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Guy-Bernier Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
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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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20 h to be committed to proliferation.
Conversely, effector T cells become committed in only 1 h, but
undergo activation-induced cell death if stimulation is prolonged
(5). Therefore, considering how critical time limitations
are for T cells to mediate early control of infection, it is of crucial
importance that the duration of cognate interactions between T cells
and APCs be neither too short nor too long (4, 6, 7).
Premature termination of T cell/APC interaction may hinder the
generation of a protective immune response, while failure to terminate
this interaction can lead to T cell exhaustion (5, 8, 9, 10, 11). It is generally considered that the duration of Ag presentation is limited to a large extent by the finite half-life of APCs. However, following in vivo interactions with T cells, it is not clear whether the demise of professional APCs is due to their basal turnover rate or to killing by Ag-specific T cells. It has been clearly demonstrated that under in vitro culture conditions, both CD4+ and CD8+ Ag-primed T cells kill dendritic cells, macrophages, and B cells in an Ag-specific manner (8, 9, 12, 13, 14). In vitro, killing of APCs by CD8+ CTLs is mediated primarily by the perforin pathway and to a lesser extent via FasL/Fas interactions, whereas CD4+ T cell cytotoxicity is conducted essentially by the Fas pathway (8, 9, 12, 13, 14). However, these studies have been performed with T cell lines or clones. Thus, although they show that Ag-primed T cells can rapidly eliminate APCs, they do not allow inferences regarding interactions of APCs with naive T cells. Furthermore, one caveat of in vitro studies is that they are performed under conditions quite distinct from those found in vivo, i.e., culturing a large excess of T cells in close proximity to APCs. Nevertheless, a few studies have addressed the fate of APCs following in vivo encounter with T cells. Thus, it has recently been reported that by 48 h after injection, OVA peptide-pulsed (but not unpulsed) DCs disappeared from the lymph nodes of mice bearing high numbers of TCR transgenic CD4+ T cells specific for an OVA peptide-I-Ad complex (15). Similarly, it has been shown that anti-HY TCR CD8+ transgenic T cells could eliminate HY+ B lymphocytes in vivo (16). These observations provide direct evidence that when present in relatively large numbers, CD4+ and CD8+ T cells from transgenic animals can kill APCs in vivo. However, the occurrence of this process in real life conditions and the tempo of APC demise have yet to be evaluated. Therefore, the goal of this work was to analyze the in vivo fate of hemopoietic APCs following the presentation of different T cell epitopes to naive nontransgenic animals with a normal T cell repertoire. These studies enabled evaluation of the half-life of APCs presenting specific class I- and/or class II-associated epitopes and additionally provided insights into the effector pathways responsible for the elimination of APCs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B10.C-H7b(47N)/Sn (B10.H7b)3 mice were a gift from Dr. D. C. Roopenian (The Jackson Laboratory, Bar Harbor, ME). The following strains of mice were purchased from The Jackson Laboratory: BALB/c, B6.C-H2bm1/By (bm1), B6.C-H2bm12/KhEg (bm12), B6.MRL-Faslpr (B6lpr), B6Smn.C3H-Faslgld (gld), C3H.SW, C57BL/6J (B6), C57BL/6-Pfptm1Arp (PKO), and C57BL/10J (B10). Mice were used between 6 and 16 wk of age and were maintained in specific pathogen-free conditions according to the standards of the Canadian committee for animal protection.
Preparation of cell suspensions and DNA extraction
Resident peritoneal mononuclear cells were harvested from euthanized male mice following injection of 10 ml of DMEM (Life Technologies, Gaithersburg, MD) supplemented with 2 mM glutamine and 5% FCS into the peritoneal cavity (17). These cell suspensions were enriched in mononuclear phagocytes by adherence to 25-cm2 tissue culture flasks (Sarstedt, Newton, NC) as previously described (18). Adherent peritoneal cells from male donors were gamma-irradiated (12.5 Gy), then 5 x 105 cells resuspended in 50 µl of DMEM were injected bilaterally into foreleg footpads of female recipients. Recipients were sacrificed at different times after injection, and their axillary and brachial lymph nodes were carefully dissected. DNA was extracted from lymph node cells using the Qiamp Tissue Kit (Qiagen, Mississauga, Canada), following the manufacturer’s protocol. The concentration and purity of the DNA samples were evaluated by spectrophotometry at 260 and 280 nm wavelengths.
Nested semiquantitative PCR amplification
Ube1y, a gene that maps to a region of the mouse Y chromosome required for normal spermatogonial proliferation (19, 20), was used as a marker gene to differentiate male from female cells. Conditions for PCR amplification were optimized using serial dilutions of B6 male cells admixed with B6 female cells so that one male cell in 1 x 106 female cells was reproducibly detectable. For each sample, PCR amplification was performed on six aliquots of 1 µg of purified DNA. For the first amplification, each DNA aliquot was amplified in a 50-µl reaction volume containing 25 pmol of each oligonucleotide primer, 0.2 mM dNTPs, 2.5 U of Taq DNA polymerase (Life Technologies), 20 mM Tris-HCl (pH 8.4), 50 mM KCl, and 1.5 mM MgCl2. Oligonucleotides for this first amplification of the DNA samples were 5'-TTGTGGTGCCTGTGCAGCTAGACT-3' and 5'-TCAACAAAGGCGTCCTTCTC-3', and generated a 525-bp fragment. DNA was subjected to amplification in a Gene Amp PCR system 9600 (PE Applied Biosystems, Foster City, CA). Cycle conditions included an initial 94°C denaturation step of 4.5 min followed by 25 cycles consisting of a 94°C denaturation step (30 s), a 55°C annealing step (15 s), and a 72°C extension step (15 s). The final extension time was prolonged to 5 min.
Upon completion of the first amplification round, 5 µl of the amplified mixture was reamplified for another 25 cycles using the same parameters as those described above, except for the use of nested oligonucleotide primers. For this second amplification, oligonucleotide primers were internal to the original primers (5'-GACATTTTCCCTGGAGAAAG-3' and 5'-CATGTCTAGACAGAGGACAG-3' and generated a smaller 377-bp fragment.
Aliquots of 10 µl from the second PCR amplification were analyzed by electrophoresis in 1% agarose gel (Bio-Rad Laboratories, Hercules, CA) in Tris-acetate-EDTA buffer containing 0.5 µg/ml of ethidium bromide and were visualized under UV light. The first PCR amplification product of positive samples was then serially diluted and reamplified under the same conditions as those described above for the second PCR amplification. The number of dilutions generating a UV-detectable signal permitted quantification of the samples (21). In each experiment, a positive control consisted of B6 male cells, and a negative control consisted of B6 female cells. PCR procedures included strict measures to avoid contamination (22, 23).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We developed our experimental protocol in an effort to mimic real
life conditions. Thus, we elected to measure the survival of realistic
numbers of APCs carried by the afferent lymph into peripheral lymph
nodes. Careful studies during the course of respiratory Sendai virus
infection in mice have shown that frequencies of APCs presenting MHC
class I- and MHC class II-restricted viral epitopes reached a peak of
102/106 lymph node cells
(24). Detection of such low cell frequencies is best
accomplished by PCR methodology. Therefore, we elaborated a model in
which male APCs are injected into the foreleg footpads of female
recipients and, at various times after injection, the numbers of male
APCs in the draining axillary and brachial lymph nodes were measured
using a previously validated sensitive semiquantitative nested PCR
assay (21). We used Ube1y, a Y-linked gene, as
a marker gene. To estimate the frequency of male APCs, DNA extracted
from recipient’s axillary and brachial lymph nodes was amplified, and
the product of this first amplification reaction was serially diluted
10-fold from 100 to 105.
Each fraction was PCR amplified with nested oligonucleotide primers,
then aliquots of the second amplification were electrophoresed on a 1%
agarose gel and stained with ethidium bromide. The results depicted in
Fig. 1
A show that this assay
was reproducible (cf., concordance between samples), specific (female
cells always gave negative results), and sensitive, as it could detect
DNA from one male cell in 106 female cells.
Furthermore, within the range tested, there was a log-linear
relationship between the number of PCR-positive bands and the number of
male cells in the sample. Thus, this methodology provided a good
estimate of the proportion of male cells over the range of cell
frequencies of interest for this study.
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66% monocytes/macrophages, 33% B lymphocytes,
and 1% DCs (17, 18, 25, 26). Peritoneal cells were
irradiated (12.5 Gy) to preclude proliferation into allogeneic
recipients. In dose-finding experiments, we observed that 2–24 h after
injection of 5 x 105 male APCs into each
foreleg footpad of female B6 recipients, we reproducibly obtained the
desired APC frequency in axillary and brachial lymph nodes, i. e.,
101–102
APCs/106 lymph node cells (Fig. 1
B).
When assessed at various time points, no male cells could be detected
outside the draining lymph nodes, i.e., in spleen or in inguinal lymph
nodes (data not shown). Female mice with the H2b
haplotype, such as B6, can generate T cell responses toward HY epitopes
encoded by the Y chromosome. Conversely, other strains of mice, such as
BALB/c, are totally unresponsive to HY epitopes (27). To
verify whether HY-specific responses could influence APC recovery under
our assay conditions, we compared the recoveries of male B6 and BALB/c
APCs 24 and 96 h after injection into syngeneic female recipients.
No difference was observed between B6 and BALB/c mice (Fig. 1B), showing that the presence of HY epitopes does not
influence the short term recovery of injected APCs. The in vivo fate of APCs presenting various nonself epitopes
Mice were sacrificed between days 1 and 21 after s.c. injection of
APCs, and the frequency of (male) APCs in their axillary and brachial
lymph nodes was assessed by PCR assay. The survival of injected cells
was estimated in a variety of mouse strain combinations to elucidate
how MHC class I- and/or class II-restricted interactions with T cells
would influence the fate of APCs (Fig. 2). Donor/recipient combinations used in
these experiments were incompatible for either minor (MiHA) or major
histocompatibility Ags and are presented in Table I.
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, the nature of nonself Ag expressed by
APCs had a dramatic influence on their survival. Thus, at one end of
the scale, HY had little, if any, influence on the persistence of APC,
because only on day 21 did the frequency of APCs drop below the
threshold of 10 cells/million in one of two mice tested (Fig. 2A). In contrast, APCs incompatible for a full MHC haplotype
(H2b or H2k) were rapidly
eliminated as their frequency dropped below this threshold 2–3 days
after injection (Fig. 2, B and C).
MHC class I (bm1) and class II (bm12) mutants differ by only a few
amino acids from the wild-type molecules, and they elicit pure
CD8+ and CD4+ T cell
responses, respectively (28, 29, 30). Therefore, they
represent a most useful paradigm to study MHC class I- and class
II-restricted responses. Interestingly, MHC class I and class II
incompatibilities had quite divergent effects on the persistence of
APCs. Class I incompatibility (bm1
B6; Fig. 2F) was
sufficient to induce APC disappearance as rapidly as that seen in the
case of a full MHC mismatch. In contrast, class II incompatibility
(bm12B6; Fig. 2G) had no apparent influence on APC
survival. Similar results were observed in the reciprocal combinations,
i.e., B6bm1 and B6bm12 (data not shown). These results indicate
that induction of class I-restricted, but not class II-restricted, T
cell responses can lead to rapid clearance of APCs.
