transfer of CD4+ and CD8+ T
cells leads to tumor eradication. On day 5 eradication was not
complete, and some tumor tissue could still be discerned (Figs. 8 and 9). At later time points tumor
tissue could not be obtained reproducibly from animals in this
experimental group. Tumors from AB1-HA-inoculated animals that received
CD8+ T cells alone showed little if any T cell
infiltration (Fig. 8, A and B). The predominant
infiltrating cell was the class II- macrophage,
which compromised up to 50% of the tumor mass (data not shown)
(20). Tumors from the parental AB1-inoculated animals
showed little if any T cell infiltration regardless of the cells
adoptively transferred (data not shown). Tumors from mice that were
adoptively transferred with CD4+ T cells only
showed CD4+, but not CD8+,
T cell infiltration (Fig. 8, C and D). In
contrast, there was an intense CD4+ and
CD8+ T cell infiltrate within the tumor milieu
from mice that had received both cell types (Fig. 8, E and
F). CD4+ and
CD8+ T cells were present in approximately equal
numbers. In addition, when either CD4+ T cells
alone or the combination of CD8+ plus
CD4+ T cells were transferred, MHC class
II+ cells were present throughout the tumor (Fig. 9, C and E). Again,
in contrast to mice that received CD8+ T cells
only, when either CD4+ T cells or
CD8+ and CD4+ T cells were
cotransferred, ICAM expression was also detected throughout the tumor
(Fig. 9, D and F). Similar experiments were
performed in which T cells were adoptively transferred into animals
with established tumors. Under these circumstances, tumor regression
does not occur. The pattern of infiltrating cells was similar to that
seen when tumor inoculation and adoptive transfer of T cells occurred
concurrently, that is, only when CD4+ and
CD8+ T cells were cotransferred were both cell
types found within the tumor (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There is a limited window of efficacy for transferred cells to eradicate tumors
The observation that upon titration of tumor-specific T cells of either subpopulation the efficacy of tumor eradication is reduced supports the idea that one reason for the failure of tumor eradication is a relative numerical imbalance of tumor cells and T cells. The fact that so many cells are essential to ensure tumor eradication and at such a short period of time after tumor inoculation (<1 wk) probably explains why this tumor is unable to be rejected in syngeneic recipients that bear a competent repertoire for the tumor Ag. Why there is a need for a 1:1 ratio of CD8+:CD4+ T cells is unclear, as CD4+ cells themselves are unable to act as anti-tumor effectors and, as discussed below, this numerical relationship is probably not required for CTL generation. This 1:1 ratio contrasts with the data reported by Kurts et al., who showed in their transgenic model of autoimmunity that relatively few CD4+ T cells facilitated T cell-mediated organ destruction (9). The reasons for these differences have yet to be fully elucidated; however, it is clear that although the requirement for such a relatively large number of adoptively transferred T cells may partly reflect the nature of the model, a s.c. inoculation of relatively fast-growing cells, CD8+ T cells alone are not sufficient to eradicate tumor.
Induction of CTL function is not sufficient for tumor rejection
The inadequacy of CD8+ T cells to reject tumors was not due to an inability of the transferred CD8+ T cells to differentiate into effectors, as shown by the in vivo CTL and ELISPOT data. We interpret the generation of CTLs in this system to be consistent with a requirement for CD4+ T cell licensing of DCs. Preliminary data in our laboratory, where mice have been depleted of CD4+ T cells and inoculated with tumor, and then specific CD8+ T cells adoptively transferred, show abrogated CTL activity, demonstrating CD4+ T cell dependency (unpublished observations). Therefore in the experiments described here, when specific CD4+ T cells were not cotransferred, the endogenous repertoire was sufficient to aid in the generation of these effectors. However, the induction of CTLs is clearly not enough to induce tumor eradication as shown here in the adoptive transfer experiments. In fact, a number of studies have demonstrated that CTL activity does not necessarily correlate with the ability to eradicate tumor. In our own system, 50% of transgenic mice expressing an HA-specific, class I-restricted TCR cannot reject the AB1-HA tumor (12). Wick and colleagues showed that anti-Ld TCR transgenic mice were unable to reject an allogenic tumor (23). More recently, Sarma and colleagues have shown that TCR transgenic mice cannot reject tumors expressing the endogenous tumor Ag P1A (24). The question is why, despite demonstrable CTL activity in these studies, CTL activity is not effective against the target tumor in vivo, i.e., why is the CTL effector function restrained?
