|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3338-3345
OX40 Costimulation Enhances Interleukin-4 (IL-4) Expression at
Priming and Promotes the Differentiation of Naive Human
CD4+ T Cells Into High IL-4-Producing Effectors
By
Yusei Ohshima,
Liang-Peng Yang,
Takashi Uchiyama,
Yuetsu Tanaka,
Peter Baum,
Martin Sergerie,
Patrice Hermann, and
Guy Delespesse
From the University of Montreal, Centre de Recherche Louis-Charles
Simard, Notre-Dame Hospital, and the Department of Obstetrics and
Gynecology, Montreal, Quebec, Canada; the Institute for Virus Research,
Kyoto University, Kyoto, Japan; Kitasato University, Kitasato,
Sagamihara, Kanagawa, Japan; and Immunex Research and Development Corp,
Seattle, WA.
 |
ABSTRACT |
Th2 cell development is critically dependent on the presence of
interleukin-4 (IL-4) at priming. The cellular origin and the mechanisms
regulating this early production of IL-4 at the site of naive T-cell
priming are extensively investigated. We previously reported that
anti-CD3-activated and CD28-costimulated naive human CD4+ T cells themselves release very low but sufficient
levels of IL-4 to support their development into high IL-4-producing
cells. We show here that ligation of OX40 Ag, a member of the tumor
necrosis factor receptor (TNF-R) family, on activated
umbilical cord blood CD4+ T cells upregulates IL-4
production at priming and thereby promotes their development into
effector cells producing high levels of the type 2 cytokines IL-4,
IL-5, and IL-13. OX40 ligation increases four times the expression of
IL-4 mRNA after 48 hours of anti-CD3/B7.1 activation and significantly
augments the release of IL-4 and IL-13 in primary cultures. The effects
of OX40 costimulation on Th cell differentiation are observed in the
presence of optimal and suboptimal CD28 stimulation. Because OX40
ligand is expressed on dendritic cells, the OX40 costimulation pathway
may be involved in the physiological regulation of Th cell development
by augmenting the differentiation of IL-4-producing cells.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
IN VIVO AND IN VITRO observations have
indicated that Th subset development is regulated very early in the
course of the immune response, at the time when naive CD4+
T cells first encounter Ag presented by dendritic cells
(DC).1,2 Several factors have been implicated in the
regulation of naive T-cell differentiation into Th1 or Th2 effectors,
including (1) the intensity and the nature of T-cell receptor
(TCR)-mediated activation signal3-8; (2) the
strength and the nature of costimulatory signals9-12; (3)
the cytokine and hormonal milieu in which T cells are
primed1,2,13; and (4) the genetic background of the naive T
cells.14 Among all these factors, cytokines appear to exert
the most important role, with interleukin-4 (IL-4) and IL-12 promoting
Th2 and Th1 responses, respectively.15,16 The other factors
may act by influencing the production of these two cytokines at
priming. Whereas the cellular origin and the mechanisms leading to the early production of IL-12 at the time of T-cell priming have been elucidated,17-19 the origin and the regulation of IL-4
production at priming are still under investigation.20
Depending on the experimental system used to induce a Th2 response,
different types of cells were shown to be involved in the early
production of IL-4, including CD4+ NK1.1+ T
cells,   T cells, and Fc R1-bearing cells.21-24 More
recent studies showed that naive T cells themselves may be the original source of IL-4, which they release in very small but sufficient amounts
to promote their development into high IL-4 producers via an autocrine
pathway.5,6,8,25,26 For example, cell-sorted purified and
phenotypically naive murine CD4+ T cells were shown to
release IL-4 at priming and to develop into Th2 effectors upon in vitro
priming with a low concentration of Ag or altered peptide
ligands.8 Moreover, the acquisition of a Th2 phenotype was
abolished by neutralization of IL-4 in priming cultures. In agreement
with these observations, we previously reported that virtually every
naive human CD4+ T cell of neonatal or adult origin grown
in single-cell culture developed into high IL-4/IL-5 producers after
multiple cycles of stimulation with anti-CD3 monoclonal antibody (MoAb)
immobilized on CD32/B7.1-transfected L cells and IL-2
expansion.27 That IL-4 was released during the first 3 days
of anti-CD3/B7.1 activation was evidenced by the following three
observations: (1) the addition of anti-IL-4R neutralizing Ab to
primary cultures reduced the acquisition of IL-4/IL-5-producing
capacity while increasing that of interferon-
(IFN-)28; (2) IL-4 mRNA was detected after 48 hours of
naive CD4+ T-cell stimulation with a mixture of soluble
anti-CD3 and anti-CD28 MoAb; and (3) IL-4 protein could be measured in
the supernatant fluids of priming cultures performed in the presence of
anti-IL-4R blocking MoAb, preventing IL-4 consumption by activated
naive CD4+ T cells.29 Further studies in the
murine as well as in the human system showed that IL-4 production at
priming was critically dependent on CD28
costimulation.8,29,30 Indeed, IL-4 production during
primary activation of naive TCR Tg T cells by altered peptide ligand
was strictly dependent on CD28/B7 costimulation.8
Similarly, IL-4 release by anti-CD3-activated human naive T cells was
significantly higher when the anti-CD3 MoAb was immobilized on
CD32/B7.1 L transfectants expressing high levels of B7.1 than when it
was immobilized on CD32 single L transfectants, expressing low but
functionally sufficient levels of mouse
B7.1.29 We are here reporting a novel
mechanism that may regulate IL-4 production at priming in the presence
of both optimal and suboptimal CD28 costimulation. We provide evidence that ligation of OX40 Ag, a member of the tumor necrosis factor receptor (TNF-R) family,31 increases IL-4
production by naive T cells and promotes their development into
effector cells producing high levels of the Th2 cytokines IL-4, IL-5,
and IL-13.
| |
MATERIALS AND METHODS |
Reagents.
Anti-CD3 MoAb (64.1) was a gift of Bristol-Myers (Seattle, WA).
Anti-OX40 MoAbs (315 and 131) and anti-OX40L/gp34 MoAb (5A8) were
described previously.32,33 Anti-OX40 MoAb (Act35) was purchased from PharMingen (Mississauga, Ontario, Canada).
Neutralizing anti-IL-4 receptor MoAb (MoAb 230) was from R&D Systems
(Minneapolis, MN). Isotype-matched negative control MoAbs (mouse IgG1
and mouse IgG2a) were prepared in our laboratory. Recombinant human
granulocyte-macrophage colony-stimulating factor
(rhGM-CSF), rhIL-4, rhIL-2, and rhIL-12 were kindly
provided by Dr D. Bron (Institute Bordet, Brussels, Belgium), Dr C. Maliszewski (Immunex Corp, Seattle, WA), Dr F.K. Kahn (Hoffmann-La
Roche, Nutley, NJ), and Dr M. Gately (Hoffmann-La Roche), respectively.
Recombinant human tumor necrosis factor- (rhTNF-)
was purchased from Genzyme (Cambridge, MA). CD32 and B7.1
double-transfected mouse L fibroblasts were prepared and selected, as
described,28 for the expression of high levels of B7.1.
Human OX40L cDNA in pDC410 generated by Immunex Corp was subcloned into
pBJ expression vector.34 OX40L transfected L fibroblasts
were prepared as described.35
CD4+ T-cell purification and culture conditions.
