| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Laboratoire d’Immunologie des Tumeurs and
Département d’Hématologie, Institut Paoli-Calmettes, Université de la Méditerranée, Marseille, France;
Institut National de la Santé et la Recherche Médicale Unité 119, Marseille, France; and
Department of Immunology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, or TNF-
compared with unstimulated DCs. However, LIGHT cooperates with CD154
(CD40 ligand) in DC maturation, with particular potentiation of
allogeneic T cell proliferation and cytokine secretion of IL-12, IL-6,
and TNF-. Moreover, LIGHT costimulation allows DCs to prime in
vitro-enhanced specific CTL responses. Our results suggest that LIGHT
plays an important role in DC-mediated immune responses by regulating
CD154 signals and represents a potential tool for DC-based cancer
immunotherapy. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD40 is member of TNFR family that plays a pivotal role in both
cell-mediated as well as humoral responses. CD40 has wide tissue and
cell distribution including B lymphocytes, monocytes, hematopoietic
progenitors, DCs, endothelial cells, and epithelial cells. In contrast,
CD154, the ligand for CD40, is mainly expressed on activated
CD4+ T lymphocytes. CD40 triggering on DCs
induces phenotypic and functional maturation of DCs (i.e.,
up-regulation of costimulatory molecules such as CD54, CD58, CD80, and
CD86) and enhanced capacity to induce T cell proliferation and cytokine
secretion including IL-1, IL-6, IL-8, IL-10, IL-12, TNF-, and
macrophage-inhibitory protein 1 (2). In vivo activation
of APCs, presumably DCs, through CD40 cross-linking can replace the
requirement for CD4+ T cell help for the
induction of CTL responses (3, 4, 5).
LIGHT is a recently identified member of the TNF superfamily
(6) that, like CD154, is expressed on activated T
lymphocytes (7), but also on monocytes, granulocytes, and
immature DCs (iDCs) (8, 9). LIGHT recognizes three
different members of the TNFR family, herpesvirus entry mediator
(HVEM), lymphtoxin receptor (LTR), and decoy receptor 3 (DcR3,
TR6) (6, 10). HVEM was initially characterized as mediator
of HSV-1 infection (11), and this process is inhibited by
LIGHT (6). HVEM is broadly expressed on cells of the
immune system, such as T and B lymphocytes, NK cells (12, 13), and DCs (14), but it is also expressed on
endothelial cells. LTR plays a key role in the development and
organization of lymphoid tissue, but it is absent on mature T and B
lymphocytes, primary monocytes, and peripheral DCs (15).
DcR3, a TNFR lacking a transmembrane region, is predominantly expressed
in lung tissue and the colon carcinoma cell line SW480 and may serve to
modulate LIGHT function in vivo (10).
Functionally, LIGHT can mediate apoptosis of some tumor cells in vitro
and in vivo (9, 16). Although this effect appeared to
require coexpression at the cell surface of both HVEM and LTR,
recent studies demonstrated that LTR expression is necessary and
sufficient (17). LIGHT-mediated apoptosis activates death
signals through selective recruitment of TNFR-associated factor 3 by
LTR, implicated by their colocalization. Through its interaction
with HVEM, LIGHT is also an important costimulatory molecule for T cell
activation. LIGHT stimulated T cell proliferation in a three-way MLR
(16), which was inhibited by a neutralizing Ab to HVEM.
Moreover, blockade of LIGHT inhibited DC-mediated allogeneic T cell
responses (8). LIGHT stimulation of T cells activated
NF-
B (8), induced production of IFN-
(8), and led to down-modulation of HVEM (7).
In vivo, LIGHT is implicated in the development of the T cell immune
response in tumor and graft-vs-host disease models in the mouse, but
the molecular mechanism of LIGHT function in these models remains to be
elucidated (18). Because CD40-independent pathways are
implicated in the T cell help for priming of CD8+
cytotoxic T lymphocytes by DCs (19), we examined the
effect of LIGHT on DC maturation and their capacity to prime a CTL
response.