CD4+ T cells maintain the CD8+ T cell pool as well as CTL activity
We show that CD4+ T cells have at least three functions subsequent to licensing events during an effective anti-tumor response. The first of these is maintenance of the CTL pool. Mice that received both CD4+ and CD8+ T cell populations maintained higher numbers of tetramer-positive cells, within a tighter range, over the period of the experiment than those that received CD8+ T cells only. These results are consistent with our previous finding that a greater number of class I-restricted, HA peptide-reactive cells are recoverable from animals adoptively transferred with both CD8+ and CD4+ populations than from CD8+ T cells alone (25). One can envisage that this potentiation of CD8 numbers is particularly necessary when the immune system is responding to a target that has the capacity to multiply or regenerate, as is the case with tumors and viruses. The ability of CD4+ T cells to maintain the CD8 pool has been described in other models, such as the cross-presentation of a transgenic self Ag and chronic viral infection (9, 26). In the transgenic autoimmune model in which OVA is expressed as a model self Ag in the islets of the pancreas, it has been demonstrated that specific CD4+ T cells moderate the loss of CD8+ T cells that occurs due to deletion after cross-presentation of Ag on APCs (9). The exact mechanism by which CD4+ T cells maintain CD8+ T cell numbers in our model is unknown. It does not appear to be related to modulation of the Fas-Fas ligand system (12), which has been implicated in the cross-presentation model described by Heath and colleagues. A recent paper has shown that anti-CTLA4 treatment increases the number of T cells in the draining LNs after Ag stimulation, probably by inhibiting inhibitory signals associated with binding of CTLA4 to B7 molecules (27). It was also shown that this phenomenon is CD4+ T cell independent. The authors hypothesize that this accumulation of CD8+ T cells due to anti-CTLA4 administration leads to the tumor regression observed in some studies (28). Anti-CTLA4 treatment of AB1-HA-inoculated mice also results in tumor regression (A.L.M., R.A.L., B.W.S.R., and B.S., unpublished observations), and it will be interesting to determine in that system whether an accumulation of tumor-specific cells can be observed and thereby support the hypothesis of McCoy and colleagues (27).
The second postlicensing function of CD4+ T cells is the maintenance of CTL function. In our experiments there was a correlation between CD8+ T cell number and CTL function. Both parameters remained high when CD4+ T cells were cotransferred. Although this may not be immediately surprising, and one might argue that if the numbers are higher, then CTL will also be higher, in the literature there are a number of models in which cells may be detected but are apparently nonfunctional. For example, in some viral infections CD4+ T cells are not necessarily required for the induction of primary CTL responses (29, 30), but in the absence of CD4+ T cells in the chronic phase of disease, although specific CD8+ T cells are still present, CTL activity is diminished (26). How CD4+ T cells act to ensure CTL function is not clear, but maintenance of function is important to ensure a pool of reactive cells that have the potential to eradicate their target.
CD4+ T cells allow CD8+ T cells to traffic to the tumor
Even so, large numbers of CTL effectors are not sufficient for tumor eradication. Thus, a third and very important postlicensing function of CD4+ T cells is allowing CD8+ T cell infiltration of the tumor. Because CD8+ T cells transferred alone do not traffic to the tumor, one can now offer a reason for why CTL cells can be generated but have no therapeutic effect. Onrust and colleagues have also demonstrated that Ag-specific CTLs cannot enter a tumor despite an inflammatory site, composed of the same CTLs, occurring directly adjacent to the tumor tissue (31). This inability of specific T cells to enter the tumor correlates with a differential expression of endothelial expressed integrins. Of particular interest in these studies was L-selectin expression, which was down-regulated on the vessels at the tumor site, but not at the site of inflammation. L-selectin was initially characterized as a homing receptor for lymphocytes. Previously, Ando and colleagues (32) had shown that CTLs do not necessarily enter tissues or organs that express specific Ag. In their study the target tissues were not sites of tumor growth or inflammation, so one could argue that there was no reason to expect T cell trafficking to a site of Ag expression. However, in these studies it was found that CTLs could enter tissues in which the constituent blood vessels were characterized by discontinuous endothelium and the absence of a basement membrane. These authors proposed that other components of the immune system, such as CD4+ T cells, might act to modify or disrupt the microvasculature and allow CTL entry of otherwise normal vessels during processes such as infection. We have also hypothesized that the absolute requirement for CD4+ T cells in rejecting the AB1-HA tumor is not solely as helper cells, but also as potential modifiers of the tumor milieu (25). In this paper we showed that after activation in the draining LN, CD4+ T cells, which cannot specifically kill the tumor, are not restricted from trafficking to the tumor and, in fact, allow CD8+ T cells to infiltrate the tumor. How do the CD4+ T cells influence the trafficking pattern of CD8+ T cells? CD4+ T cell trafficking is associated with the up-regulation of class II and the induction of ICAM expression within the tumor site, although the mechanism by which CD4+ T cells contribute to this change, either directly or indirectly, has not yet been established. Perhaps the up-regulation of inflammatory-associated molecules coincides with the activation or modification of the tumor vasculature as suggested by Ando and colleagues (32).
Alternatively, rather than CD4+ T cells altering
the CD8 trafficking patterns allowing CTLs to enter the tumor, we may
be observing the retention and accumulation of
CD8+ T cells. A current paradigm is that naive
cells remain within the lymphoid tissues, whereas activated cells
migrate from LNs and spleen to pass through tissues in search of Ag.