CD4+ T cells were isolated from umbilical cord blood of
healthy neonates as described.28 Briefly, mononuclear cells
were obtained by centrifugation on Lymphoprep (Nycomed Pharma As, Oslo, Norway) and were treated with L-Leucine methyl ester to remove monocytes and natural killer (NK) cells. Cell preparation
was enriched in T cells by E-rosetting and CD4+ cells were
obtained by treating rosette-forming cells with Lympho-kwik T helper
(One Lambda, Canoga Park, CA). The resulting populations were greater
than 98% viable (trypan blue negative); were greater than 98%
CD3+, CD4+/CD8 , and
CD45RA+; and contained no detectable CD45ROhi,
CD25+, CD19+, and CD56+ cells.
CD4+ T cells (1 × 106/mL) were cultured
in 48-well culture plates in 0.4 mL of RPMI 1640 medium containing 10%
fetal calf serum (FCS), 5 mmol/L L-glutamine, 50 IU
penicillin G, and 50 µg streptomycin and were primed with anti-CD3
MoAb (100 ng/mL) and anti-OX40 MoAb (5 µg/mL) or control mouse IgG in
the presence of mitomycin C-treated CD32/B7.1 L cells (0.25 × 106/mL). Alternatively, T cells were stimulated with
anti-CD3 (100 ng/mL) and mitomycin C-treated OX40L L cells or L cells
(0.25 × 106/mL) in 24-well plates (1 mL/ well). After
3 days, cells were washed and cultured at 0.25 × 106/mL in culture medium supplemented with 50 U/mL rhIL-2
in 24-well plates. After 4 days of IL-2 expansion, cells were washed
and stimulated for cytokine production.
Dendritic cell preparation and mixed leukocyte cultures (MLR).
Monocyte-derived DC (Mo-DC) were prepared as previously
described.36 Monocytes were isolated from peripheral blood
mononuclear cells (PBMC) from healthy donors by cold
aggregation followed by E-rosetting and plastic plate adhesion. The
adherent cells were cultures in RPMI/10% FCS supplemented with 800 U/mL GM-CSF and 25 ng/mL IL-4. On day 4, the cultures were fed by
replacing two thirds of supernatant fluids with fresh medium containing GM-CSF, IL-4, and TNF- (final concentration, 10 ng/mL). After 7 days
of culture, the cells were washed and treated with mitomycin C (25 µg/mL for 30 minutes).
Primary MLR were conducted in 96-well U-bottom tissue culture plates by
adding different numbers of mitomycin C-treated Mo-DC to 2 × 105 allogenic CD4+ T cells in 200 µL culture medium in the presence of anti-OX40L MoAb (5A8) or control
mouse IgG1 (10 µg/mL). After 5 days of culture, 100 µL of
supernatants was replaced with fresh medium containing 100 U/mL of
IL-2. On days 7 and 9, cultures were split and expanded in the presence
of 50 U/mL of IL-2. After 5 days of IL-2 expansion, cells were washed
and tested for cytokine production.
Flow cytometric analysis.
Cells were stained with fluorescein isothiocyanate
(FITC)-conjugated Act35 or control mouse IgG1. Stained
cells were analyzed with a FACSort (Becton Dickinson, Mountain View,
CA).
Cytokine measurements.
To determine cytokine production capacity, T cells (1 × 106/mL) were restimulated with anti-CD3 (100 ng/mL)
immobilized on mitomycin C-treated CD32/B7.1 L cells (0.25 × 106/mL) and the cell-free supernatants were collected after
24 or 48 hours, as indicated. IL-4, IL-5, and IFN- were measured
using a two-site sandwich enzyme-linked immunosorbent assay (ELISA) or
radioimmunoassay (RIA), exactly as
described.28 IL-13 and IL-4 in primary cultures were
measured with Quantikine IL-13 and Quantikine HS IL-4 (R&D Systems),
respectively.
IL-4 mRNA analysis.
T cells were collected after 48 hours of anti-CD3/B7.1 stimulation and
total RNA was prepared with RNAeasy Total RNA kit (Qiagen, Chasworth,
CA). One microgram of RNA from each sample was reverse transcribed by
GeneAmp RNA polymerase chain reaction (PCR) kit from Perkin Elmer
(Cetus, Emeryville, CA) with oligo d(T)16 as the
first-strand cDNA primer. One twentieth volume of reverse-transcription product was mixed with known quantities of serially diluted competitive internal standards (PCR MIMICs; Clontech, Palo Alto, CA) and was subjected to quantitative reverse transcriptase-PCR
(RT-PCR) according to the manufacturer's protocol.
Target-specific primer pairs of IL-4 and G3PDH were also purchased from
Clontech. After 40 cycles of amplification, the PCR products were
resolved on a 1.8% agarose gel containing ethidium bromide. The
intensities of competitor-generated bands and the cDNA sample-generated
bands were compared to determine the quantity of target gene product.
The amount of target cDNA was ascertained by determining the amount of
competitor required to produce equal molar quantities of target and
competitor products. The photographs of agarose gels were further
analyzed by computer imaging (NIH image, version 1.61; National
Institutes of Health, Bethesda, MD) and the ratio of mean histogram of
target-generated to competitor-generated band was calculated. The
specificity of the amplified bands was validated by their predicted
size.
Statistical analysis.
The paired t-test was used to determine statistical
significance of the data. Vaules of P < .05 were chosen for
rejection of the null hypothesis. The cDNA concentrations were
calculated by linear regression test after logarithmic transformation
of the concentrations of competitors and the ratio of gel band
intensities. The 95% confidence limits are shown in parenthesis.
| |
RESULTS |
Ligation of OX40 promotes the development of naive T cells into
Th2-like effectors.
In initial studies we determined the time course expression of OX40 on
neonatal CD4+ T cells activated with anti-CD3 MoAb
immobilized on CD32/B7.1 L transfectants. OX40 was detected by flow
cytometry using FITC-conjugated MoAb (clone Act35) after 1, 8, 24, 48, 72, and 168 hours of stimulation. As shown in
Fig 1, OX40 was absent on freshly isolated
T cells, became detectable after 8 hours of stimulation, reached
maximal levels at 48 hours, and was still upregulated at 168 hours
after activation. Further experiments showed that the addition of
CTLA4-Ig to these cultures slightly delayed but did not reduce OX40
expression after 40 hours of activation, suggesting that
TCR/CD3-mediated signals were sufficient for OX40 expression (data not
detailed). The influence of OX40 ligation on Th cell development was
next examined in three-step cultures in which neonatal
CD4+T cells were first activated with anti-CD3 MoAb
cross-linked on CD32/B7.1 L cells (refered to hereafter as
anti-CD3/B7.1 activation) in the presence of anti-OX40 MoAb or isotype
control mouse IgG. After 3 days of priming, cells were washed and
expanded with IL-2 for 4 days. The cells were then washed and
restimulated (anti-CD3/B7.1) for cytokine production. As seen in
Fig 2A, cells primed in the presence of
anti-OX40 MoAb (clone 315) produced much more IL-4 (3.7-fold increase),
IL-13 (2.7-fold increase), and IL-5 (3.0-fold increase) but
significantly less IFN- (75% inhibition) than did cells primed in
the presence of control mouse IgG. Similar results were obtained by
using another anti-OX40 MoAb (clone 131), whereas a third clone (Act35)
used to stain the cells in Fig 1 was inactive. To ascertain that OX40
signaling may skew the cytokine production pattern of developing Th
cells toward Th2, naive CD4+ T cells were primed with
anti-CD3 MoAb (clone 64.1) in the presence of OX40 ligand
(OX40L)-transfected L cells or untransfected L cells. As previously
reported,29 64.1 anti-CD3 MoAb is capable of triggering
naive T-cell proliferation and maturation when used in soluble form
together with either anti-CD28 MoAb or untransfected L cells,
expressing low but functional levels of mouse B7.1. The three
experiments summarized in Fig 2B showed that cells primed in the
presence of OX40L transfectants produced at least 10 times more IL-4
and much less IFN- than did those primed in the presence of L cells.