Here we demonstrate that LIGHT, a new member of the TNF superfamily, costimulates CD154-induced DC maturation. Moreover, this costimulation increases DC conditioning to elicit, in vitro, an enhanced primary specific CTL activity against a tumor Ag.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PBMC from healthy donors were isolated on Ficoll-Hypaque gradients (20). T lymphocytes were isolated as the CD2+ PBMC population, corresponding to cells that adhere to sheep erythrocytes (21) in the E rosetting technique but fail to adhere to plastic dishes after overnight incubation in medium plus 30% FCS.
CD154-, LIGHT-, and LIGHT plus CD154-transfected cell lines
Full-length cDNA of human CD154 and human LIGHT were cloned in pcDNA3.1/Neo and pcDNA3.1/Hygro (Invitrogen, Groningen, The Netherlands), respectively, and transfected alone or sequentially by electroporation (960 µF, 220V) into Ltk murine fibroblasts. Stably transfected cells, selected by resistance to geneticin (Life Technologies, Rockville, MD), hygromycin B (Invitrogen), or both were then selected for ligand expression by three rounds of FACS sorting. CD32-transfected fibroblasts were a kind gift from Schering-Plough (Dardilly, France).
Culture conditions and DC generation
Culture experiments were performed in RPMI 1640 with 10% FBS (BioWhittaker, Walkersville, MD). For DC generation, T cell-depleted PBMC were depleted of nonadherent cells by a 4-h adhesion on plastic dishes. Adherent cells were extensively washed and then cultured in RPMI 1640 (Bioproducts) and 10% FCS with GM-CSF (Novartis, Berne, Switzerland) at 100 ng/ml and IL-4 (a kind gift from Schering-Plough) at 10 ng/ml for 5 days. The medium was replenished with cytokines every 2–3 days. At day 5, final maturation was induced by the addition of irradiated (75 Gy) L cells at a ratio of 1:10 for an additional 72 h.
Flow cytometry studies
For cell surface staining, cells were processed following standard procedures, and analysis was performed on a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA). The mAbs directed against HVEM (12C5 and 20D4, both murine IgG1) and LIGHT (2C8, murine IgG2b) were generated at SmithKline Beecham Pharmaceuticals (King of Prussia, PA) by conventional hybridoma methodology from mice immunized with the respective recombinant proteins and screening the hybridomas by ELISAs. The mAbs to CD1a, CD3, CD4, CD8, CD14, CD19, CD25, CD40, CD54, CD56, CD69, CD83, and HLA-DR were purchased from Beckman Coulter (Marseille, France). The mAb to CD80 was obtained from BD Biosciences, and the mAbs to CD86 and CD154 from BD PharMingen (San Diego, CA). Cell surface CD40 and HVEM were quantified on iDCs by indirect immunofluorescence staining using QIFIKIT (DAKO, Glostrup, Denmark)
Primary MLR
Serial dilutions (3 x 103-14 cells/well) of irradiated (25 Gy) stimulator cells were cultured in triplicate with 105 allogenic naive CD4+ T cells in 96-well round-bottom plates (Costar; Corning Glass, Corning NY). Naive CD4+ T cells were prepared from purified T cells by three rounds of negative depletion using magnetic beads (Beckman Coulter) incubated with mAbs to CD8 and CD45RO (Beckman Coulter). Proliferation of T cells was monitored by measuring [methyl-3H]thymidine (1 µCi/well; Amersham, Little Chalfont, U.K.) incorporation during the last 16 h of a 6-day culture. Thymidine uptake was counted on a gas-phase beta counter (Matrix 9600; Packard Instruments, Meriden, CT). The iDCs or DCs matured by coincubation with L cells expressing CD154, LIGHT, or LIGHT plus CD154 were used as stimulators.
Macropinocytosis assay
Mannose receptor-mediated fluid phase macropinocytosis, measured by the cellular uptake of FITC-dextran, was used as a surrogate marker for Ag capture. On day 8, 105 of the iDCs and matured DCs were incubated in medium containing 0.5 mg/ml FITC-dextran (molecular mass of 40,000 kDa; Sigma-Aldrich, St. Louis, MO) for 1 h at 37°C or 4°C (negative control). After four washes with cold PBS, cells were analyzed by flow cytometry for uptake of the FITC-dextran.
