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*
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and
Laboratory for Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda MD 20235
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To understand the mechanism of the development of CTL response, it is crucial to consider DCs as APCs. DCs appear to be the principal APC in the initiation of CD8+ T cell responses to many Ags (22, 23, 24, 25). DCs present Ags to both MHC class II-restricted CD4+ and class I-restricted CD8+ T cells by classical Ag-presenting pathways (26, 27). DCs can actively acquire exogenous Ags and generate MHC class I-restricted peptides via both TAP-dependent and -independent pathways (28, 29, 30, 31, 32). Immunization of animals with DCs pulsed with various Ags has been shown to induce protective cytotoxic responses against viruses (33, 34) and tumor cells (35, 36, 37). In this study, we have further dissected the mechanism of help in the induction of CTL response in vivo using DCs generated from spleen. Our data in the present study extend the previous finding from early studies and indicates that CD4+ T cells can still provide the help essential for activation of naive CD8+ T cells without interacting with the same APC. More important, our data show that CD8+ T cells can also provide help for their own activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six-week-old C57BL/6 mice (B6) were obtained from The Jackson
Laboratory (Bar Harbor, ME), Taconic Farms (Germantown, NY), or the
National Institutes of Health Genetic Stock Center (Taconic Farms).
B6 mice carrying a mutation in either the IA
(B6.129-Abbtm1; IA%)
(38, 39) or 2-microglobulin
(2m) gene (B6.129P2(B6)-B2
Mtm1Unc;
2m%) (40, 41) have previously been described and were further backcrossed
to B6 mice a minimum of nine times. P14 mice (B6.D2-TgN(TcrLCMV)327Sdz)
expressing the H2-Db-restricted tg TCR specific
for the determinant (amino acid 33–41) derived from the lymphocytic
choriomeningitis virus (LCMV) gp33 (42) were obtained from
The Jackson Laboratory (at N4) and further backcrossed to B6 mice a
minimum of five times. B6 mice tg for green fluorescent protein (GFP)
expressed under the control of the H2-Kb promoter
(B6-TgN(KbP-EGFP) were generated in our
laboratory (43). As expected for a gene under the control
of a MHC class I promoter, GFP expression is not down-regulated in T
cells following activation and is a reliable marker for T cells derived
from GFP-expressing mice. All animals used were maintained under
specific pathogen-free conditions in the American Association of
Laboratory Animal Care-accredited University of North Carolina
Department of Laboratory Animal Medicine Facilities (Chapel Hill,
NC).
Peptides
The following antigenic peptides were synthesized by the
University of North Carolina Microchemical Facility and purified by
HPLC: LCMV gp33–41 (restricted by H2-Db),
vesicular stomatitis virus (VSV) N52–59
and OVA257–264 (restricted by
H2-Kb), and peptide 324–332 derived from the
nuclear protein of Sendai virus (restricted by both
Kb and Db). All the
peptides were dissolved in 50% (v/v) DMSO in water at a concentration
of 10 mg/ml. The amino acid sequences of the peptides were confirmed by
mass spectroscopy and shown in Table I
.
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DCs derived from the spleen were used in the experiments for
this study. Spleen cell suspensions were prepared from B6 mice, MHC
class II-knockout, or 2m-knockout mice and
RBCs lysed. Cells were cultured in 5% CO2 at
37°C in six-well low adherence plates (Costar 3471; Corning Glass,
Corning, NY) at 2 x 106/ml in a volume of 3
ml RPMI 1640 medium supplemented with 50 µM 2-ME, 10% FBS,
glutamine, 10 ng/ml mouse GM-CSF (BD PharMingen, La Jolla CA), and 1
ng/ml human TGF-1(R&D Systems, Minneapolis, MN). Following culture
for 7 days, cells were harvested, washed, and placed into culture in
fresh medium prepared as described above. Cultures were typically split
every 2–3 days based on the density of cells in each well. To assay
for cell surface phenotype, DCs were stained with
fluorochrome-conjugated mAbs specific for MHC class I (KH95), class II
(25-9-17), CD11b (M1/70), CD11c (HL3), CD40 (HM40-3), CD80 (16-10A1),
and CD86 (GL1) (BD PharMingen) and analyzed by flow cytometry. A
homogenous population of DCs was obtained as assessed by their
morphology, size (measured by forward scatter), and the expression of
surface Ags CD11b, CD11c, CD40, CD80, CD86, and MHC class I and class
II. DCs have been cultured and maintained for several months under
these conditions with continuous growth and little change in cell
surface phenotype.