As expected,29 the basal levels of IL-4 production by T
cells primed with anti-CD3 together with L cells (Fig 2B) were lower
than those of anti-CD3/B7.1-primed T cells (Fig 2A), confirming the
enhancing effect of CD28 cosignal on IL-4 production. Collectively,
these two series of experiments thus indicated that OX40 ligation
favored the differentiation of IL-4-producing effector cells in the
presence of both optimal (Fig 2A) or suboptimal (Fig 2B) CD28
costimulation. Because OX40L is expressed on DC,36 we next
examined the role of OX40/OX40L costimulation pathway in the
differentiation of naive CD4+ T cells stimulated with
allogeneic DC. Neonatal CD4+ T cells were cocultured with
allogeneic DC at low (15/1) or high (300/1) T cells/DC ratios in the
presence of a blocking anti-OX40L MoAb (clone 5A8) or isotype control
mouse IgG. These cultures were supplemented with IL-2 at day 5 and T
cells were stimulated for cytokine production at day 10. As
expected,19 cells primed at a high T/DC ratio produced
significantly more IL-4 and IL-5 but slightly less IFN- than did
those primed at a low T/DC ratio (Fig 2C). In each case, anti-OX40L
MoAb significantly inhibited the development of IL-4/IL-5-producing
cells, a finding consistent with the notion that signaling through OX40
enhances the acquisition of IL-4-producing capacity. Interestingly,
anti-OX40L MoAb did not affect the development of IFN--producing
cells, indicating that blocking the OX40/OX40L pathway during naive
T-cell/DC interaction suppressed the acquisition of IL-4- but not of
IFN--producing capacity.
View larger version (18K):
[in this window]
[in a new window]
| Fig 1.
Expression of OX40 Ag on naive T cells. Neonatal
CD4+ T cells were stimulated with anti-CD3 MoAb and
CD32/B7.1 L cells and stained after the indicated intervals with
FITC-conjugated Act35 (dark lines) or control mouse IgG1 (faint
lines).
|
|
View larger version (37K):
[in this window]
[in a new window]
| Fig 2.
OX40 costimulation at priming deviates the cytokine
production profile of primed T cells. T cells were primed either with
anti-CD3 and anti-OX40 (clone 315) or control mouse IgG2a together with
CD32/B7.1 L cells (A) or with anti-CD3 and OX40L L cells (B). In (C), T
cells were cocultured with allogenic DC in the presence of anti-OX40L
or control mouse IgG1. In each case, cells were restimulated for
cytokine production after IL-2 expansion. IL-4, IL-5, and IFN- were
measured after 24 hours and IL-13 after 48 hours of stimulation. Shown
are the mean ± SEM of five experiments. *P < .05;
**P < .01.
|
|
OX40 ligation enhances IL-4 production at priming.
Given the essential role of IL-4 in the generation of Th2 cells, we
examined whether the effects of OX40 ligation on naive T-cell
maturation were dependent on the endogenous release of IL-4 in primary
cultures. This appeared to be the case inasmuch as addition of
neutralizing anti-IL-4R MoAb or anti-IL-4 MoAb to primary cultures
markedly inhibited the effects of OX40 ligation on Th cell
differentiation (Fig 3). These results not
only indicated that the effects of OX40 costimulation were
IL-4-dependent, but also supported the notion that IL-4 was produced
in primary cultures. We next asked whether the OX40 cosignal enhanced
the acquisition of IL-4-producing capacity by upregulating IL-4
expression during primary T-cell activation. IL-4 mRNA levels were
measured 48 hours after anti-CD3/B7.1 activation of neonatal
CD4+ T cells in the presence of anti-OX40 MoAb or control
IgG by means of a quantitative RT-PCR assay using competitive
PCR-MIMICS. These experiments (Fig 4)
showed that OX40 ligation increased the expression of IL-4
transcription from 2.0 (1.3 to 3.3) to 8.1 (4.7 to 13.6) × 103 attomoles, corresponding to a fourfold increase.
The decision to measure IL-4 transcripts after 48 hours of activation
was based on previous studies, including ours,3,25,29
showing that, whereas IL-4 mRNA is easily detected within a few hours
after the activation of memory/effector CD4+ T cells, it
becomes detectable only 36 to 48 hours after naive T-cell activation.
View larger version (32K):
[in this window]
[in a new window]
| Fig 3.
Effects of anti-IL-4R neutralizing Ab added at priming
on the cytokine profile at restimulation. Cells were primed with
anti-CD3, anti-OX40 (clone 315) or control mouse IgG2a, and CD32/B7.1 L
cells in the presence of anti-IL-4R (5 µg/mL;  ) or control mouse
IgG2a (). Primed cells were restimulated for cytokine production as
in the legend to Fig 2. Cells primed with anti-CD3 and CD32/B7.1 alone
( ). Shown are the mean ± SEM of five experiments.
*P < .05; **P < .01.
|
|
View larger version (30K):
[in this window]
[in a new window]
| Fig 4.
Quantitative analysis of IL-4 and G3PDH mRNA by
competitive PCR. CD4+ T cells were stimulated with
anti-CD3 MoAb and CD32/B7.1-transfected L cells in the presence of
control mouse IgG2a or anti-OX40 MoAb (clone 315; 5 µg/mL) for 48 hours. Total RNAs of both groups of cells were prepared, and cDNA was
synthesized. Quantitative PCR was performed in the presence of a
twofold dilution of competitive internal standards (PCR MIMICs) of IL-4
(A) and G3PDH (B). The mean histogram of each band was analyzed by
computer imaging. The ratio of target to competitors was plotted
against the reciprocal of the concentrations of competitors added to
the PCR reaction in log scale (C and D). Data were derived from RNA of
( ) control IgG2a-treated cells and ( ) anti-OX40 MoAb-treated
cells.
|
|
To examine the release of IL-4 in primary cultures, neonatal
CD4+ T cells were stimulated for 3 days in the presence or
absence of anti-IL-4R MoAb and the cell-free supernatant fluids were
assayed by means of the ultrasensitive Quantikine HS IL-4 ELISA,
allowing for the detection of 0.25 pg/mL of IL-4. As seen in
Table 1, trace amounts of IL-4 were
released by anti-CD3/B7-stimulated cells and these were marginally
increased by anti-OX40 stimulation. However, the addition of IL-4R MoAb
to priming cultures drastically increased IL-4 levels, indicating that
endogenously produced IL-4 was consumed by activated naive T cells.
Furthermore, OX40 ligation consistently increased the levels of IL-4
released in priming cultures. It is of note that the IL-4 levels
measured in the five experiments summarized in Table 1 were quite
variable and that the enhancing effect of OX40 costimulation on IL-4
protein production was less pronounced than that on IL-4 mRNA
expression. A possible explanation is that IL-4 transcripts, unlike
IL-4 protein, were measured after stimulation in the absence of IL-4R
MoAb so that, as it has been suggested, endogenous IL-4 could
upregulate IL-4 gene expression in an autocrine manner.37
That naive T-cell-derived IL-4 may regulate cytokine production during
the first 72 hours of primary activation was confirmed by measuring
IL-13 and IFN- in the same culture supernatants as those used to
measure IL-4 (Table 1). As seen in Fig 5,
ligation of OX40 increased IL-13 and decreased IFN- production in
primary culture and this effect was abolished by anti-IL-4R MoAb.