CD8+ T cells in tumor-inoculated mice fulfill
these criteria for migratory capacity, as they have encountered Ag in
the draining LNs (10), become activated, and differentiate
into CTL effectors. Our previous studies have demonstrated that these
CTL effectors cannot lyse tumor cells in vitro unless the cells have
been exposed to IFN- (12). This lack of target
recognition is not due to low level class I expression or to an
intrinsic resistance to lysis (12). Either the 2- to
3-fold increase in surface class I expression that results from IFN-
treatment is sufficient to increase the number of specific MHC-peptide
complexes above the threshold required for recognition or IFN-
alters the protein processing machinery, allowing more of the peptide
to be loaded into the class I molecule. Thus, in the absence of
recognition, CD8+ T cells may pass through the
tumor and die due to normal attrition following activation or may
traffic to and move into the tumor but are killed, either through
intrinsic mechanisms or due to tumor-derived factors. In either case
the histological picture would be the same, that is little or no
observable CD8+ T cell infiltrate. We postulate
that the ability of CD4+ T cells to traffic to
the tumor allows them to secrete cytokines at the site, modifying all
cells, including the tumor cells. Thus, CD4+ T
cells enter the tumor site, where they can secrete IFN-
and "reveal" the epitope required for CTL recognition, which, in
turn, leads to tumor cell lysis and the maintenance of an inflammatory
loop that ensures tumor eradication. Because the cotransfer of
CD4+ T cells leads to a greater number of
CD8+ T cells secreting IFN-, the
CD8+ T cells once in the tumor could also
contribute to IFN- production. A broader role for
CD4+ T cells has recently been described in a
vaccination model of tumor eradication where CD4+
T cell infiltration correlated with increased infiltration by other
cells, including eosinophils and macrophages that produced both
superoxide and NO (33).
In conclusion, our model has enabled us to clarify the role that CD4+ T cells have in anti-tumor immunity. We show that CD4+ T cells are not merely IL-2 factories for CD8+ effectors or potentiators of CTL induction via the licensing of DCs, but that CD4+ T cells also act to promote tumor eradication in at least three additional ways: by maintaining both numbers and cytotoxic capacity of the CD8+ T cells, by enabling CD8+ T cells to traffic to and/or remain within the tumor, and by altering tumor expression of key MHC and accessory molecules. The combination of these three mechanisms increases the chances of a tumor-CD8+ T cell interaction and thereby facilitates tumor eradication. These data have important implications for the design of tumor immunotherapy protocols. Clearly, such strategies must recruit and maintain anti-tumor CD4+ T cells, so therapies using class I epitopes alone will be most effective if agents that boost CD4+ T cell activity can be coadministered.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bernadette Scott, Monash Institute of Reproduction and Development, Level 2, 27–31 Wright Street, Clayton, Victoria 3168, Australia.
3 Abbreviations used in this paper: DC, dendritic cell; HA, hemagglutinin; ELISPOT, enzyme-linked immunospot; MM, murine malignant mesothelioma; LN, lymph node.
Received for publication January 10, 2000. Accepted for publication August 29, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184:863.- T cell receptors. Annu. Rev. Immunol. 16:523.[Medline]
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  S. A. Broomfield, R. G. van der Most, A. C. Prosser, S. Mahendran, M. G. Tovey, M. J. Smyth, B. W. S. Robinson, and A. J. Currie Locally Administered TLR7 Agonists Drive Systemic Antitumor Immune Responses That Are Enhanced by Anti-CD40 Immunotherapy J. Immunol., May 1, 2009; 182(9): 5217 - 5224. [Abstract] [Full Text] [PDF]
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Z. Liu, H. S. Noh, J. Chen, J. H. Kim, L. D. Falo Jr., and Z. You Potent Tumor-Specific Protection Ignited by Adoptively Transferred CD4+ T Cells J. Immunol., September 15, 2008; 181(6): 4363 - 4370. [Abstract] [Full Text] [PDF]
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M. Y. Gerner, K. A. Casey, and M. F. Mescher Defective MHC Class II Presentation by Dendritic Cells Limits CD4 T Cell Help for Antitumor CD8 T Cell Responses J. Immunol., July 1, 2008; 181(1): 155 - 164. [Abstract] [Full Text] [PDF]