CTL in vivo priming
To prime mice for a CD8+ CTL response, DCs
were harvested, washed twice with PBS, and incubated with 10 µM
peptide in RPMI 1640 containing 10% FCS. After incubation in 5%
CO2 at 37°C for 2–3 h, cells were washed three
times and resuspended in PBS. The 6- to 10-wk-old mice were primed by
i.v. injection (tail vein) of 2–5 x 105
peptide-pulsed DCs in 200 µl PBS. For coinjection,
2m-deficient DCs were treated as described
above but without peptide and were then mixed together with the same
number (2–5 x 105) of peptide-pulsed MHC
class II-knockout DCs in 200 µl PBS.
For the adoptive transfer experiments, splenocytes from P14 TCR-tg mice were prepared in PBS. B6 mice, 6–8 wk old, were injected i.v. with varying numbers of P14 splenocytes in 200 µl PBS and, 24 h later, received class II-knockout DCs pulsed with a peptide as described above. Mice that were injected with P14 splenocytes but not primed with peptide-pulsed DCs were used as controls.
In vitro stimulation and CTL assay
Seven days following immunization with peptide-pulsed DCs, splenocytes were isolated from immunized animals and RBCs lysed with ACK lysis buffer and resuspended in RPMI 1640 with 10% FCS, antibiotics, glutamine, and 50 µM 2-ME. Cells (1 x 106 cells/ml) were stimulated with 1 µM peptide in 75-cm3 flasks (Falcon; BD Biosciences, Franklin Lakes, NJ) in 5% CO2 at 37°C for 5 days.
Cells were then harvested, washed with PBS, resuspended in RPMI 1640 with 10% FCS, and used as effector cells in a 51Cr-release assay. Syngeneic EL4 cells were labeled with 51Cr, pulsed with peptides, and used as target cells. Standard 4-h 51Cr-release assays were performed as previously described (44). The percentage of specific lysis was calculated as previously described (45), and each data point represents the mean 51Cr release from triplicate assays.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DCs are potent APCs and have recently been used in a number of
studies to induce protective immune responses against viruses and
tumors (33, 46). We have used DCs generated in vitro to
prime CTL responses in vivo so that the function of the components in
the induction of a CTL response can be analyzed. In the present study,
our culture conditions were established to generate large numbers of
DCs from mouse spleen. Splenocytes were cultured in vitro with mouse
GM-CSF and human TGF-1 (see Materials and Methods). After
culture for 7 days, most B cells and T cells as well as other cell
types had died, whereas the remaining cells divided and formed
clusters. After expansion for 
2 wk, 3–6 x
107 cells could be harvested from a single
spleen. These cells exhibited typical DC morphology and expressed MHC
class I and II, CD11b, and CD11c, but low levels of CD80 and CD40 on
the cell surface were also observed (Fig. 1). No expression of T cell (CD3)- or B
cell (IgM)-specific surface molecules was detected (data not shown).
Upon overnight culture with LPS, cell surface expression of MHC class
II, class I, CD11b, CD11c and costimulatory molecules CD80, CD86, and
CD40 was up-regulated and the rate of pinocytosis decreased (data not
shown), consistent with maturation of the DCs. DCs derived from class
II-knockout or 2m-knockout mice expressed a
similar phenotype but lacked expression of class II or class I,
respectively.
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Consistent with the data from other studies, CTL responses specific for
LCMV gp33 were induced in B6 mice immunized with LCMV gp33-pulsed DCs
(Fig. 2A, •). In contrast,
no CTL activity specific for LCMV gp33 was detected when mice were
immunized with DCs alone (Fig. 2A, 
). These results
demonstrate that DCs generated through this protocol, without the need
for additional activation in vitro, could present exogenous peptide and
induce a CD8+ CTL response in vivo.
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Several groups have reported that activation of naive CD8+ T cells by DCs is independent of CD4+ T cells (47, 48, 49). To determine whether naive CD8+ T cells can be activated and differentiate into cytotoxic effector cells upon specific interaction with DCs but without CD4+ T cells, MHC class II-deficient DCs were used to prime CTL responses in naive B6 mice. The lack of MHC class II molecules on the surface prevents these DCs from interacting with CD4+ T cells in recipient B6 mice.