Thus, the ability of OX40 costimulation to promote the development of
anti-CD3/B7.1-activated neonatal CD4+ T cells into
Th2-like cells appeared to result from increased IL-4 production at
priming.
View larger version (12K):
[in this window]
[in a new window]
| Fig 5.
OX40 ligation regulates IL-13 and IFN- production at
priming. Cells were primed with anti-CD3, anti-OX40 (315) or control
mouse IgG2a, and CD32/B7.1 L cells in the presence of anti-IL-4R (5 µg/mL; ) or control mouse IgG2a (). Cells primed with anti-CD3
and CD32/B7.1 alone (). Supernatants were collected
after 3 days for cytokine measurement. Shown are the mean ± SEM of
five experiments. *P < .05; **P < .01.
|
|
Effects of exogenous IL-12 on OX40-mediated Th2 cell development.
Because Th subset development is known to be critically dependent on
the relative concentrations of IL-4 and IL-12 at priming, we next
examined the influence of exogenous IL-12 on the maturation of
anti-CD3/B7.1-activated and OX40-costimulated naive CD4+ T
cells. Consistent with the notion that the effects of IL-4 dominate
over those of IL-12, the experiments summarized in
Fig 6 showed that, even at a high
concentration, exogenous IL-12 did not affect the enhancing effect of
OX40 costimulation on IL-4 production. However, IL-12 slightly but
significantly reduced the OX40-mediated enhancement of IL-13 and IL-5
production, implicating that IL-12 may also downregulate these two
Th2-type cytokines in an IL-4-independent manner. Previous studies in
the mouse16,38 and in the human system (Byun and
Delespesse, unpublished observation) have demonstrated
that exogenous IL-4 reduces the ability of IL-12 to prime naive T cells
for increased IFN- production. The data in Fig 6 showed that, in
contrast to these reported effects of IL-4, OX40 costimulation did not
inhibit the IL-12-mediated upregulation of IFN- production. These
findings therefore implicate that OX40 costimulation may regulate
naive T-cell development not only by increasing early IL-4 production,
but also by additional unknown mechanisms. The ability of OX40
signaling to upregulate IL-4 without inhibiting IL-12-mediated
upregulation of IFN- production suggests that, in priming conditions
associated with high IL-12 production, the OX40 costimulation pathway
may favor the early development of mixed populations of Th cells
producing both type 1 and type 2 cytokines.
View larger version (37K):
[in this window]
[in a new window]
| Fig 6.
Interactions between exogenous IL-12 and OX40
costimulation at priming. Cells were primed with anti-CD3 and CD32/B7.1
L cells alone () or in the presence of anti-OX40 (315; ) or
control mouse IgG2a () together with the indicated concentrations of
IL-12. Primed cells were examined for cytokine
production. Shown are the mean ± SEM of five experiments. IL-12
significantly inhibits (P < .05) the enhancing effect of OX40
costimulation on IL-5 and IL-13, but not on IL-4 production.
|
|
| |
DISCUSSION |
There is increasing evidence that conventional naive CD4+ T
cells themselves may be the original source of IL-4 that is required for the development of Th2 response.5,6,8,25-27
Phenotypically naive murine and human CD4+ T cells were
shown to express IL-4 mRNA within 36 to 48 hours after primary
activation and to release low levels of IL-4 protein after 3 to 4 days;
moreover, their differentiation into IL-4-producing effectors is
inhibited by the addition of neutralizing Abs to IL-4 or IL-4R in
primary cultures. Thus, endogenously produced IL-4 appears to
upregulate in an autocrine manner the acquisition of IL-4-producing
capacity by developing Th cells. This notion is in sharp contrast with
the demonstration that IL-4 production by differentiated Th2 cells is
IL-4- and STAT-6-independent.39 Relatively little is
known regarding the regulation of this early IL-4 production, with the
noticeable exceptions that it is critically dependent on the strength
of the TCR-mediated signals and that it may be upregulated by CD28
costimulation and APC-derived IL-6.8,25,29,30 Naive T cells
stimulated with low concentrations of Ag or with low-affinity TCR
binding altered peptides produce IL-4, provided that the T cells
receive a CD28-mediated cosignal; in contrast, higher concentrations of
Ag do not trigger IL-4 production, even in conjunction with CD28
costimulation.8 IL-6 was recently shown to promote Th2
development in vitro by enhancing IL-4 production at priming, a finding
consistent with the earlier observation that NF-IL-6 and NF-IL-6
may regulate IL-4 gene promoter.25,40,41 The present
results suggest an additional mechanism regulating IL-4 production at
priming, involving the interaction between OX40 Ag, which is expressed
on activated naive T cells, and its ligand, which is expressed on DC.
The OX40 Ag is a member of the TNF-R superfamily and
binds to high-affinity ligand (OX40L) expressed on APCs such as DC and
activated B cells as well as endothelial cells.31-34,36
Expression of OX40 is restricted to activated T cells, and engagement
of OX40 by its ligand is known to costimulate the proliferation and the
production of IL-2 and IL-4 by polyclonally activated adult T
lymphocytes.31,34,42 OX40L, like the other members of the
TNF superfamily (with the exception of TNF-), is an integral type II
membrane molecule capable of signaling the cells on which it is
expressed.33,36,43 OX40L is constitutively expressed on a
subset of differentiated DC and is inducible, via CD40 ligation, on
more immature DC.36 Ligation of OX40L on CD40L-activated DC
costimulates both their cytokine production (mainly IL-12, IL-1,
IL-6, and TNF-) and their expression of surface costimulatory molecules; however, these effects are much more pronounced on immature
than on differentiated DC.36 We have shown here that OX40
was expressed within 8 hours after anti-CD3/B7.1 activation of naive
CD4+ T cells and that its ligation by selected MoAbs or by
OX40L promoted the development of effector cells, producing much higher
levels of the type 2 cytokines IL-4, IL-5, and IL-13. These effects of OX40 costimulation were observed in the presence of both infraoptimal and optimal CD28 costimulation; finally, the disruption of OX40/OX40L interaction in primary MLR between neonatal CD4+ T cells
and DC markedly inhibited the development of IL-4/IL-5-producing allo-antigen primed cells. Two observations indicated that the effects
of OX40 cosignal on naive T-cell maturation were secondary to increased
IL-4 production at priming. First, they were abolished by the addition
of neutralizing anti-IL-4R or anti-IL-4 MoAb to primary cultures (Fig
3), indicating that they were dependent on endogenously released IL-4.