Cytokine determination
After 72 h of final maturation, DC cultures were harvested
and cell-free supernatants were frozen. After thawing, cytokine
concentrations were quantified by ELISA (IL-12p75, IL-1 (R&D
Systems, Minneapolis, MN), IL-6, and TNF- (Beckman Coulter)).
Induction of specific anti Melan-A CTLs
The iDCs and matured DCs were pulsed for 2 h at 37°C in
serum free X-Vivo 15 (BioWhittaker, Walkersville, MD) with a 10-µg/ml
Melan-A26–35 peptide analog (ELAGIGILTV; the
kind gift of P. Coulie, Ludwig Institute for Cancer Research, Brussels,
Belgium) (22) together with
2-microglobulin (3 µg/ml). After two washes,
2 x 105 peptide-pulsed DCs were cultured
with 106 CD8+ purified T
cells (95% by flow cytometry), obtained by two rounds of negative
selection from purified T cells using anti-CD4 mAb (13B8.2), in 2
ml CTL medium in the presence of IL-2 (10 U/ml) and IL-7 (5 ng/ml). The
CTL medium used was IMDM (BioWhittaker) supplemented with
L-arginine (550µM), L-asparagine (240 µM),
L-glutamine (1.5 mM), 1% penicillin-streptomycin, and 10%
pooled human serum. On day 7, CTLs were harvested and restimulated at
the initial ratio with the corresponding peptide-pulsed DCs. Cytotoxic
activity was measured on days 13–14 in the
51Cr-release assay described below.
Cytotoxicity assay
The T2 cell line was labeled by incubating 106 cells in 100 µCi sodium 51Cr-labeled chromate for 2 h at 37°C and washing three times. Labeled target cells (103) and serial dilutions of effector cells in triplicate were incubated in RPMI 1640 with 10%FCS in 96-well V-bottom plates at 37°C for 4 h in the presence or absence of Melan-A26–35 (1 µg/ml) and a 30-fold excess of unlabeled K562 cells. Supernatants were then analyzed in a microplate scintillation counter (TopCount; Packard Instruments). The percentage of lysis was determined for each triplicate experiment as [(experimental 51Cr release - spontaneous 51Cr release)/(maximal 51Cr release - spontaneous 51Cr release)] x 100. Results are expressed as the percentage of specific lysis (percentage of lysis in the presence of peptide - the percentage of lysis in the absence of peptide).
IFN--secretion assay
On days 13–14, 106 CTLs, obtained as
previously described, were stimulated by 2 x
105 peptide-pulsed, autologous irradiated
(25 Gy) PBMC. After 48 h, the levels of IFN- in the culture
supernatants were measured by ELISA (OptEIA; BD PharMingen).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
HVEM, like CD40, is expressed on peripheral blood monocyte-derived
iDCs but at a lower level. LIGHT and CD154 are not expressed on resting
T lymphocytes, but both are up-regulated at the cell surface following
activation (Ref. 7 and Fig. 1
A). These cellular
distributions suggest that, similar to CD154 and CD40, the interaction
of LIGHT with HVEM is important in T cell communication with DCs. Thus,
we investigated the effects of CD154 and LIGHT, alone or in
combination, on the maturation of DCs.
|
The iDCs were generated from T cell-depleted adherent PBMC by a
5-day culture in the presence of GM-CSF and IL-4. They were then
incubated for 72 h with irradiated, stable L cell transfectants
expressing similar levels of CD32 (negative control), CD154, LIGHT, or
LIGHT plus CD154 (Table I) at a 1:10
ratio of iDC:stimulator. LIGHT-transfected L cells induced small cell
clusters, whereas cocultures with CD154- or CD154 plus
LIGHT-transfected L cells formed large cell clusters (Fig. 1
B). No clusters were observed with control CD32-transfected
cells, and the DCs remained nonadherent. The cell surface phenotypes of
these differentially matured DCs were compared by flow cytometry (Fig. 2A). As expected, CD154
stimulation led to complete DC maturation. The CD154-treated DCs
expressed CD83, were HLA-DRhigh, and expressed
high levels of adhesion (CD54) and costimulatory (CD80 and CD86)
molecules. CD154 stimulation also enhanced the expression of its own
receptor (CD40) but had little or no effect on HVEM. LIGHT stimulation
induced maturation of a subpopulation of the iDCs. In different
experiments, 38 ± 11% of the DCs (n = 13)
acquired the mature phenotype of CD83+ and
HLA-DRhigh. This subpopulation also showed
increased levels of the costimulatory molecules CD86 and CD40, but
unlike CD154-stimulated DCs, there was little effect on CD80.