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 Y. Sun, M. Song, E. Jager, C. Schwer, S. Stevanovic, S. Flindt, J. Karbach, X. D. Nguyen, D. Schadendorf, and K. Cichutek Human CD4+ T Lymphocytes Recognize a Vascular Endothelial Growth Factor Receptor-2-Derived Epitope in Association with HLA-DR Clin. Cancer Res., July 1, 2008; 14(13): 4306 - 4315. [Abstract] [Full Text] [PDF]
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 S. Caserta, P. Alessi, J. Guarnerio, V. Basso, and A. Mondino Synthetic CD4+ T Cell-Targeted Antigen-Presenting Cells Elicit Protective Antitumor Responses Cancer Res., April 15, 2008; 68(8): 3010 - 3018. [Abstract] [Full Text] [PDF]
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S. B. J. Wong, R. Bos, and L. A. Sherman Tumor-Specific CD4+ T Cells Render the Tumor Environment Permissive for Infiltration by Low-Avidity CD8+ T Cells J. Immunol., March 1, 2008; 180(5): 3122 - 3131. [Abstract] [Full Text] [PDF]
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 D. Atanackovic, N. K. Altorki, Y. Cao, E. Ritter, C. A. Ferrara, G. Ritter, E. W. Hoffman, C. Bokemeyer, L. J. Old, and S. Gnjatic Booster vaccination of cancer patients with MAGE-A3 protein reveals long-term immunological memory or tolerance depending on priming PNAS, February 5, 2008; 105(5): 1650 - 1655. [Abstract] [Full Text] [PDF]
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P. Stoitzner, L. K. Green, J. Y. Jung, K. M. Price, C. H. Tripp, B. Malissen, A. Kissenpfennig, I. F. Hermans, and F. Ronchese Tumor Immunotherapy by Epicutaneous Immunization Requires Langerhans Cells J. Immunol., February 1, 2008; 180(3): 1991 - 1998. [Abstract] [Full Text] [PDF]
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M. L. Hwang, J. R. Lukens, and T. N. J. Bullock Cognate Memory CD4+ T Cells Generated with Dendritic Cell Priming Influence the Expansion, Trafficking, and Differentiation of Secondary CD8+ T Cells and Enhance Tumor Control J. Immunol., November 1, 2007; 179(9): 5829 - 5838. [Abstract] [Full Text] [PDF]
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E. Ko, W. Luo, L. Peng, X. Wang, and S. Ferrone Mouse Dendritic-Endothelial Cell Hybrids and 4-1BB Costimulation Elicit Antitumor Effects Mediated by Broad Antiangiogenic Immunity Cancer Res., August 15, 2007; 67(16): 7875 - 7884. [Abstract] [Full Text] [PDF]
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R. J. May, T. Dao, J. Pinilla-Ibarz, T. Korontsvit, V. Zakhaleva, R. H. Zhang, P. Maslak, and D. A. Scheinberg Peptide Epitopes from the Wilms' Tumor 1 Oncoprotein Stimulate CD4+ and CD8+ T Cells That Recognize and Kill Human Malignant Mesothelioma Tumor Cells Clin. Cancer Res., August 1, 2007; 13(15): 4547 - 4555. [Abstract] [Full Text] [PDF]
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T. Kaiga, M. Sato, H. Kaneda, Y. Iwakura, T. Takayama, and H. Tahara Systemic Administration of IL-23 Induces Potent Antitumor Immunity Primarily Mediated through Th1-Type Response in Association with the Endogenously Expressed IL-12 J. Immunol., June 15, 2007; 178(12): 7571 - 7580. [Abstract] [Full Text] [PDF]
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G. Rudge, S. P. Barrett, B. Scott, and I. R. van Driel Infiltration of a Mesothelioma by IFN-{gamma}-Producing Cells and Tumor Rejection after Depletion of Regulatory T Cells J. Immunol., April 1, 2007; 178(7): 4089 - 4096. [Abstract] [Full Text] [PDF]
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A. Saha, S. K. Chatterjee, K. A. Foon, E. Celis, and M. Bhattacharya-Chatterjee Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen Cancer Res., March 15, 2007; 67(6): 2881 - 2892. [Abstract] [Full Text] [PDF]
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 |
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 Y. Zhang, D. Wakita, K. Chamoto, Y. Narita, N. Matsubara, H. Kitamura, and T. Nishimura Th1 cell adjuvant therapy combined with tumor vaccination: a novel strategy for promoting CTL responses while avoiding the accumulation of Tregs Int. Immunol., February 1, 2007; 19(2): 151 - 161. [Abstract] [Full Text] [PDF]
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J. Gamrekelashvili, C. Kruger, R. von Wasielewski, M. Hoffmann, K. M. Huster, D. H. Busch, M. P. Manns, F. Korangy, and T. F. Greten Necrotic Tumor Cell Death In Vivo Impairs Tumor-Specific Immune Responses J. Immunol., February 1, 2007; 178(3): 1573 - 1580. [Abstract] [Full Text] [PDF]
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T. H. Kang, J. H. Lee, C. K. Song, H. D. Han, B. C. Shin, S. I. Pai, C.-F. Hung, C. Trimble, J.-S. Lim, T. W. Kim, et al. Epigallocatechin-3-Gallate Enhances CD8+ T Cell-Mediated Antitumor Immunity Induced by DNA Vaccination Cancer Res., January 15, 2007; 67(2): 802 - 811. [Abstract] [Full Text] [PDF]
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G. Bioley, C. Jandus, S. Tuyaerts, D. Rimoldi, W. W. Kwok, D. E. Speiser, J.-M. Tiercy, K. Thielemans, J.-C. Cerottini, and P. Romero Melan-A/MART-1-Specific CD4 T Cells in Melanoma Patients: Identification of New Epitopes and Ex Vivo Visualization of Specific T Cells by MHC Class II Tetramers J. Immunol., November 15, 2006; 177(10): 6769 - 6779. [Abstract] [Full Text] [PDF]
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 M. Maksimow, M. Miiluniemi, F. Marttila-Ichihara, S. Jalkanen, and A. Hanninen Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity Blood, August 15, 2006; 108(4): 1298 - 1305. [Abstract] [Full Text] [PDF]
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R. A. Willemsen, Z. Sebestyen, C. Ronteltap, C. Berrevoets, J. Drexhage, and R. Debets CD8{alpha} Coreceptor to Improve TCR Gene Transfer to Treat Melanoma: Down-Regulation of Tumor-Specific Production of IL-4, IL-5, and IL-10 J. Immunol., July 15, 2006; 177(2): 991 - 998. [Abstract] [Full Text] [PDF]
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L. Peng, E. Ko, W. Luo, X. Wang, P. A. Shrikant, and S. Ferrone CD4-Dependent Potentiation of a High Molecular Weight-Melanoma-Associated Antigen-Specific CTL Response Elicited in HLA-A2/Kb Transgenic Mice J. Immunol., February 15, 2006; 176(4): 2307 - 2315. [Abstract] [Full Text] [PDF]
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K. Chamoto, D. Wakita, Y. Narita, Y. Zhang, D. Noguchi, H. Ohnishi, T. Iguchi, T. Sakai, H. Ikeda, and T. Nishimura An Essential Role of Antigen-Presenting Cell/T-Helper Type 1 Cell-Cell Interactions in Draining Lymph Node during Complete Eradication of Class II-Negative Tumor Tissue by T-Helper Type 1 Cell Therapy Cancer Res., February 1, 2006; 66(3): 1809 - 1817. [Abstract] [Full Text] [PDF]
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H. Geng, G.-M. Zhang, D. Li, H. Zhang, Y. Yuan, H.-G. Zhu, H. Xiao, L.-F. Han, and Z.-H. Feng Soluble Form of T Cell Ig Mucin 3 Is an Inhibitory Molecule in T Cell-Mediated Immune Response J. Immunol., February 1, 2006; 176(3): 1411 - 1420. [Abstract] [Full Text] [PDF]
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T. D. Zwar, S. Read, I. R. van Driel, and P. A. Gleeson CD4+CD25+ Regulatory T Cells Inhibit the Antigen-Dependent Expansion of Self-Reactive T Cells In Vivo J. Immunol., February 1, 2006; 176(3): 1609 - 1617. [Abstract] [Full Text] [PDF]
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R. B. Batchu, A. M. Moreno, S. M. Szmania, G. Bennett, G. C. Spagnoli, S. Ponnazhagan, B. Barlogie, G. Tricot, and F. van Rhee Protein Transduction of Dendritic Cells for NY-ESO-1-Based Immunotherapy of Myeloma Cancer Res., November 1, 2005; 65(21): 10041 - 10049. [Abstract] [Full Text] [PDF]
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T. A. Rohn, A. Reitz, A. Paschen, X. D. Nguyen, D. Schadendorf, A. B. Vogt, and H. Kropshofer A Novel Strategy for the Discovery of MHC Class II-Restricted Tumor Antigens: Identification of a Melanotransferrin Helper T-Cell Epitope Cancer Res., November 1, 2005; 65(21): 10068 - 10078. [Abstract] [Full Text] [PDF]
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S. Allen, S. Read, R. DiPaolo, R. S. McHugh, E. M. Shevach, P. A. Gleeson, and I. R. van Driel Promiscuous Thymic Expression of an Autoantigen Gene Does Not Result in Negative Selection of Pathogenic T Cells J. Immunol., November 1, 2005; 175(9): 5759 - 5764. [Abstract] [Full Text] [PDF]
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M. Moeller, N. M. Haynes, M. H. Kershaw, J. T. Jackson, M. W. L. Teng, S. E. Street, L. Cerutti, S. M. Jane, J. A. Trapani, M. J. Smyth, et al. Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection Blood, November 1, 2005; 106(9): 2995 - 3003. [Abstract] [Full Text] [PDF]
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F. Benigni, V. S. Zimmermann, S. Hugues, S. Caserta, V. Basso, L. Rivino, E. Ingulli, L. Malherbe, N. Glaichenhaus, and A. Mondino Phenotype and Homing of CD4 Tumor-Specific T Cells Is Modulated by Tumor Bulk J. Immunol., July 15, 2005; 175(2): 739 - 748. [Abstract] [Full Text] [PDF]
|
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T. Tsuji, M. Yasukawa, J. Matsuzaki, T. Ohkuri, K. Chamoto, D. Wakita, T. Azuma, H. Niiya, H. Miyoshi, K. Kuzushima, et al. Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes Blood, July 15, 2005; 106(2): 470 - 476. [Abstract] [Full Text] [PDF]
|
|
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K. L. Bondurant, M. D. Crew, A. D. Santin, T. J. O'Brien, and M. J. Cannon Definition of an Immunogenic Region Within the Ovarian Tumor Antigen Stratum Corneum Chymotryptic Enzyme Clin. Cancer Res., May 1, 2005; 11(9): 3446 - 3454. [Abstract] [Full Text] [PDF]
|
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M. A. Lyman, C. T. Nugent, K. L. Marquardt, J. A. Biggs, E. G. Pamer, and L. A. Sherman The Fate of Low Affinity Tumor-Specific CD8+ T Cells in Tumor-Bearing Mice J. Immunol., March 1, 2005; 174(5): 2563 - 2572. [Abstract] [Full Text] [PDF]
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P. A. Antony, C. A. Piccirillo, A. Akpinarli, S. E. Finkelstein, P. J. Speiss, D. R. Surman, D. C. Palmer, C.-C. Chan, C. A. Klebanoff, W. W. Overwijk, et al. CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells J. Immunol., March 1, 2005; 174(5): 2591 - 2601. [Abstract] [Full Text] [PDF]
|
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J. J. Roszkowski, G. E. Lyons, W. M. Kast, C. Yee, K. Van Besien, and M. I. Nishimura Simultaneous Generation of CD8+ and CD4+ Melanoma-Reactive T Cells by Retroviral-Mediated Transfer of a Single T-Cell Receptor Cancer Res., February 15, 2005; 65(4): 1570 - 1576. [Abstract] [Full Text] [PDF]
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Y. Tanaka, S. Koido, M. Ohana, C. Liu, and J. Gong Induction of Impaired Antitumor Immunity by Fusion of MHC Class II-Deficient Dendritic Cells with Tumor Cells J. Immunol., February 1, 2005; 174(3): 1274 - 1280. [Abstract] [Full Text] [PDF]
|
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W. J. Simmons, M. Koneru, M. Mohindru, R. Thomas, S. Cutro, P. Singh, R. H. DeKruyff, G. Inghirami, A. J. Coyle, B. S. Kim, et al. Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms J. Immunol., February 1, 2005; 174(3): 1405 - 1415. [Abstract] [Full Text] [PDF]
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 G. Zhou, Z. Lu, J. D. McCadden, H. I. Levitsky, and A. L. Marson Reciprocal Changes in Tumor Antigenicity and Antigen-specific T Cell Function during Tumor Progression J. Exp. Med., December 20, 2004; 200(12): 1581 - 1592. [Abstract] [Full Text] [PDF]
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A. B. Kamath, J. Woodworth, X. Xiong, C. Taylor, Y. Weng, and S. M. Behar Cytolytic CD8+ T Cells Recognizing CFP10 Are Recruited to the Lung after Mycobacterium tuberculosis Infection J. Exp. Med., December 6, 2004; 200(11): 1479 - 1489. [Abstract] [Full Text] [PDF]
|
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P. A. Stumbles, R. Himbeck, J. A. Frelinger, E. J. Collins, R. A. Lake, and B. W. S. Robinson Cutting Edge: Tumor-Specific CTL Are Constitutively Cross-Armed in Draining Lymph Nodes and Transiently Disseminate to Mediate Tumor Regression following Systemic CD40 Activation J. Immunol., November 15, 2004; 173(10): 5923 - 5928. [Abstract] [Full Text] [PDF]
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Q. Lou, R. J. Kelleher Jr, A. Sette, J. Loyall, S. Southwood, R. B. Bankert, and S. H. Bernstein Germ line tumor-associated immunoglobulin VH region peptides provoke a tumor-specific immune response without altering the response potential of normal B cells Blood, August 1, 2004; 104(3): 752 - 759. [Abstract] [Full Text] [PDF]
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Y. Tanaka, S. Koido, J. Xia, M. Ohana, C. Liu, G. M. Cote, D. B. Sawyer, S. Calderwood, and J. Gong Development of Antigen-Specific CD8+ CTL in MHC Class I-Deficient Mice through CD4 to CD8 Conversion J. Immunol., June 15, 2004; 172(12): 7848 - 7858. [Abstract] [Full Text] [PDF]
|
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M. A. Lyman, S. Aung, J. A. Biggs, and L. A. Sherman A Spontaneously Arising Pancreatic Tumor Does Not Promote the Differentiation of Naive CD8+ T Lymphocytes into Effector CTL J. Immunol., June 1, 2004; 172(11): 6558 - 6567. [Abstract] [Full Text] [PDF]
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A. Bonehill, C. Heirman, S. Tuyaerts, A. Michiels, K. Breckpot, F. Brasseur, Y. Zhang, P. van der Bruggen, and K. Thielemans Messenger RNA-Electroporated Dendritic Cells Presenting MAGE-A3 Simultaneously in HLA Class I and Class II Molecules J. Immunol., June 1, 2004; 172(11): 6649 - 6657. [Abstract] [Full Text] [PDF]
|
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|
|
|
M. V. Maus, B. Kovacs, W. W. Kwok, G. T. Nepom, K. Schlienger, J. L. Riley, D. Allman, T. H. Finkel, and C. H. June Extensive Replicative Capacity of Human Central Memory T Cells J. Immunol., June 1, 2004; 172(11): 6675 - 6683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Laurie, N. L. La Gruta, N. Koch, I. R. van Driel, and P. A. Gleeson Thymic Expression of a Gastritogenic Epitope Results in Positive Selection of Self-Reactive Pathogenic T Cells J. Immunol., May 15, 2004; 172(10): 5994 - 6002. [Abstract] [Full Text] [PDF]
|
|
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|
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|
E. H. Slager, C. E. van der Minne, M. Kruse, D. D. Krueger, M. Griffioen, and S. Osanto Identification of Multiple HLA-DR-Restricted Epitopes of the Tumor-Associated Antigen CAMEL by CD4+ Th1/Th2 Lymphocytes J. Immunol., April 15, 2004; 172(8): 5095 - 5102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Hanson, S. S. Kang, L. A. Norian, K. Matsui, L. A. O'Mara, and P. M. Allen CD4-Directed Peptide Vaccination Augments an Antitumor Response, but Efficacy Is Limited by the Number of CD8+ T Cell Precursors J. Immunol., April 1, 2004; 172(7): 4215 - 4224. [Abstract] [Full Text] [PDF]
|
|
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|
|
|
R. S. Friedman, C. S. Bangur, E. J. Zasloff, L. Fan, T. Wang, Y. Watanabe, and M. Kalos Molecular and Immunological Evaluation of the Transcription Factor SOX-4 as a Lung Tumor Vaccine Antigen J. Immunol., March 1, 2004; 172(5): 3319 - 3327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Chamoto, T. Tsuji, H. Funamoto, A. Kosaka, J. Matsuzaki, T. Sato, H. Abe, K. Fujio, K. Yamamoto, T. Kitamura, et al. Potentiation of Tumor Eradication by Adoptive Immunotherapy with T-cell Receptor Gene-Transduced T-Helper Type 1 Cells Cancer Res., January 1, 2004; 64(1): 386 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
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R. S. Goldszmid, J. Idoyaga, A. I. Bravo, R. Steinman, J. Mordoh, and R. Wainstok Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma J. Immunol., December 1, 2003; 171(11): 5940 - 5947. [Abstract] [Full Text] [PDF]
|
|
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|
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|
A. S. Lonsdorf, H. Kuekrek, B. V. Stern, B. O. Boehm, P. V. Lehmann, and M. Tary-Lehmann Intratumor CpG-Oligodeoxynucleotide Injection Induces Protective Antitumor T Cell Immunity J. Immunol., October 15, 2003; 171(8): 3941 - 3946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Loirat, M. Mancini-Bourgine, J.-P. Abastado, and M.-L. Michel HBsAg/HLA-A2 transgenic mice: a model for T cell tolerance to hepatitis B surface antigen in chronic hepatitis B virus infection Int. Immunol., October 1, 2003; 15(10): 1125 - 1136. [Abstract] [Full Text] [PDF]
|
|
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|
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L. Lefrancois, A. Marzo, and K. Williams Sustained Response Initiation Is Required for T Cell Clonal Expansion But Not for Effector or Memory Development In Vivo J. Immunol., September 15, 2003; 171(6): 2832 - 2839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bonehill, C. Heirman, S. Tuyaerts, A. Michiels, Y. Zhang, P. van der Bruggen, and K. Thielemans Efficient Presentation of Known HLA Class II-restricted MAGE-A3 Epitopes by Dendritic Cells Electroporated with Messenger RNA Encoding an Invariant Chain with Genetic Exchange of Class II-associated Invariant Chain Peptide Cancer Res., September 1, 2003; 63(17): 5587 - 5594. [Abstract] [Full Text] [PDF]
|
|
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|
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E. Davila, R. Kennedy, and E. Celis Generation of Antitumor Immunity by Cytotoxic T Lymphocyte Epitope Peptide Vaccination, CpG-oligodeoxynucleotide Adjuvant, and CTLA-4 Blockade Cancer Res., June 15, 2003; 63(12): 3281 - 3288. [Abstract] [Full Text] [PDF]
|
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J. H. Pinthus, T. Waks, K. Kaufman-Francis, D. G. Schindler, A. Harmelin, H. Kanety, J. Ramon, and Z. Eshhar Immuno-Gene Therapy of Established Prostate Tumors Using Chimeric Receptor-redirected Human Lymphocytes Cancer Res., May 15, 2003; 63(10): 2470 - 2476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Orsini, R. Bellucci, E. P. Alyea, R. Schlossman, C. Canning, S. McLaughlin, P. Ghia, K. C. Anderson, and J. Ritz Expansion of Tumor-specific CD8+ T Cell Clones in Patients with Relapsed Myeloma after Donor Lymphocyte Infusion Cancer Res., May 15, 2003; 63(10): 2561 - 2568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Nowak, R. A. Lake, A. L. Marzo, B. Scott, W. R. Heath, E. J. Collins, J. A. Frelinger, and B. W. S. Robinson Induction of Tumor Cell Apoptosis In Vivo Increases Tumor Antigen Cross-Presentation, Cross-Priming Rather than Cross-Tolerizing Host Tumor-Specific CD8 T Cells J. Immunol., May 15, 2003; 170(10): 4905 - 4913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Stober, I. Jomantaite, R. Schirmbeck, and J. Reimann NKT Cells Provide Help for Dendritic Cell-Dependent Priming of MHC Class I-Restricted CD8+ T Cells In Vivo J. Immunol., March 1, 2003; 170(5): 2540 - 2548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Hural, R. S. Friedman, A. McNabb, S. S. Steen, R. A. Henderson, and M. Kalos Identification of Naturally Processed CD4 T Cell Epitopes from the Prostate-Specific Antigen Kallikrein 4 Using Peptide-Based In Vitro Stimulation J. Immunol., July 1, 2002; 169(1): 557 - 565. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. L. Berinstein Carcinoembryonic Antigen as a Target for Therapeutic Anticancer Vaccines: A Review J. Clin. Oncol., April 15, 2002; 20(8): 2197 - 2207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Huang, F. Li, J. R. Gordon, and J. Xiang Synergistic Enhancement of Antitumor Immunity with Adoptively Transferred Tumor-specific CD4+ and CD8+ T Cells and Intratumoral Lymphotactin Transgene Expression Cancer Res., April 1, 2002; 62(7): 2043 - 2051. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
N. Shibagaki and M. C. Udey Dendritic Cells Transduced with Protein Antigens Induce Cytotoxic Lymphocytes and Elicit Antitumor Immunity J. Immunol., March 1, 2002; 168(5): 2393 - 2401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Tham, P. Shrikant, and M. F. Mescher Activation-Induced Nonresponsiveness: A Th-Dependent Regulatory Checkpoint in the CTL Response J. Immunol., February 1, 2002; 168(3): 1190 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
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|
A. Ribas, L. H. Butterfield, S. N. Amarnani, V. B. Dissette, D. Kim, W. S. Meng, G. A. Miranda, H.-J. Wang, W. H. McBride, J. A. Glaspy, et al. CD40 Cross-Linking Bypasses the Absolute Requirement for CD4 T Cells during Immunization with Melanoma Antigen Gene-modified Dendritic Cells Cancer Res., December 1, 2001; 61(24): 8787 - 8793. [Abstract] [Full Text] [PDF]
|
|
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J. Kjaergaard, L. Peng, P. A. Cohen, J. A. Drazba, A. D. Weinberg, and S. Shu Augmentation Versus Inhibition: Effects of Conjunctional OX-40 Receptor Monoclonal Antibody and IL-2 Treatment on Adoptive Immunotherapy of Advanced Tumor J. Immunol., December 1, 2001; 167(11): 6669 - 6677. [Abstract] [Full Text] [PDF]
|
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D. G. McNeel, L. D. Nguyen, and M. L. Disis Identification of T Helper Epitopes from Prostatic Acid Phosphatase Cancer Res., July 1, 2001; 61(13): 5161 - 5167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Ju, Q. Tao, G. Lou, M. Bai, L. He, Y. Yang, and X. Cao Interleukin 18 Transfection Enhances Antitumor Immunity Induced by Dendritic Cell-Tumor Cell Conjugates Cancer Res., May 1, 2001; 61(9): 3735 - 3740. [Abstract] [Full Text]
|
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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. C. Eck and L. A. Turka Adoptive Transfer Enables Tumor Rejection Targeted against a Self-Antigen without the Induction of Autoimmunity Cancer Res., April 1, 2001; 61(7): 3077 - 3083. [Abstract] [Full Text]
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). BALB/c mice were also inoculated with AB1-HA at the same time as
either HA-specific CD8+ (•) or CD4+ (
) LN
cells were adoptively transferred i.v. and subsequently on either day 7
(A) or day 14 (B) were given the
reciprocal population. Control mice received the AB1-HA tumor cells
only (
). Data are representative of three experiments with five
animals per group.