Second, OX40 ligation significantly increased IL-4 mRNA expression and
IL-4 secretion in primary cultures. The OX40-mediated upregulation of
IL-4 at priming accounted for the increased production of IL-13 and the
decreased production of IFN- in primary cultures. Because IL-13,
like IL-4, downregulates IL-12 production by APC and because IFN-
has the reverse effect,17 these findings suggest that OX40
may promote Th2 development not only via a direct effect on T cells,
but also indirectly, by reducing IL-12 production by DC. However, and
most interestingly, unlike exogenous IL-4, OX40 cosignal did not
inhibit IL-12 priming for increased IFN-
production,16,38 suggesting that this costimulation pathway
may support the emergence of IL-4-producing effectors in the early
stage of a polarized Th1 response against pathogens capable of
triggering IL-12 production by APCs. Alternatively, it is also possible
that, in the presence of IL-12, OX40 ligation favors the development of
Th0 effectors, producing both IL-4 and IFN-, as described most
recently.44 In fact, OX40/OX40L interaction is
bidirectional. On one hand, engagement of OX40 on activated T cells by
its ligand expressed on DC enhances their production of IL-4, whereas,
on the other hand, ligation of OX40L on DC upregulates their production
of IL-12.36
The mechanisms whereby OX40 upregulates IL-4 gene expression in naive T
cells remain to be determined, and the OX40 signal transduction pathway
is currently being investigated. Recent results showed that OX40
associates with TNF receptor-associated factor 2 (TRAF2) and TRAF3 and
activates NF- B as well as c-Jun, a component of AP-1.45
Because these two transcription factors are known to upregulate IL-6
gene promoter activity,46 we have examined whether OX40
might increase IL-4 indirectly by increasing IL-6 expression. Indeed,
naive T cells are capable of producing IL-6,47 and, as
mentioned earlier, IL-6 promotes Th2 development presumably by
augmenting IL-4 at priming.25 We found that OX40 ligation increased IL-6 mRNA expression in naive T cells by threefold (as shown
by quantitative competitive RT-PCR) from 0.55 × 103 to 1.8 × 103 attomoles;
however, the levels of IL-6 transcripts were one order of magnitude
lower than those of IL-4 and, most importantly, neutralizing anti-IL-6R MoAb did not alter the effects of OX40 ligation on cytokine
production (data not shown). Thus, the enhancing effect of OX40
ligation on IL-4 expression in naive T cells was not secondary to
increased IL-6 production. There is increasing evidence that, in
addition to being the most efficient APC to prime naive T cells, DC
also play a decisive role in determining the fate of the activated T
cells. As recently reviewed, DC may either initiate virogous T-cell-dependent immune response or induce T-cell
tolerance/anergy.48 In addition to providing B7-dependent
costimulation, which is critical for the development of Th2 response
and enhances Th1 cell development,8 DC also regulate Th
subset development by producing IL-1217,49 or by expressing
costimulatory molecules belonging to the TNF/TNF receptor families.
Some of these, such as OX40L, may promote the expression of Th2
cytokine, whereas others, such as 4-1BBL and CD40, favor Th1 cell
development either directly or indirectly by inducing IL-12
production.11,50
| |
FOOTNOTES |
Submitted April 22, 1998;
accepted June 21, 1998.
Address reprint requests to Guy Delespesse, MD, PhD, Université
de Montréal, Centre de recherche Louis-Charles Simard,
Laboratoire de recherche en Allergie (M4211-K), Hôpital
Notre-Dame, 1560 Sherbrooke St E, Montreal, Quebec H2L 4M1, Canada;
e-mail: delespeg{at}ere.umontreal.CA.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Seder R,
Paul WE:
Acquisition of lymphokine-producing phenotype by CD4+ T cells.
Annu Rev Immunol
12:635,
1994[Medline]
[Order article via Infotrieve]
2.
O'Garra A,
Murphy K:
Role of cytokines in development of Th1 and Th2 cells.
Chem Immunol
63:1,
1996[Medline]
[Order article via Infotrieve]
3.
Constant SL,
Bottomly K:
Induction of Th1 and Th2 CD4+ T cell responses: The alternative approaches.
Annu Rev Immunol
15:297,
1997[Medline]
[Order article via Infotrieve]
4.
Nakamura T,
Kamogawa Y,
Bottomly K,
Flavell RA:
Polarization of IL-4- and IFN--producing CD4+ T cells following activation of naive CD4+ T cells.
J Immunol
158:1085,
1997[Abstract]
5.
Constant S,
Pfeiffer C,
Woodard A,
Pasqualini T,
Bottomly K:
Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells.
J Exp Med
182:1591,
1995[Abstract/Free Full Text]
6.
Hosken NA,
Shibuya K,
Heath AW,
Murphy KM,
O'Garra A:
The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-a-transgenic model.
J Exp Med
182:1579,
1995[Abstract/Free Full Text]
7.
Pfeiffer C,
Stein J,
Southwood S,
Ketelaar H,
Sette A,
Bottomly K:
Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo.
J Exp Med
181:1569,
1995[Abstract/Free Full Text]
8.
Tao X,
Constant S,
Jorritsma P,
Bottomly K:
Strength of TCR signal determines the costimulatory requirements for Th1 and Th2 CD4+ T cell differentiation.
J Immunol
159:5956,
1997[Abstract]
9.
Gause WC,
Halvorson MJ,
Lu P,
Greenwald R,
Linsley P,
Urban JF,
Finkelman FD:
The function of costimulatory molecules and the development of IL-4-producing T cells.
Immunol Today
18:115,
1997[Medline]
[Order article via Infotrieve]
10.
Del Prete G,
De Carli M,
D'Elios MM,
Daniel KC,
Almerigogna F,
Alderson M,
Smith CA,
Thomas E,
Romagnani S:
CD30-mediated signaling promotes the development of human T helper type 2-like T cells.
J Exp Med
182:1655,
1995[Abstract/Free Full Text]
11.
Stüber E,
Strober W,
Neurath M:
Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.
J Exp Med
183:693,
1996[Abstract/Free Full Text]
12.
Lenschow DJ,
Herold KC,
Rhee L,
Patel B,
Koons A,
Qin HY,
Fuchs E,
Singh B,
Thompson CB,
Bluestone JA:
CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes.
Immunity
5:285,
1996[Medline]
[Order article via Infotrieve]
13.
Ramirez F,
Fowell DJ,
Puklavec M,
Simmonds S,
Manson D:
Glucocorticoids promote a Th2 cytokine response by CD4+ T cells in vitro.
J Immunol
156:2406,
1996[Abstract]
14.
Hsieh CS,
Macatonia SE,
O'Garra A,
Murphy KM:
T cell genetic background determines default T helper phenotype development in vitro.
J Exp Med
181:713,
1995[Abstract/Free Full Text]
15.
Seder RA,
Paul W,
Davis MM,
Fazekas de St Groth B:
The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice.
J Exp Med
176:1091,
1992[Abstract/Free Full Text]
16.
Hsieh CS,
Macatonia SE,
Tripp CS,
Wolf SF,
O'Garra A,
Murphy KM:
Development of Th1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages.
Science
260:547,
1993[Abstract/Free Full Text]
17.
Ma X,
D'Andrea A,
Kubin M,
Aste-Amezaga M,
Sartori A,
Monteiro J,
Showe L,
Wysocka M,
Trinchieri G:
Production of interleukin-12.
Res Immunol
146:432,
1996
18.
Macatonia SE,
Hosken NA,
Litton M,
Vieira P,
Hsieh CS,
Culpepper JA,
Wysocka M,
Trinchieri G,
Murphy KM,
O'Garra A:
Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells.
J Immunol
154:5071,
1995[Abstract]
19.
Ohshima Y,
Delespesse G:
T cell-derived IL-4 and dendritic cell-derived IL-12 regulate the lymphokine-producing phenotype of alloantigen-primed naive human CD4 T cells.
J Immunol
158:629,
1997[Abstract]
20.