Consistent with the observation of DC cluster formation, LIGHT
stimulation induced up-regulation of the adhesion molecule CD54.
Moreover, LIGHT down-regulated its own receptor, HVEM, as previously
observed on T lymphocytes (7). The iDCs cocultured with L
cells expressing both LIGHT and CD154 acquired a mature phenotype
distinct from that obtained by CD154 or LIGHT stimulation alone. In
comparison to stimulation with CD154 alone, these DCs expressed higher
levels of HLA-DR, CD54, and costimulatory molecules (particularly CD86,
with the mean fluorescence intensity rising from 1014 ± 235 for
CD154 stimulation alone to 1646 ± 310 for LIGHT plus CD154
stimulation; n = 5 and p < 0.01) and
showed down-modulation of HVEM. These phenotypic changes were specific
for CD154 and LIGHT stimulation because addition of mAbs to CD154
and/or LIGHT (10 µg/ml) completely inhibited the elaboration of these
markers. Similarly, iDCs cultured with CD32-transfected L cells
maintained the immature phenotype of
CD83-HLA-DRlowCD80lowCD86low.
Moreover the effect of LIGHT on DC maturation is inhibited by blocking
anti-HVEM mAb (18D4) (Fig. 2B).
|
|
During the maturation process, DCs lose their ability to capture
exogenous Ag and, in turn, acquire potent Ag-presenting capacity. We
examined the effect of LIGHT stimulation on these functional parameters
of DC maturation. On day 8, iDCs, CD154-, LIGHT-, and LIGHT plus
CD154-matured DCs, generated as described above, were harvested and
evaluated for their macropinocytic activity. FITC-dextran uptake was
measured by flow cytometry and the results expressed as percentage of
positive cells (Fig. 3A).
Under the control condition of incubation with CD32 L cells, most of
the iDCs (79 ± 4% of positive cells) captured FITC-dextran,
whereas few of the CD154-matured DCs (12 ± 7% positive cells)
showed uptake. LIGHT stimulation resulted in the loss of the capacity
to take up FITC-dextran for a subpopulation of the DCs (47 ± 4%
positive cells). This subpopulation corresponds to the
CD83+ DCs (Fig. 3B), consistent with
the expected phenotype of mature DCs. As expected, LIGHT plus
CD154-matured DCs, like CD154-matured DCs, did not capture FITC-dextran
(9 ± 1% positive cells).
|
C).
CD154-matured DCs show a stronger capacity to activate T cells compared
with iDCs. LIGHT-matured DCs showed only modest enhancement of T cell
proliferation and only at DC:T cell ratios of
<1:500. In contrast, LIGHT in combination with CD154 markedly increased T cell proliferation relative to CD154 alone.> LIGHT synergizes with CD154 for some cytokine secretion
The DC maturation process is associated with cytokine synthesis.
Secretion of immunoregulatory and proinflammatory cytokines plays a
pivotal role during T cell priming in the lymphoid organs. As expected,
CD154 stimulation induced significant levels of secreted IL-12, IL-6,
TNF-, and IL-1 compared with those produced by unstimulated DCs
(Fig. 4). Consistent with their weak
effect in the MLR, LIGHT-stimulated DCs only modestly induced IL-12 and
TNF- and had no effect on IL-6 and IL-1 relative to control
unstimulated DCs. This low response could not be attributed to a toxic
effect of LIGHT on cytokine secretion pathways because IL-8 secretion
was not inhibited (data not shown). Moreover, LIGHT cooperated with
CD154 to induce significantly higher levels of IL-12, IL-6, and TNF-
than observed for CD154 alone. IL-12 production raised from 2,958
± 1,703 pg/106 cells to 17,165 ± 6,489
pg/106 cells, IL-6 production raised from
1,649 ± 344 pg/106 cells to 20,395 ±
14,335 pg/106 cells, and TNF- production
raised from 1,646 ±527 pg/106 cells to
13,522 ± 4,961 pg/106 cells
(p < 0.05). In contrast, this combination had
little effect on IL-1 secretion.
|
Recent publications (3, 4, 23) have proposed a
two-step model for the induction of cytotoxic T cell responses in which
DCs play the role of "temporal bridge." First Th cells activate the
DCs via the interaction of CD154 and CD40. Then, DCs are conditioned to
prime CTL responses. We developed an in vitro model of CTL priming
against a tumor Ag consistent with this hypothesis. iDCs and matured
DCs were pulsed with Melan-A26–35 peptide and
incubated with autologous, purified CD8+ T cells.