Seven days after immunization with LCMV gp33-pulsed class II-negative
DCs, the B6 splenocytes were isolated and restimulated in vitro with
the same peptide. CTL activity was measured by a standard 4-h
51Cr-release assay. Cytotoxic activity was also
examined in mice receiving wild-type DCs pulsed with LCMV gp33 peptide.
Wild-type B6 DCs pulsed with LCMV gp33 peptide were capable of priming
naive B6 mice (Fig. 2
B, filled symbols). In stark contrast,
no CTL response was detected in cultures prepared from mice receiving
DCs lacking MHC class II expression (Fig. 2B, open symbols),
even after three injections of peptide-pulsed DCs (data not shown).
CD8+ T cells were purified and restimulated with
irradiated syngeneic spleen cells pulsed with peptide. CTL activity was
detected from mice immunized with peptide-pulsed B6 DCs, but not from
mice primed with peptide-pulsed class II-deficient DCs (data not
shown). This indicates that the failure to induce a CTL response with
class II-deficient DCs is due to the absence of
CD4+ T cells during priming in vivo.
In addition to CTL activity, restimulation in vitro with LCMV gp33 peptide resulted in proliferation, expansion, and activation (measured by flow cytometry) of CD8+ T cells from mice primed with normal DCs. After culture, there was a significant expansion of CD8+ T cells and increased numbers of CD25+ and CD69+ cells. >70% of CD8+ T cells in mice primed with B6 DCs were CD69 positive. In contrast, only 18% of the CD8+ T cells were CD69+ in culture prepared from mice primed with MHC class II-deficient DCs.
To ensure that the failure to prime CTLs was not due to some other
defect than MHC class II deficiency, we stimulated TCR-tg
CD8+ T cells with MHC class II-deficient DCs
pulsed with LCMV gp33 peptide in vitro. Both B6 DCs (Fig. 2C, •) and MHC class II-deficient DCs (Fig. 2C,
) could stimulate proliferation of P14 TCR-tg T cells in vitro to
the same extent and with identical kinetics, suggesting that the latter
is not defective in activating CD8+ T cells. We
have also used B6 DCs to immunize mice lacking
CD4+ T cells, due to a targeted disruption of the
class II gene. Transfer of B6 DCs pulsed with LCMV gp33 peptide
into class II-knockout mice failed to prime a
CD8+ T cell response (Fig. 3B), whereas the same DCs
induced an easily detected CTL response in B6 mice (Fig. 3A, •).
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CD4+ and CD8+ T cells are not required to interact with the same APC
The two-cell model proposes two sequential events during
activation of CD8+ T cells. Accordingly,
CD4+ Th cells first interact with DCs, and the
"conditioned" DCs then encounter and activate naive
CD8+ T cells. Indeed, treatment of APCs with
anti-CD40 Ab in vitro or in vivo can overcome the requirement of
CD4+ Th cells for the activation of cytotoxic T
cells (11, 12, 13). These data can explain the role of DCs in
the activation of CD8+ T cells in vivo. Indeed,
several studies have found that CTL immunity was induced in MHC class
II-deficient mice by virus infection (16, 17), presumably
because virus infection resulted in activation of APCs such as DCs.
However, these studies lack evidence for how, in the two-cell model,
CD4+ T cells condition DCs. We reasoned that the
DCs used in our experiments would have been conditioned because they
were cultured in the presence of CD4+ T cells,
which should be able to interact with DCs carrying Ag derived from
culture medium. Therefore, once conditioned, these DCs should be able
to prime naive CD8+ T cells in vivo without the
need for CD4+ T cells. However, the results
presented in Fig. 3 show that this was not the case.
To gain insight into how CD4+ T cells provide
help, B6 mice were primed by coinjection of LCMV gp33 peptide-pulsed
DCs from MHC class II-knockout mice and
2m-knockout DCs that were not incubated with
any specific peptides. Two immune reactions could take place in vivo.
First, MHC class II-deficient DCs pulsed with peptide interact with
CD8+ T cells, but not CD4+
T cells. In contrast, the 2m-knockout DCs
carrying MHC class II-restricted Ags from the culture medium could
interact with CD4+ T cells. However, these DCs
could not present Ags to CD8+ T cells because
they lack MHC class I molecules. As described above, LCMV gp33
peptide-pulsed-B6 DCs induced a strong CTL response (Fig. 4, ), whereas MHC class II-knockout
DCs failed to do so (Fig. 4, ). Interestingly, coinjection of
2m-knockout DCs with MHC class II-knockout DCs
induced a modest CTL response (Fig. 4, •).
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). As
described above, B6 mice were primed with DCs prepared from B6 or class
II-knockout mice or by coinjection of peptide-pulsed DCs deficient for
class II and 2m-deficient DCs. Regardless of
MHC restriction or origin of the peptides used,
CD8+ T cell responses specific for each of the
determinants were induced in mice primed with peptide-pulsed B6 DCs
(Fig. 5, •). The activation of
CD8+ T cells specific for each of the CTL
epitopes is CD4+ Th cell-dependent because
peptide-pulsed class II-knockout DCs were not able to prime B6 mice for
CTL response (Fig. 5, ). However, coinjection of
2m-knockout DCs with peptide-pulsed class
II-knockout DCs restored at least partial CTL reactivity to all the
tested peptides (Fig. 5, ).
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The help essential for CD8+ T cell activation can also be provided by CD8+ T cells themselves
We next wanted to determine whether CD8+ T
cells in high numbers could substitute for CD4+
Th cells. We studied P14 TCR-tg mice bred onto the
recombination-activating gene-deficient background, which nearly
exclusively produce CD8+ T cells expressing a TCR
specific for the LCMV gp33 determinant and have very few
CD4+ T cells. Despite the absence of
CD4+ T cells, the tg CD8+ T
cells can be activated by LCMV infection class I tetramers
(44) or by LCMV gp33 peptide-pulsed DCs, respectively
(data not shown). Consistent with these findings, peptide-pulsed DCs
prepared from class II-knockout mice are equally as competent as B6 DCs
in activating naive tg CD8+ T cells (Fig. 2C).
These findings suggest either that 1) TCR-tg CD8+
T cells from P14 mice differ intrinsically from wild-type B6 mice in
their requirement for CD4+ Th cell-mediated help,
or 2) high numbers of CD8+ T cells expressing the
Ag-specific TCR in P14 mice generate the help required for their own
activation. To distinguish between these possibilities, we injected
increasing numbers of splenocytes from P14 TCR-tg mice into B6 mice,
and 1 day later, the recipient mice were either injected with class
II-knockout DCs pulsed with LCMV gp33 or left untreated. Following
immunization, spleen cells were restimulated in vitro for 5 days, and
the CTL response was measured as described above. As shown in Fig. 6, peptide-pulsed DCs prepared from class
II-knockout mice did not induce CTL activity in mice without the
transfer of P14 TCR-tg T cells, consistent with the previous results
(Fig. 6, far right). CTL activity was not detected in mice
that were injected with TCR-tg spleen cells but not primed (),
indicating that activation of CD8+ T cells
requires immunization with DCs. Ag-specific CTL responses were elicited
in B6 mice that had received higher doses of P14 TCR-tg spleen cells,
and the CTL induction was dependent on the numbers of TCR-tg spleen
cells transferred. For example, transfer of 6 x
104 tg spleen cells (which contained 2 x
104 TCR-tg CD8+ T cells)
resulted in CTL activity. However, no CTL activity was induced in mice
that received 3 x 104 TCR-tg
splenocytes.
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, ). Because CD69 is considered
an early activation marker and might have been down-regulated, we also
performed the identical experiment using the cell surface markers
CD25+, CD44high, and
CD62Llow with similar results (data not shown).
In addition, when we tested these cells for expression of IFN-
by
intracellular cytokine staining, all of the IFN--producing cells
were CD69+. Several studies have demonstrated
that TCR-tg T cells were activated and then deleted in vivo following
peptide immunization (20, 21). It is possible that, upon
DC priming, the transferred TCR-tg T cells were activated in vivo and
subsequently deleted after restimulation. Expansion of
CD8+ cells or CTLs was not detected in the
recipient mice without priming with DCs, although donor cells were
found among a small number of CD8+ cells
expressing CD69 (Fig. 7, 
). This effect was observed when we
transferred 10-fold more T cells than were typically required for
priming. It seems unlikely that these few donor T cells are responsible
for the cytolysis observed in our CTL assay. This is supported by the
observation that the fraction of donor cells actually decreases in
primed mice following in vitro activation, suggesting that the P14-tg T
cells are actually at a competitive disadvantage compared with the host
gp33-specific T cell pool. These findings demonstrate that the
activation of endogenous CD8+ T cells is
responsible for the observed CTL activity. It is unclear how the
transfer of TCR-tg T cells resulted in the activation of endogenous
CD8+ cells. Because MHC class II-knockout DCs
were used to prime the recipient mice, the involvement of
CD4+ T cells was excluded. Therefore, our data
suggest that the transferred CD8+ TCR-tg T cells
provided help for the activation of host naive
CD8+ T cells.
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B, filled symbols). In
contrast, when mice were immunized with the same DCs but pulsed with
only LCMV gp33 peptide, no CTL activity was detected (Fig. 8A, ). As a control, B6 DCs pulsed with both LCMV and VSV
peptides induced a LCMV gp33-specific CTL response (Fig. 8A, •). Our
data suggest that increased numbers of specific
CD8+ T cell precursors can help their own
activation into effector cells. The identical experiment has been
performed using OVA peptide in place of VSV with similar results.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The requirement for CD4+ Th cells in generating CD8+ CTL responses varies considerably among systems (4, 5, 6, 7, 8, 15, 16, 17, 18). In our study, activation of CD8+ T cells was assessed in the absence of preactivated APCs or inflammatory signals normally associated with viral or bacterial infections, which may substitute for help required for activation of CD8+ T cells (51, 52). Indeed, we show that CD8+ T cells themselves can provide help for other responding CD8+ T cells if present in sufficient numbers. This provides one mechanism for CD4+ Th cell-independent CD8+ T cell responses. Possibly, other cells (particularly NK cells) can also substitute for CD4+ Th cells under the appropriate conditions. In retrospect, it is not surprising that the dependence of CD8+ T cell responses on CD4+ Th cells varies considerably with the exact conditions of the experimental system, given the permutations for activating different cell types in different anatomical locations in different ways.
Our findings provide insight into how CD4+ Th
cells (and by inference, other cell types) help the activation of naive
CD8+ T cells. The observation that
2m-knockout DCs are required for the partial
induction of determinant-specific CTL by peptide-pulsed MHC class
II-knockout DCs raises three important points. First, because
CD4+ T cells can interact with APCs distinct from
those encountering naive CD8+ T cells, the help
is likely being provided by cytokine secretion. Second, this
cytokine-based help is inefficient relative to both
CD4+ T cells and CD8+
cytotoxic T cells interacting with the same DC, either because of a
higher concentration of cytokines at the site of
CD4+ Th cell activation or the modification of
DCs by their interaction with CD4+ T cells.
Third, activation of CD8+ T cells in these
experiments is not due to the interaction between
CD8+ T cells and DCs activated by
CD4+ T cells, because the DCs that can interact
with CD4+ T cells lack MHC class I molecules
(2m-knockout DCs). These results do not
support the two-cell model, which suggests that DCs first activated by
CD4+ T cells in turn interact with
CD8+ T cells, leading to the activation of
CD8+ T cells.
Importantly, we found that CD8+ T cells can also
provide help when tg CD8+ T cells were adoptively
transferred into mice receiving peptide-pulsed MHC class II-knockout
DCs. In support of this, a CTL response specific to LCMV gp33 was also
induced when mice were immunized with class II-deficient DCs pulsed
with both LCMV gp33 and VSV N52–59. But class
II-knockout DCs pulsed with only LCMV gp33 could not prime CTL in B6
mice. Two major possibilities exist for how CD8+
T cells mediate help under these conditions. First, the simultaneous
interaction and activation of a critical number of
CD8+ T cells establishes a microenvironment in
which cytokine concentration exceeds the threshold necessary for
activating naive CD8+ T cells. This could account
for the priming of LCMV gp33-specific T cells in P14 TCR-tg
recombination-activating gene-knockout mice by peptide-pulsed DCs in
the absence of CD4+ T cells (our unpublished
data). This interpretation is supported by our previous data
demonstrating that MHC class I tetramers alone were sufficient to
activate naive CD8+ T cells from P14 TCR-tg mice
(44), accompanied by production of large amounts of both
IL-2 and IFN-. Our intracellular staining demonstrates that
CD8+ T cells made more IFN- (data not
shown).
Second, the interaction of a large number of CD8+ T cells with DCs may activate the DCs and lead to up-regulation of costimulatory molecules or secretion of cytokines by DCs. There is increasing evidence for this type of mechanism. It has been reported that both influenza virus and LCMV induce maturation and activation of DCs, which can then directly activate CD8+ T cells (51, 53). Recent data from three groups indicates that DCs activated by anti-CD40 mAb either in vitro or in vivo can induce a CTL response in MHC class II-deficient mice, and MHC class II-deficient DCs activated by anti-CD40 mAb prime CTL responses in the absence of CD4+ T cells (11, 12, 13). Similarly, mice treated with anti-CD40 mAb can generate CD8+ T cell-mediated CTL responses against tumors in the absence of CD4+ T cells (54).
One explanation that could explain part of our data is that the lack of CD4 help has no effect in vivo, but, simply, the lack of CD4 priming only impacts the expansion of the CD8+ T cells in vitro. Although this explanation could explain some of the results, it cannot explain the fact that increasing the number of CD8+ responding cells alone, either by transfer of CD8+ TCR-tg cells or by mixing two different peptides, now allows CD8 priming. Under these conditions, the number of primed CD4 cells would be equal in all cultures (i.e., low), because the priming occurred with class II knockout DCs.
In conclusion, we have demonstrated that the induction of CD8+ CTL responses requires help that can be obtained from multiple sources, including CD4+ T cells and CD8+ T cells. These findings provide a basis for understanding the variable requirement for CD4+ T cells in generating CD8+ T cells responses that has been recorded in the literature, because experimental systems are expected to vary in the extent to which non-CD4 cells could provide help. The important practical implication is that the induction of help should be taken into account in the design of vaccines meant to induce CD8+ CTL responses (55, 56).
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Acknowledgments |
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Footnotes |
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2 Current address: Division of Endocrinology, Children’s Hospital Medical Center, Cincinnati, OH 45229.
3 This work was initiated while J.A.F. was on leave at the Laboratory for Viral Diseases, National Institute of Allergy and Infectious Diseases (Bethesda, MD).
4 Address correspondence and reprint requests to Dr. Jeffrey A. Frelinger, Department of Microbiology and Immunology, University of North Carolina, Campus Box 7290, Mary Ellen Jones Building, Chapel Hill, NC 27599-7290. E-mail address: jfrelin{at}med.unc.edu
5 Abbreviations used in this paper: DC, dendritic cell; 2m, 2-microglobulin; LCMV, lymphocytic choriomeningitis virus; GFP, green fluorescent protein; VSV, vesicular stomatitis virus; tg, transgenic.
Received for publication March 6, 2001. Accepted for publication May 24, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 
T cell subsets in viral immunity. Annu. Rev. Immunol. 10:123.[Medline]
4+CD8+ T cell activation associated with latent murine gammaherpesvirus infection. J. Immunol. 163:3403., interferon, perforin, or costimulation through CD28. J. Virol. 73:3702.2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature 344:742.[Medline]
2M, MHC class I proteins, and CD8+ T cells. Science 248:1227.2-microglobulin-deficient mice. J. Virol. 71:8392.[Abstract]
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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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J. Kan-Mitchell, B. Bisikirska, F. Wong-Staal, K. L. Schaubert, M. Bajcz, and M. Bereta The HIV-1 HLA-A2-SLYNTVATL Is a Help-Independent CTL Epitope J. Immunol., May 1, 2004; 172(9): 5249 - 5261. [Abstract] [Full Text] [PDF]
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 S. C. Derrick, C. Repique, P. Snoy, A. L. Yang, and S. Morris Immunization with a DNA Vaccine Cocktail Protects Mice Lacking CD4 Cells against an Aerogenic Infection with Mycobacterium tuberculosis Infect. Immun., March 1, 2004; 72(3): 1685 - 1692. [Abstract] [Full Text] [PDF]
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J.-C. E. Wang and A. M. Livingstone Cutting Edge: CD4+ T Cell Help Can Be Essential for Primary CD8+ T Cell Responses In Vivo J. Immunol., December 15, 2003; 171(12): 6339 - 6343. [Abstract] [Full Text] [PDF]
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M. F. Kircher, J. R. Allport, E. E. Graves, V. Love, L. Josephson, A. H. Lichtman, and R. Weissleder In Vivo High Resolution Three-Dimensional Imaging of Antigen-Specific Cytotoxic T-Lymphocyte Trafficking to Tumors Cancer Res., October 15, 2003; 63(20): 6838 - 6846. [Abstract] [Full Text] [PDF]
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M. L. Moore, C. C. Brown, and K. R. Spindler T Cells Cause Acute Immunopathology and Are Required for Long-Term Survival in Mouse Adenovirus Type 1-Induced Encephalomyelitis J. Virol., September 15, 2003; 77(18): 10060 - 10070. [Abstract] [Full Text] [PDF]
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 M. Wuthrich, H. I. Filutowicz, T. Warner, G. S. Deepe Jr., and B. S. Klein Vaccine Immunity to Pathogenic Fungi Overcomes the Requirement for CD4 Help in Exogenous Antigen Presentation to CD8+ T Cells: Implications for Vaccine Development in Immune-deficient Hosts J. Exp. Med., June 2, 2003; 197(11): 1405 - 1416. [Abstract] [Full Text] [PDF]
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 H. Beacock-Sharp, A. M. Donachie, N. C. Robson, and A. M. Mowat A role for dendritic cells in the priming of antigen-specific CD4+ and CD8+ T lymphocytes by immune-stimulating complexes in vivo Int. Immunol., June 1, 2003; 15(6): 711 - 720. [Abstract] [Full Text] [PDF]
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Y. Zhai, L. Meng, R. W. Busuttil, M. H. Sayegh, and J. W. Kupiec-Weglinski Activation of Alloreactive CD8+ T Cells Operates Via CD4-Dependent and CD4-Independent Mechanisms and Is CD154 Blockade Sensitive J. Immunol., March 15, 2003; 170(6): 3024 - 3028. [Abstract] [Full Text] [PDF]
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M. S. Vacchio and R. J. Hodes CD28 Costimulation Is Required for In Vivo Induction of Peripheral Tolerance in CD8 T Cells J. Exp. Med., January 6, 2003; 197(1): 19 - 26. [Abstract] [Full Text] [PDF]
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J. de Jersey, D. Carmignac, T. Barthlott, I. Robinson, and B. Stockinger Activation of CD8 T Cells by Antigen Expressed in the Pituitary Gland J. Immunol., December 15, 2002; 169(12): 6753 - 6759. [Abstract] [Full Text] [PDF]
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A. M. Vlad, S. Muller, M. Cudic, H. Paulsen, L. Otvos Jr., F.-G. Hanisch, and O. J. Finn Complex Carbohydrates Are Not Removed During Processing of Glycoproteins by Dendritic Cells: Processing of Tumor Antigen MUC1 Glycopeptides for Presentation to Major Histocompatibility Complex Class II-restricted T Cells J. Exp. Med., December 2, 2002; 196(11): 1435 - 1446. [Abstract] [Full Text] [PDF]
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Y. Zhai, L. Meng, F. Gao, R. W. Busuttil, and J. W. Kupiec-Weglinski Allograft Rejection by Primed/Memory CD8+ T Cells Is CD154 Blockade Resistant: Therapeutic Implications for Sensitized Transplant Recipients J. Immunol., October 15, 2002; 169(8): 4667 - 4673. [Abstract] [Full Text] [PDF]
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C. A. Lawendowski, G. M. Giurleo, Y. Y. Huang, G. J. Franklin, J. M. Kaplan, B. L. Roberts, and C. A. Nicolette Solid-Phase Epitope Recovery: A High Throughput Method for Antigen Identification and Epitope Optimization J. Immunol., September 1, 2002; 169(5): 2414 - 2421. [Abstract] [Full Text] [PDF]
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D. Marsac, D. Loirat, C. Petit, O. Schwartz, and M.-L. Michel Enhanced Presentation of Major Histocompatibility Complex Class I-Restricted Human Immunodeficiency Virus Type 1 (HIV-1) Gag-Specific Epitopes after DNA Immunization with Vectors Coding for Vesicular Stomatitis Virus Glycoprotein- Pseudotyped HIV-1 Gag Particles J. Virol., June 27, 2002; 76(15): 7544 - 7553. [Abstract] [Full Text] [PDF]
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R. B. Mailliard, S. Egawa, Q. Cai, A. Kalinska, S. N. Bykovskaya, M. T. Lotze, M. L. Kapsenberg, W. J. Storkus, and P. Kalinski Complementary Dendritic Cell-activating Function of CD8+ and CD4+ T Cells: Helper Role of CD8+ T Cells in the Development of T Helper Type 1 Responses J. Exp. Med., February 19, 2002; 195(4): 473 - 483. [Abstract] [Full Text] [PDF]
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