Noben-Trauth N,
Shultz LD,
Brombacher F,
Urban JF Jr,
Gu H,
Paul WE:
An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice.
Proc Natl Acad Sci USA
94:10838,
1997[Abstract/Free Full Text]
21.
Yoshimoto T,
Paul WE:
CD4pos, NK1.1pos T cells promptly produce interleukin 4 in response to in vivo challenge with anti-CD3.
J Exp Med
179:1285,
1994[Abstract/Free Full Text]
22.
Ferrick DA,
Schrenzel MD,
Mulvania T,
Hsieh B,
Ferlin WG,
Lepper H:
Differential production of interferon- and interleukin-4 in response to Th1- and Th2-stimulating pathogens by T cells in vivo.
Nature
373:255,
1995[Medline]
[Order article via Infotrieve]
23.
Seder RA,
Paul WE,
Dvorak AM,
Sharkis SJ,
Kagey-Sobotka A,
Niv Y,
Finkelman FD,
Barbieri SA,
Galli SJ,
Plaut M:
Mouse splenic and bone marrow cell populations that express high-affinity FcE receptors and produce interleukin 4 are highly enriched in basophils.
Proc Natl Acad Sci USA
88:2835,
1991[Abstract/Free Full Text]
24.
Gollob KJ,
Coffman RL:
A minority subpopulation of CD4+ T cells directs the development of naive CD4+ T cells into IL-4-secreting cells.
J Immunol
152:5180,
1994[Abstract]
25.
Rincon M,
Anguita J,
Nakamura T,
Fikrig E,
Flavell RA:
Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.
J Exp Med
185:461,
1997[Abstract/Free Full Text]
26.
Croft M,
Swain SL:
Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL-4 to drive differentiation to secretion of T helper 2-type cytokines.
J Immunol
154:4269,
1995[Abstract]
27.
Yang LP,
Byun DG,
Demeure CE,
Vezzio N,
Delespesse G:
Default development of cloned human naive CD4 T cells into interleukin-4- and interleukin-5-producing effector cells.
Eur J Immunol
25:3517,
1995[Medline]
[Order article via Infotrieve]
28.
Demeure CE,
Yang LP,
Byun DG,
Ishihara I,
Vezzio N,
Delespesse G:
Human naive CD4 T cells produce interleukin-4 at priming and acquire a Th2 phenotype upon repetitive stimulations in neutral conditions.
Eur J Immunol
25:2722,
1995[Medline]
[Order article via Infotrieve]
29.
Yang LP,
Demeure CE,
Byun DG,
Vezzio N,
Delespesse G:
Maturation of neonatal human CD4 T cells: III. Role of B7 co-stimulation at priming.
Int Immunol
7:1987,
1995[Abstract/Free Full Text]
30.
Rulifson IC,
Sperling AI,
Fields PE,
Fitch FW,
Bluestone JA:
CD28 promotes the production of Th2 cytokines.
J Immunol
158:658,
1997[Abstract]
31.
Mallett S,
Fossum S,
Barclay AN:
Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes A molecule related to nerve growth factor receptor.
EMBO J
9:1063,
1990[Medline]
[Order article via Infotrieve]
32.
Imura A,
Hori T,
Imada K,
Ishikawa T,
Tanaka Y,
Maeda M,
Imamura S,
Uchiyama T:
The human OX40/gp34 system directly mediates adhesion of activated T cells to vascular endothelical cells.
J Exp Med
183:2185,
1996[Abstract/Free Full Text]
33.
Tozawa H,
Andoh S,
Takayama Y,
Tanaka Y,
Lee B,
Nakamura H,
Hayami M,
Hinuma Y:
Species-dependent antigenicity of the 34-kDa glycoprotein found on the membrane of various primate lymphocytes transformed by human T-cell leukemia virus type-I (HTLV-I) and simian T-cell leukemia virus (STLV-I).
Int J Cancer
41:231,
1988[Medline]
[Order article via Infotrieve]
34.
Baum PR,
Gayle RB III,
Ramsdell F,
Srinivasan S,
Sorensen RA,
Watson ML,
Seldin MF,
Baker E,
Sutherland GR,
Clifford KN,
Alderson MR,
Goodwin RG,
Fanslow WC:
Molecular characterization of murine and human OX40/OX40 ligand systems: Identification of a human OX40 ligand as the HTLV-1-regulated protein gp34.
EMBO J
13:3992,
1994[Medline]
[Order article via Infotrieve]
35.
Azuma M,
Cayabyab M,
Phillips JH,
Lanier L:
Requirements for CD28-dependent T cell-mediated cytotoxicity.
J Immunol
150:2091,
1993[Abstract]
36.
Ohshima Y,
Tanaka Y,
Tozawa H,
Takahashi Y,
Maliszewski C,
Delespesse G:
Expression and function of OX40 ligand on human dendritic cells.
J Immunol
159:3838,
1997[Abstract]
37.
Lederer JA,
Perez VL,
DesRoches L,
Kim SM,
Abbas AK,
Lichtman AH:
Cytokine transcriptional events during helper T cell subset differentiation.
J Exp Med
184:379,
1996
38.
Seder RA,
Gazzinelli R,
Sher A,
Paul WE:
Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon production and diminishes interleukin 4 inhibition of such priming.
Proc Natl Acad Sci USA
90:10188,
1993[Abstract/Free Full Text]
39.
Huang H,
Hu-Li J,
Chen H,
Ben-Sasson SZ,
Paul WE:
IL-4 and IL-13 production in differentiated T helper type 2 cells is not IL-4 dependent.
J Immunol
159:3731,
1997[Abstract]
40.
Davydov IV,
Krammer PH,
Li-Weber M:
Nuclear factor-IL-6 activates the human IL-4 promoter in T cells.
J Immunol
155:5273,
1995[Abstract]
41.
Li-Weber M,
Salgame P,
Hu C,
Davydov IV,
Krammer PH:
Differential interaction of nuclear factors with the PRE-I enhancer element of the human IL-4 promoter in different T cell subsets.
J Immunol
158:1194,
1997[Abstract]
42.
Godfrey WR,
Fagnoni FF,
Harara MA,
Buck D,
Engleman EG:
Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor.
J Exp Med
180:757,
1994[Abstract/Free Full Text]
43.
Stüber E,
Neurath M,
Calderhead D,
Fell HP,
Strober W:
Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells.
Immunity
2:507,
1995[Medline]
[Order article via Infotrieve]
44.
Miner K,
Croft M:
Generation, persistence, and modulation of Th0 effector cells: Role of autocrine IL-4 and IFN-.
J Immunol
160:5280,
1998[Abstract/Free Full Text]
45.
Arch RH,
Thompson CB:
4-1BB and OX40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB.
Mol Cell Biol
18:558,
1998[Abstract/Free Full Text]
46.
Akira S,
Kishimoto T:
NF-IL6 and NF-B in cytokine gene regulation.
Adv Immunol
65:1,
1997[Medline]
[Order article via Infotrieve]
47.
Van Kooten C,
Rensink I,
Pascual-Salcedo D,
van Oers R,
Aarden L:
Monokine production by human T cells; IL-1a production restricted memory T cells.
J Immunol
146:2654,
1991[Abstract]
48.
Banchereau J,
Steinman RM:
Dendritic cells and the control of immunity.
Nature
392:245,
1998[Medline]
[Order article via Infotrieve]
49.
Reis e Sousa C,
Hieny S,
Scharton-Kersten T,
Jankovic D,
Charest H,
Germain RN,
Sher A:
In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas.