After two rounds of stimulation, CD8+ T cells
were tested for their anti-Melan-A CTL activity against T2 cells
(Fig. 5A). LIGHT-matured DCs,
like iDCs, were unable to prime CTL activity. As predicted by the model
described above, CD154-matured DCs induced Melan-A-specific lysis
ranging from 8 ± 1% to 18 ± 2%, at E:T ratios of >10:1.
LIGHT plus CD154-matured DCs induced a marked increase of the
anti-Melan-A cytotoxic activity relative to CD154 alone, showing
specific lysis from 17 ± 2% to 34 ± 1% over the same
range of E:T ratios.
|
levels were measured to further assess the relative priming
activity of the DCs matured in the presence of LIGHT and/or CD154. On
days 13–14 after the initial DC stimulation, T cells were harvested,
challenged for 48 h with autologous, irradiated Melan-A-pulsed
PBMC, and tested for levels of IFN- secretion. Consistent with the
cytotoxicity assays, LIGHT-matured DCs, much like iDCs, failed to prime
T cells for IFN- secretion. CD8+ T cells
obtained by coculture with CD154-matured DCs produced only a modest
level of IFN-. In sharp contrast, CD8+ T cells
primed by LIGHT plus CD154 DCs secreted large amounts of IFN-. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and IL-1 (25) or the
activated T cell molecules CD154 and TNF-related activation-induced
cytokine (TRANCE) (26, 27) represent endogenous
stimuli that enhance the stimulatory capacity of DCs.
LIGHT, like CD154 and TRANCE, is a member of the TNF family that is
induced on T cells following activation (7). Upon LIGHT
stimulation, only a fraction of monocyte-derived iDCs acquire the fully
mature phenotype characterized by expression of CD83 and high levels of
HLA-DR. This is not due to insufficient level of LIGHT because
stimulation at increased ratios of LIGHT L cell:DC or stimulation with
L cells expressing 3-fold higher levels of LIGHT on their surface does
not improve the DC response (data not shown). Furthermore, the LIGHT L
cells used in this study expressed similar cell surface levels to
activated T cells (see Fig. 1A). Moreover, because LIGHT
interaction with HVEM appears to down-modulate this receptor
(7), the absence of HVEM on a majority of DCs stimulated
with LIGHT (Fig. 2) indicates that most cells responded. Because LTR
is not on T and B cells or DCs (15), and because blocking
anti-HVEM mAb (12) inhibits LIGHT-mediated DC
maturation (Fig. 2B), LIGHT presumably stimulates DCs
through its interaction with HVEM. Based on our data, even if HVEM
seems to be involved in LIGHT-mediated DC maturation, there is no
evidence to rule out the implication of other LIGHT receptors (e.g.,
LTR and DcR3), in the phenomenon observed. Moreover, DcR3 mRNA, even
if predominantly expressed in lung tissue and in the SW480 cell line,
is weakly expressed in most hematopoietic cells (10),
including DC (data not shown). Because DcR3 is a soluble decoy receptor
for LIGHT, it might regulate LIGHT stimulation in our experimental
system.
LIGHT-stimulated DCs are unable to secrete significant amounts of
IL-12, IL-6, TNF-, and IL-1 compared with unstimulated DCs. The
weak cytokine secretion cannot be attributed to insufficient
stimulation or to a different kinetics than CD154 stimulation. Although
signaling via HVEM alone is inefficient at inducing cytokine
production, it synergizes with CD40-mediated IL-12, IL-6, and TNF-,
but not IL-1 secretion. The molecular basis of this synergy remains
to be elucidated.
Generation of specific CTL responses by the immune system may provide a
therapeutic approach to cancer. Cross-presentation is a mechanism that
allows exogenous Ags such as tumor, viral, or transplantation Ags to be
presented to class I-restricted CTLs by the APC (28, 29).
It has been demonstrated that induction of specific
CD8+ CTL response by such a cross-priming
mechanism requires cognate CD4+ T cell help
(30). This CD4+ T cell help is
particularly necessary under noninflammatory conditions, as occur in
most cancers, including noninflammatory persistent tumor viruses (human
papillomavirus or EBV) (31). Recent papers (3, 4, 23) have demonstrated that the CD4+ T cell
help for the cytotoxic T cell response can be bypassed by activation of
APCs through CD40. APCs also function as a temporal bridge in that,
once activated, APCs are conditioned to deliver a "license to kill"
to CD8+ CTLs. Ridge et al. (23) have
implicated DCs in this model, suggesting that the activation state of
DCs is more important than the CD4+ T cell help
itself (31). In our in vitro CTL induction experiments, we
used phenotypically defined DC populations, as underscored by
Schuurhuis et al. (32). Human monocyte-derived iDCs
express low levels of HLA class II and costimulatory molecules. Upon
coculture with CD154 L cells, these DCs exhibit the characteristic
phenotype of mature DCs (1), i.e., expression of CD83 and
high levels of HLA class II and costimulatory molecules. The LIGHT plus
CD154-costimulated DCs show a similar phenotype of mature DC but with
down-regulated HVEM expression and with enhanced functional capacity.
We developed an in vitro model of CTL differentiation against the human
melanoma Ag Melan-A/Mart-1 to test the specific CTL-priming capacity of
these differentially matured DCs. CD154-matured DCs elicit moderate
anti-Melan-A cytotoxic activity, whereas LIGHT plus
CD154-costimulated DCs are able to prime a significantly enhanced
anti-Melan-A cytotoxic response. The difference between the similar
phenotype and the CTL-priming capacity of LIGHT plus CD154- vs
CD154-stimulated DCs is interesting, and some hypotheses can be
proposed. First, costimulation molecules, particularly CD86, are
expressed at higher levels on LIGHT plus CD154-stimulated DCs, allowing
an increased stimulation of CTL precursor. Then, LIGHT plus
CD154-stimulated DCs can produce higher levels of IL-12, IL-6, and
TNF-, which could increase the expansion of CTLs. Taken together,
these data suggest that help for cytotoxic T cell responses mediated by
CD40 signaling can be modulated by LIGHT costimulation. These results
are consistent with recent studies examining the role of LIGHT in tumor
and graft-vs-host disease models in mice (18).
Transfection of LIGHT cDNA into P815 tumor cells enhanced their
immunogenicity. This effect was not due to LIGHT-induced apoptosis, as
has been observed for the human colon carcinoma line HT29
(16) and the human breast carcinoma MDA-MB-231
(9). We conclude that, in addition to its costimulatory
effect on T cell activation, LIGHT costimulates DCs by modulating CD40
signals. The DCs then achieve an activation state in which they are
able to elicit an enhanced anti-tumoral CTL response.
CD40-independent pathways of T cell help for CTL priming have been
reported (19). In addition to LIGHT, these pathways may
involve other TNF/TNFR family members. TRANCE/receptor activator of
NF-B ligand is reported to enhance the adjuvant properties of
DCs in a in vivo model of delayed-type hypersensitivity
(33). OX40 ligand is expressed on matured DCs
(34), and mice lacking this gene show an impaired APC
function in both priming and effector phases of T cell activation
(35). Thus, we propose that the model for priming of CTLs
by Th cell-matured DCs (19) could be extended to include
the LIGHT-HVEM interaction and perhaps other TNF/TNFR family members.
In initial studies, immunization of human subjects with autologous ex
vivo-modified DCs efficiently primed and boosted
CD4+ and CD8+ T cells
(36). Our results suggest that LIGHT/HVEM may enhance this
response and lead to applications in DC-mediated cancer
immunotherapy.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Daniel Olive, Laboratoire d’Immunologie des Tumeurs, Institut Paoli-Calmettes, Université de la Méditerranée, 232 Boulevard de Sainte Marguerite, 13009 Marseille, France. E-mail address: olive{at}marseille.inserm.fr
3 Abbreviations used in this paper: DC, dendritic cell; HVEM, herpesvirus entry mediator; LIGHT, homologous to lymphotoxins, shows inductible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes; LTR, lymphotoxin receptor; DcR3, decoy receptor 3; iDC, immature DC; TRANCE, TNF-related activation-induced cytokine.