Interpretation of the above results must take into account the fact
that, like their wild-type homologs, MHC mutant molecules are expressed
at 105 copies/APC, so that their cell surface
abundance is superior to that of most conventional epitopes, which are
usually expressed at 
103 copies/cell (31, 32). Thus, the question arises as to whether more typical class
I-restricted T cell epitopes, with a cell surface density on the order
of 101–103 copies/cell,
can cause rapid demise of APCs. We have shown above that a single HY
disparity had little or no effect on APC clearance (Fig. 2A). However, the single class I-restricted HY peptide
presented by H2b mice is expressed at only 10
copies/cell and is a nondominant epitope, i.e., it can elicit a T cell
response when presented alone, but is neglected when presented together
with other epitopes on the same APCs (33, 34). Conversely,
the B6dom1 MiHA, a nonapeptide presented by the
H2-Db molecule, is expressed at
103 copies/cell and is immunodominant when
presented with numerous other MiHAs (33, 34, 35). It has
recently been found that B6dom1 is encoded by the
H7 MiHA locus originally discovered by Snell 35 years ago
(36, 37). Thus, by injecting B10 APCs into
H7b congeneic recipients, we could
evaluate the impact of the immunodominant B6dom1
epitope (encoded by the H7a allele) on APC
clearance. In this strain combination, APC frequency decreased below 10
cells/million by day 8 (Fig. 2E). Similar results with
regard to the kinetics of APC clearance were observed in the
B6C3H.SW strain combination (Fig. 2D) as well as in the
reciprocal combination C3H.SWB6 (data not shown), in which APCs
present multiple incompatible MiHAs. These observations demonstrate
that presentation of immunodominant epitopes such as
B6dom1 (H7a), either alone
(B10B10.C-H7b) or together with other
Ags (B6C3H.SW), leads to a rapid clearance of APCs.
Considering that bm1 mutants probably elicit more vigorous
CD8+ T cell responses than most conventional
microbial epitopes, the clearance of
B6dom1-incompatible APCs may be more
representative of what can be expected with conventional Ags under real
life conditions.
Clearance of APCs is mediated partly, but not solely, by the perforin pathway
In an effort to gain some insight into the mechanisms responsible
for the clearance of APCs, we studied the fate of APCs in strain
combinations in which the perforin- or Fas-dependent cytotoxic pathway
was defective (Fig. 3). Taking into
account the finding that clearance of APCs was regulated essentially by
MHC class I-restricted effectors (Fig. 2), we followed the fate of bm1
APCs after injection into perforin- or FasL-deficient B6 recipients.
Whereas bm1 APCs dropped below the threshold of 10 cells/million by day
2 following injection into normal (Fig. 2F) or
FasL-deficient hosts (Fig. 3A), they persisted for 4–14
days when injected into perforin-deficient hosts (Fig. 3B).
These observations provide evidence for a role of perforin, but not
Fas, in the clearance of APCs. It is notable, however, that the APC
clearance rate was substantially more variable (4–14 days) in
perforin-deficient recipients than in other hosts. This suggests that
although they may be less effective, perforin-independent pathways can
contribute to the clearance of APCs.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our conclusions regarding the differential effects of class I- vs class
II-restricted interactions are based on the study of bm1 and bm12
mutants. Studies regarding in vitro and in vivo T cell proliferation as
well as induction of graft-vs-host disease and skin graft rejection
have shown that responses of B6 T cells to bm1 and bm12 Ags have
similar kinetics (time of onset and expansion rate) and intensity
(29, 38, 39); responses against bm1 are neither more rapid
nor more vigorous. Thus, the rapid clearance of bm1, but not bm12, APCs
reported herein (Fig. 2) cannot be ascribed to a superior
immunogenicity of bm1 relative to bm12. Rather, under the conditions we
employed, this finding provides strong evidence that interactions with
CD4+ and CD8+ T cells have
qualitatively different consequences for the APC, and that only class
I-restricted interactions are lethal for the APC. Therefore, it appears
logical to infer that one important function of class I-restricted CTLs
may be to control the duration of Ag presentation. Furthermore,
selective killing of APCs by CD8+ T cells
could explain previous documentation that, at least in vitro, expansion
of anti-bm1 CD8+ T cells is of shorter
duration than that of anti-bm12 CD4+ T cells
(29).
The delayed clearance of APCs in perforin-deficient hosts indicates
that the perforin pathway is one, but not the sole, pathway that
regulates the fate of APCs. The influence of perforin is consistent
with observations showing that under most circumstances, MHC class
I-restricted CTLs lyse target cells preferentially via the perforin
pathway (40, 41). However, the results presented in Fig. 3
also indicate that APC demise can be induced by perforin-independent
mechanisms, and that Fas has a minor influence, if any, on the fate of
APCs. It has been shown that effector CTLs harbor potent killing
mechanisms in addition to those provided by the Fas and
perforin/granzyme B pathways (42). These alternative
pathways involve members of the TNF family, ATP, IFN-
, as well as
some undefined signal elicited by TCR binding of the 
2 domain of MHC
class I molecules on the target cell (43, 44, 45, 46, 47). A plausible
rationale for this redundancy of lethal mechanisms is to deal with the
array of antiapoptotic molecules elaborated by intracellular pathogens
to extend the life of infected cells (48). Clearly,
further studies will be required to decipher the mechanisms responsible
for the perforin-independent clearance of APCs shortly after productive
interactions with CTL precursors. It is noteworthy that the persistence
of APCs in PKO recipients (4–14 days; see Fig. 3B) was
substantially more variable than that in other mice. This suggests that
the efficiency of the other mechanisms may be less predictable than
that of the perforin pathway.
The differential influence of dominant vs nondominant epitopes on APC survival impinges on our understanding of the mechanisms of immunodominance. MHC class I-restricted immunodominant epitopes differ from nondominant epitopes in two ways (49). First, when both types of Ag are presented separately, dominant epitopes evoke more powerful T cell responses (34, 50, 51, 52). Second, when dominant and nondominant epitopes are presented together, recognition of the dominant epitopes suppresses responses to nondominant epitopes, and thereby restricts the diversity of the repertoire of CTL responses (33, 53). This inhibitory effect of dominant epitopes on recognition of nondominant epitopes has been referred to as the immunodominance effect or immunodomination and is a central feature of all CTL responses that follow confrontation with numerous epitopes (54, 55). Interestingly, immunodomination is observed only when both the dominant and nondominant epitopes are presented at the same time on the same APC (33, 49). Suppression of CTL responses to nondominant epitopes does not take place when the dominant and nondominant epitopes are presented at different time points or if they are presented concomitantly but on separate APCs. The present demonstration that APC survival is curtailed following presentation of an immunodominant (B6dom1), but not a nondominant (HY), class I-restricted epitope could provide a plausible basis for immunodomination. Accordingly, we propose that by killing APCs, CTLs specific for immunodominant determinants reduce the duration of Ag presentation and consequently impede the generation of CTL responses toward nondominant Ags. It is notable that, like APC killing, immunodomination seems to be primarily a characteristic of CD8+ as opposed to CD4+ T cell responses (49, 56).
Conceptually, it is tempting to speculate that killing of APCs by CTLs specific for immunodominant epitopes may represent a sensible way to regulate T cell responses. 1) It would terminate Ag presentation only when CTLs specific for the best (immunodominant) epitopes have been primed (49). 2) In the case of infection with many intracellular micro-organisms, killing of monocyte-macrophage APCs would lead to elimination of an important reservoir of pathogens. 3) Limiting the duration of Ag presentation may reduce the risk of T cell exhaustion, and thus of tolerance. 4) Restricting the diversity of the T cell repertoire could lessen the risk of collateral autoimmune damage by cross-reactive CTLs (54, 57). Finally, it makes good sense that in a system where regulation of immune responses involves killing APCs, Ag presentation be conducted primarily by disposable cells with a rapid renewal rate, such as professional hemopoietic APCs.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Claude Perreault, Guy-Bernier Research Center, Maisonneuve-Rosemont Hospital, 5415 de l’Assomption Boulevard, Montreal, Quebec, Canada H1T 2 M4. E-mail address:
3 Abbreviations used in this paper: B6, C57BL/6J; B10, C57BL/10J; B10.H7b, B10.C-H7b(47N)/Sn; bm1, B6.C-H2bm1/By; bm12, B6.C-H2bm12/KhEg; B6lpr, B6.MRL-Faslpr; C3Hlpr, C3H.MRL-Faslpr; gld, B6Smn.C3H-Faslgld; PKO, C57BL/6-Pfptm1Arp; FasL, Fas ligand.
Received for publication June 11, 1999. Accepted for publication October 5, 1999.
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References |
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pathways as specific and bystander killing mechanisms of hepatitis C virus-specific human CTL. J. Immunol. 158:5283.[Abstract]
2 domain signals rapid Fas-independent cell death: a direct pathway for T cell-mediated killing of target cells?. J. Immunol. 160:4343.This article has been cited by other articles:
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  Y. Matsunaga, D. Fukuma, S. Hirata, S. Fukushima, M. Haruta, T. Ikeda, I. Negishi, Y. Nishimura, and S. Senju Activation of Antigen-Specific Cytotoxic T Lymphocytes by {beta}2-Microglobulin or TAP1 Gene Disruption and the Introduction of Recipient-Matched MHC Class I Gene in Allogeneic Embryonic Stem Cell-Derived Dendritic Cells J. Immunol., November 1, 2008; 181(9): 6635 - 6643. [Abstract] [Full Text] [PDF]
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C. Baron, M.-C. Meunier, E. Caron, C. Cote, M. J. Cameron, D. J. Kelvin, R. LeBlanc, V. Rineau, and C. Perreault Asynchronous Differentiation of CD8 T Cells That Recognize Dominant and Cryptic Antigens J. Immunol., December 15, 2006; 177(12): 8466 - 8475. [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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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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M. H. Newberg, K. J. McEvers, D. A. Gorgone, M. A. Lifton, S. H. C. Baumeister, R. S. Veazey, J. E. Schmitz, and N. L. Letvin Immunodomination in the Evolution of Dominant Epitope-Specific CD8+ T Lymphocyte Responses in Simian Immunodeficiency Virus-Infected Rhesus Monkeys J. Immunol., January 1, 2006; 176(1): 319 - 328. [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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 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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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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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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 W. Chen, J. R. Bennink, P. A. Morton, and J. W. Yewdell Mice Deficient in Perforin, CD4+ T Cells, or CD28-Mediated Signaling Maintain the Typical Immunodominance Hierarchies of CD8+ T-Cell Responses to Influenza Virus J. Virol., September 11, 2002; 76(20): 10332 - 10337. [Abstract] [Full Text] [PDF]
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H. C. Probst, T. Dumrese, and M. F. van den Broek Cutting Edge: Competition for APC by CTLs of Different Specificities Is Not Functionally Important During Induction of Antiviral Responses J. Immunol., June 1, 2002; 168(11): 5387 - 5391. [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 4, 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 4, 2001; 194(5): F23 - F26. [Full Text] [PDF]
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E. Y. Choi, Y. Yoshimura, G. J. Christianson, T. J. Sproule, S. Malarkannan, N. Shastri, S. Joyce, and D. C. Roopenian Quantitative Analysis of the Immune Response to Mouse Non-MHC Transplantation Antigens In Vivo: The H60 Histocompatibility Antigen Dominates Over All Others J. Immunol., April 1, 2001; 166(7): 4370 - 4379. [Abstract] [Full Text] [PDF]
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10/106
cells. B, Recovery of B6 and BALB/c male APCs 96 h
following s.c. injection of 5 x 105 APCs into each
foreleg footpad of syngeneic female recipients. Similar results were
obtained 24 h following injection of APCs (data not shown). In
A and B each bar represents one
mouse.