J Exp Med
186:1819,
1997[Abstract/Free Full Text]
50.
Kim YJ,
Kim SH,
Mantel P,
Kwon BS:
Human 4-1BB regulates CD28 co-stimulation to promote Th1 cell responses.
Eur J Immunol
28:881,
1998[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
P. Krause, M. Bruckner, C. Uermosi, E. Singer, M. Groettrup, and D. F. Legler
Prostaglandin E2 enhances T-cell proliferation by inducing the costimulatory molecules OX40L, CD70, and 4-1BBL on dendritic cells
Blood,
March 12, 2009;
113(11):
2451 - 2460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kobayashi, K. Iijima, S. Radhakrishnan, V. Mehta, R. Vassallo, C. B. Lawrence, J.-C. Cyong, L. R. Pease, K. Oguchi, and H. Kita
Asthma-Related Environmental Fungus, Alternaria, Activates Dendritic Cells and Produces Potent Th2 Adjuvant Activity
J. Immunol.,
February 15, 2009;
182(4):
2502 - 2510.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-E. Lamhamedi-Cherradi, R. E. Martin, T. Ito, F. Kheradmand, D. B. Corry, Y.-J. Liu, and M. Moyle
Fungal Proteases Induce Th2 Polarization through Limited Dendritic Cell Maturation and Reduced Production of IL-12
J. Immunol.,
May 1, 2008;
180(9):
6000 - 6009.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Blazquez and M. C. Berin
Gastrointestinal Dendritic Cells Promote Th2 Skewing via OX40L
J. Immunol.,
April 1, 2008;
180(7):
4441 - 4450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. So, J. Song, K. Sugie, A. Altman, and M. Croft
Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment
PNAS,
March 7, 2006;
103(10):
3740 - 3745.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. R Blazar and W. J Murphy
Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD)
Phil Trans R Soc B,
September 29, 2005;
360(1461):
1747 - 1767.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Morita, T. Uchiyama, and T. Hori
Nitric Oxide Inhibits IFN-{alpha} Production of Human Plasmacytoid Dendritic Cells Partly via a Guanosine 3',5'-Cyclic Monophosphate-Dependent Pathway
J. Immunol.,
July 15, 2005;
175(2):
806 - 812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. M. C. Gaspal, M.-Y. Kim, F. M. McConnell, C. Raykundalia, V. Bekiaris, and P. J. L. Lane
Mice Deficient in OX40 and CD30 Signals Lack Memory Antibody Responses because of Deficient CD4 T Cell Memory
J. Immunol.,
April 1, 2005;
174(7):
3891 - 3896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-Y. Kim, V. Bekiaris, F. M. McConnell, F. M. C. Gaspal, C. Raykundalia, and P. J. L. Lane
OX40 Signals during Priming on Dendritic Cells Inhibit CD4 T Cell Proliferation: IL-4 Switches off OX40 Signals Enabling Rapid Proliferation of Th2 Effectors
J. Immunol.,
February 1, 2005;
174(3):
1433 - 1437.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-i. Kashiwakura, H. Yokoi, H. Saito, and Y. Okayama
T Cell Proliferation by Direct Cross-Talk between OX40 Ligand on Human Mast Cells and OX40 on Human T Cells: Comparison of Gene Expression Profiles between Human Tonsillar and Lung-Cultured Mast Cells
J. Immunol.,
October 15, 2004;
173(8):
5247 - 5257.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Zingoni, T. Sornasse, B. G. Cocks, Y. Tanaka, A. Santoni, and L. L. Lanier
Cross-Talk between Activated Human NK Cells and CD4+ T Cells via OX40-OX40 Ligand Interactions
J. Immunol.,
September 15, 2004;
173(6):
3716 - 3724.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Weinberg, D. E. Evans, C. Thalhofer, T. Shi, and R. A. Prell
The generation of T cell memory: a review describing the molecular and cellular events following OX40 (CD134) engagement
J. Leukoc. Biol.,
June 1, 2004;
75(6):
962 - 972.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ito, R. Amakawa, M. Inaba, T. Hori, M. Ota, K. Nakamura, M. Takebayashi, M. Miyaji, T. Yoshimura, K. Inaba, et al.
Plasmacytoid Dendritic Cells Regulate Th Cell Responses through OX40 Ligand and Type I IFNs
J. Immunol.,
April 1, 2004;
172(7):
4253 - 4259.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. So, S. Salek-Ardakani, H. Nakano, C. F. Ware, and M. Croft
TNF Receptor-Associated Factor 5 Limits the Induction of Th2 Immune Responses
J. Immunol.,
April 1, 2004;
172(7):
4292 - 4297.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Toennies, J. M. Green, and R. H. Arch
Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms
J. Leukoc. Biol.,
February 1, 2004;
75(2):
350 - 357.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Finney, A. N. Akbar, and A. D. G. Lawson
Activation of Resting Human Primary T Cells with Chimeric Receptors: Costimulation from CD28, Inducible Costimulator, CD134, and CD137 in Series with Signals from the TCR{zeta} Chain
J. Immunol.,
January 1, 2004;
172(1):
104 - 113.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Martin-Orozco, Z. Chen, L. Poirot, E. Hyatt, A. Chen, O. Kanagawa, A. Sharpe, D. Mathis, and C. Benoist
Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand
J. Immunol.,
December 15, 2003;
171(12):
6954 - 6960.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. R. Humphreys, L. Edwards, G. Walzl, A. J. Rae, G. Dougan, S. Hill, and T. Hussell
OX40 Ligation on Activated T Cells Enhances the Control of Cryptococcus neoformans and Reduces Pulmonary Eosinophilia
J. Immunol.,
June 15, 2003;
170(12):
6125 - 6132.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Straw, A. S. MacDonald, E. Y. Denkers, and E. J. Pearce
CD154 Plays a Central Role in Regulating Dendritic Cell Activation During Infections That Induce Th1 or Th2 Responses
J. Immunol.,
January 15, 2003;
170(2):
727 - 734.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Ekkens, Z. Liu, Q. Liu, J. Whitmire, S. Xiao, A. Foster, J. Pesce, J. VanNoy, A. H. Sharpe, J. F. Urban, et al.