Received for publication February 14, 2001. Accepted for publication June 11, 2001.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
are ligands for herpesvirus entry mediator. Immunity 8:21.[Medline]
receptor and TR2/HVEM, induces apoptosis and suppresses in vivo tumor formation via gene transfer. J. Clin. Invest. 102:1142.[Medline]
receptor on follicular stromal cells in human lymphoid tissues. Cell Death Differ. 5:497.[Medline]
receptor is necessary and sufficient for LIGHT-mediated apoptosis of tumor cells. J. Biol. Chem. 275:14307.This article has been cited by other articles:
|
|
 |
|
  X. Liu, M. Alexiou, N. Martin-Orozco, Y. Chung, R. I. Nurieva, L. Ma, Q. Tian, G. Kollias, S. Lu, D. Graf, et al. Cutting Edge: A Critical Role of B and T Lymphocyte Attenuator in Peripheral T Cell Tolerance Induction J. Immunol., April 15, 2009; 182(8): 4516 - 4520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F.-c. Lin, Y. Peng, L. A. Jones, P. H. Verardi, and T. D. Yilma Incorporation of CD40 Ligand into the Envelope of Pseudotyped Single-Cycle Simian Immunodeficiency Viruses Enhances Immunogenicity J. Virol., February 1, 2009; 83(3): 1216 - 1227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. W. Steinberg, O. Turovskaya, R. B. Shaikh, G. Kim, D. F. McCole, K. Pfeffer, K. M. Murphy, C. F. Ware, and M. Kronenberg A crucial role for HVEM and BTLA in preventing intestinal inflammation J. Exp. Med., June 9, 2008; 205(6): 1463 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Xu, D. Liu, I. Okwor, Y. Wang, H. Korner, S. K. P. Kung, Y.-X. Fu, and J. E. Uzonna LIGHT Is Critical for IL-12 Production by Dendritic Cells, Optimal CD4+ Th1 Cell Response, and Resistance to Leishmania major J. Immunol., November 15, 2007; 179(10): 6901 - 6909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Xu, D. Liu, Y. Fan, X. Yang, H. Korner, Y.-X. Fu, and J. E. Uzonna Lymphotoxin {alpha}beta2 (Membrane Lymphotoxin) Is Critically Important for Resistance to Leishmania major Infection in Mice J. Immunol., October 15, 2007; 179(8): 5358 - 5366. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Loeffler, G. Le'Negrate, M. Krajewska, and J. C. Reed Attenuated Salmonella engineered to produce human cytokine LIGHT inhibit tumor growth PNAS, July 31, 2007; 104(31): 12879 - 12883. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tuyaerts, S. Van Meirvenne, A. Bonehill, C. Heirman, J. Corthals, H. Waldmann, K. Breckpot, K. Thielemans, and J. L. Aerts Expression of human GITRL on myeloid dendritic cells enhances their immunostimulatory function but does not abrogate the suppressive effect of CD4+CD25+ regulatory T cells J. Leukoc. Biol., July 1, 2007; 82(1): 93 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Summers-deLuca, D. D. McCarthy, B. Cosovic, L. A. Ward, C. C. Lo, S. Scheu, K. Pfeffer, and J. L. Gommerman Expression of lymphotoxin-{alpha}{beta} on antigen-specific T cells is required for DC function J. Exp. Med., May 14, 2007; 204(5): 1071 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J Sedgmen, W. Dawicki, J. L Gommerman, K. Pfeffer, and T. H Watts LIGHT is dispensable for CD4+ and CD8+ T cell and antibody responses to influenza A virus in mice Int. Immunol., May 1, 2006; 18(5): 797 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-G. Wang, K. D. Kim, J. Wang, P. Yu, and Y.-X. Fu Stimulating Lymphotoxin {beta} Receptor on the Dendritic Cells Is Critical for Their Homeostasis and Expansion J. Immunol., November 15, 2005; 175(10): 6997 - 7002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yang, K.-Y. Tsang, and J. Schlom Induction of Higher-Avidity Human CTLs by Vector-Mediated Enhanced Costimulation of Antigen-Presenting Cells Clin. Cancer Res., August 1, 2005; 11(15): 5603 - 5615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Wang, R. A. Anders, Y. Wang, J. R. Turner, C. Abraham, K. Pfeffer, and Y.-X. Fu The Critical Role of LIGHT in Promoting Intestinal Inflammation and Crohn's Disease J. Immunol., June 15, 2005; 174(12): 8173 - 8182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lustgarten, A. L. Dominguez, and M. Thoman Aged Mice Develop Protective Antitumor Immune Responses with Appropriate Costimulation J. Immunol., October 1, 2004; 173(7): 4510 - 4515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yu, C. Kovacs, F. Y. Yue, and M. A. Ostrowski The Role of the p38 Mitogen-Activated Protein Kinase, Extracellular Signal-Regulated Kinase, and Phosphoinositide-3-OH Kinase Signal Transduction Pathways in CD40 Ligand-Induced Dendritic Cell Activation and Expansion of Virus-Specific CD8+ T Cell Memory Responses J. Immunol., May 15, 2004; 172(10): 6047 - 6056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hagihara, A. Higuchi, N. Tamura, Y. Ueda, K. Hirabayashi, Y. Ikeda, S. Kato, S. Sakamoto, T. Hotta, S. Handa, et al. Platelets, after Exposure to a High Shear Stress, Induce IL-10-Producing, Mature Dendritic Cells In Vitro J. Immunol., May 1, 2004; 172(9): 5297 - 5303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Liu, C. S. Schmidt, F. Zhao, A. J. Okragly, A. Glasebrook, N. Fox, E. Galbreath, Q. Zhang, H. Y. Song, S. Na, et al. LIGHT-deficiency impairs CD8+ T cell expansion, but not effector function Int. Immunol., July 1, 2003; 15(7): 861 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Yu, J. X. Gu, C. Kovacs, J. Freedman, E. K. Thomas, and M. A. Ostrowski Cooperation of TNF Family Members CD40 Ligand, Receptor Activator of NF-{kappa}B Ligand, and TNF-{alpha} in the Activation of Dendritic Cells and the Expansion of Viral Specific CD8+ T Cell Memory Responses in HIV-1-Infected and HIV-1-Uninfected Individuals J. Immunol., February 15, 2003; 170(4): 1797 - 1805. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Gill, J. Ni, and J. S. Hunt Differential Expression of LIGHT and Its Receptors in Human Placental Villi and Amniochorion Membranes Am. J. Pathol., December 1, 2002; 161(6): 2011 - 2017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Castellano, C. Van Lint, V. Peri, E. Veithen, Y. Morel, R. Costello, D. Olive, and Y. Collette Mechanisms Regulating Expression of the Tumor Necrosis Factor-related light Gene. ROLE OF CALCIUM-SIGNALING PATHWAY IN THE TRANSCRIPTIONAL CONTROL J. Biol. Chem., November 1, 2002; 277(45): 42841 - 42851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Scheu, J. Alferink, T. Potzel, W. Barchet, U. Kalinke, and K. Pfeffer Targeted Disruption of LIGHT Causes Defects in Costimulatory T Cell Activation and Reveals Cooperation with Lymphotoxin {beta} in Mesenteric Lymph Node Genesis J. Exp. Med., June 17, 2002; 195(12): 1613 - 1624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tamada, J. Ni, G. Zhu, M. Fiscella, B. Teng, J. M. A. van Deursen, and L. Chen Cutting Edge: Selective Impairment of CD8+ T Cell Function in Mice Lacking the TNF Superfamily Member LIGHT J. Immunol., May 15, 2002; 168(10): 4832 - 4835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Wilcox, A. I. Chapoval, K. S. Gorski, M. Otsuji, T. Shin, D. B. Flies, K. Tamada, R. S. Mittler, H. Tsuchiya, D. M. Pardoll, et al. Expression of Functional CD137 Receptor by Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4262 - 4267. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