The Role of OX40 Ligand Interactions in the Development of the Th2 Response to the Gastrointestinal Nematode Parasite Heligmosomoides polygyrus
J. Immunol.,
January 1, 2003;
170(1):
384 - 393.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Murata, M. Nose, L. C. Ndhlovu, T. Sato, K. Sugamura, and N. Ishii
Constitutive OX40/OX40 Ligand Interaction Induces Autoimmune-Like Diseases
J. Immunol.,
October 15, 2002;
169(8):
4628 - 4636.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. De Smedt, J. Smith, P. Baum, W. Fanslow, E. Butz, and C. Maliszewski
Ox40 Costimulation Enhances the Development of T Cell Responses Induced by Dendritic Cells In Vivo
J. Immunol.,
January 15, 2002;
168(2):
661 - 670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. C. Henderson, M. M. Kamdar, and A. Bamezai
Ly-6A.2 Expression Regulates Antigen-Specific CD4+ T Cell Proliferation and Cytokine Production
J. Immunol.,
January 1, 2002;
168(1):
118 - 126.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati
Role of CD47 in the Induction of Human Naive T Cell Anergy
J. Immunol.,
September 1, 2001;
167(5):
2459 - 2468.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. C. Ndhlovu, N. Ishii, K. Murata, T. Sato, and K. Sugamura
Critical Involvement of OX40 Ligand Signals in the T Cell Priming Events During Experimental Autoimmune Encephalomyelitis
J. Immunol.,
September 1, 2001;
167(5):
2991 - 2999.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Takahashi, Y. Tanaka, A. Yamashita, Y. Koyanagi, M. Nakamura, and N. Yamamoto
OX40 Stimulation by gp34/OX40 Ligand Enhances Productive Human Immunodeficiency Virus Type 1 Infection
J. Virol.,
August 1, 2001;
75(15):
6748 - 6757.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
E. Baba, Y. Takahashi, J. Lichtenfeld, R. Tanaka, A. Yoshida, K. Sugamura, N. Yamamoto, and Y. Tanaka
Functional CD4 T Cells after Intercellular Molecular Transfer of OX40 Ligand
J. Immunol.,
July 15, 2001;
167(2):
875 - 883.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Nakae, M. Asano, R. Horai, N. Sakaguchi, and Y. Iwakura
IL-1 Enhances T Cell-Dependent Antibody Production Through Induction of CD40 Ligand and OX40 on T Cells
J. Immunol.,
July 1, 2001;
167(1):
90 - 97.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Nohara, H. Akiba, A. Nakajima, A. Inoue, C.-S. Koh, H. Ohshima, H. Yagita, Y. Mizuno, and K. Okumura
Amelioration of Experimental Autoimmune Encephalomyelitis with Anti-OX40 Ligand Monoclonal Antibody: A Critical Role for OX40 Ligand in Migration, But Not Development, of Pathogenic T Cells
J. Immunol.,
February 1, 2001;
166(3):
2108 - 2115.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.-N. Avice, M. Rubio, M. Sergerie, G. Delespesse, and M. Sarfati
CD47 Ligation Selectively Inhibits the Development of Human Naive T Cells into Th1 Effectors
J. Immunol.,
October 15, 2000;
165(8):
4624 - 4631.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Kjærgaard, J. Tanaka, J. A. Kim, K. Rothchild, A. Weinberg, and S. Shu
Therapeutic Efficacy of OX-40 Receptor Antibody Depends on Tumor Immunogenicity and Anatomic Site of Tumor Growth
Cancer Res.,
October 1, 2000;
60(19):
5514 - 5521.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
I. Gramaglia, A. Jember, S. D. Pippig, A. D. Weinberg, N. Killeen, and M. Croft
The OX40 Costimulatory Receptor Determines the Development of CD4 Memory by Regulating Primary Clonal Expansion
J. Immunol.,
September 15, 2000;
165(6):
3043 - 3050.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Oh and M. C. Eichelberger
Polarization of Allogeneic T-Cell Responses by Influenza Virus-Infected Dendritic Cells
J. Virol.,
September 1, 2000;
74(17):
7738 - 7744.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Tanaka, C. E. Demeure, M. Rubio, G. Delespesse, and M. Sarfati
Human Monocyte-Derived Dendritic Cells Induce Naive T Cell Differentiation into T Helper Cell Type 2 (Th2) or Th1/Th2 Effectors: Role of Stimulator/Responder Ratio
J. Exp. Med.,
August 7, 2000;
192(3):
405 - 412.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. ATEN, A. ROOS, N. CLAESSEN, E. J. M. SCHILDER-TOL, I. J. M. TEN BERGE, and J. J. WEENING
Strong and Selective Glomerular Localization of CD134 Ligand and TNF Receptor-1 in Proliferative Lupus Nephritis
J. Am. Soc. Nephrol.,
August 1, 2000;
11(8):
1426 - 1438.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Morimoto, Y. Kanno, Y. Tanaka, Y. Tokano, H. Hashimoto, S. Jacquot, C. Morimoto, S. F. Schlossman, H. Yagita, K. Okumura, et al.
CD134L Engagement Enhances Human B Cell Ig Production: CD154/CD40, CD70/CD27, and CD134/CD134L Interactions Coordinately Regulate T Cell-Dependent B Cell Responses
J. Immunol.,
April 15, 2000;
164(8):
4097 - 4104.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. R. Rogers and M. Croft
CD28, Ox-40, LFA-1, and CD4 Modulation of Th1/Th2 Differentiation Is Directly Dependent on the Dose of Antigen
J. Immunol.,
March 15, 2000;
164(6):
2955 - 2963.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Weinberg, M.-M. Rivera, R. Prell, A. Morris, T. Ramstad, J. T. Vetto, W. J. Urba, G. Alvord, C. Bunce, and J. Shields
Engagement of the OX-40 Receptor In Vivo Enhances Antitumor Immunity
J. Immunol.,
February 15, 2000;
164(4):
2160 - 2169.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Akiba, Y. Miyahira, M. Atsuta, K. Takeda, C. Nohara, T. Futagawa, H. Matsuda, T. Aoki, H. Yagita, and K. Okumura
Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis
J. Exp. Med.,
January 17, 2000;
191(2):
375 - 380.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Murata, N. Ishii, H. Takano, S. Miura, L. C. Ndhlovu, M. Nose, T. Noda, and K. Sugamura
Impairment of Antigen-Presenting Cell Function in Mice Lacking Expression of Ox40 Ligand
J. Exp. Med.,
January 17, 2000;
191(2):
365 - 374.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Lane
Role of Ox40 Signals in Coordinating Cd4 T Cell Selection, Migration, and Cytokine Differentiation in T Helper (Th)1 and Th2 Cells
J. Exp. Med.,
January 17, 2000;
191(2):
201 - 206.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. D. Pippig, C. Pena-Rossi, J. Long, W. R. Godfrey, D. J. Fowell, S. L. Reiner, M. L. Birkeland, R. M. Locksley, A. N. Barclay, and N. Killeen
Robust B Cell Immunity but Impaired T Cell Proliferation in the Absence of CD134 (OX40)
J. Immunol.,
December 15, 1999;
163(12):
6520 - 6529.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. S.K. Walker, A. Gulbranson-Judge, S. Flynn, T. Brocker, C. Raykundalia, M. Goodall, R. Forster, M. Lipp, and P. Lane
Compromised Ox40 Function in Cd28-Deficient Mice Is Linked with Failure to Develop Cxc Chemokine Receptor 5-Positive Cd4 Cells and Germinal Centers
J. Exp. Med.,
October 18, 1999;
190(8):
1115 - 1122.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Akiba, H. Oshima, K. Takeda, M. Atsuta, H. Nakano, A. Nakajima, C. Nohara, H. Yagita, and K. Okumura
CD28-Independent Costimulation of T Cells by OX40 Ligand and CD70 on Activated B Cells
J. Immunol.,
June 15, 1999;
162(12):
7058 - 7066.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Jones, C. D.M. Fletcher, K. Pulford, A. Shahsafaei, and D. M. Dorfman
The T-Cell Activation Markers CD30 and OX40/CD134 Are Expressed in Nonoverlapping Subsets of Peripheral T-Cell Lymphoma
Blood,
May 15, 1999;
93(10):
3487 - 3493.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Ohshima, L-P. Yang, M-N. Avice, M. Kurimoto, T. Nakajima, M. Sergerie, C. E. Demeure, M. Sarfati, and G. Delespesse
Naive Human CD4+ T Cells Are a Major Source of Lymphotoxin {alpha}
J. Immunol.,
April 1, 1999;
162(7):
3790 - 3794.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract