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*
Department of Microbiology, Oregon State University, Corvallis, OR 97331; and
Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213
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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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The danger theory proposed by Matzinger (11) addresses
this very complex and controversial issue of immune activation and
memory T cell generation . Her hypothesis suggests that a stimulus that
facilitates some type of biologic "damage" is critical for the
induction of a long-lasting immune response. Furthermore, it is thought
that the "danger signal" can promote autoimmune disease under the
appropriate conditions, such as mice immunized with adjuvants and
myelin components in experimental autoimmune encephalomyelitis
(EAE)4
(12). Elements of the danger signal include factors that
promote destruction of tissue and/or necrotic death of cells
(13). These are not the only situations that lead to
damage, but they represent examples that can be found in nature. For
example, it has been known for some time that bacterial LPS is very
capable of promoting severe inflammation, leading to tissue destruction
(14, 15). LPS can activate macrophages to produce large
quantities of proinflammatory cytokines (TNF-
, IL-1ß, and IL-6)
that attract and stimulate other inflammatory cell types including T
cells (16, 17, 18).
LPS can interfere with peripheral tolerance (19), and
recent data show that Ag-induced peripheral T cell deletion can be
tempered in the presence of LPS stimulation (20). The
rescuing effect of LPS occurs independently of CD28 ligation, but is
profoundly dependent on TNF- production. Thus, it is likely that
stimuli similar to LPS are danger signals and may be responsible for
interfering with tolerance induction. Nevertheless, optimal T cell
immunity in vivo is multifactoral and loss of one signal or receptor
function may be compensated for by alternate ones.
Other endogenous signals have been reported to influence peripheral deletion, especially those involving members of the TNF receptor family such as FAS, CD40, and 4-1BB (21). OX40 is a member of the TNF receptor family that is expressed primarily on activated CD4+ T cells, which when engaged induces a potent costimulatory signal (22, 23). OX40+ T cells have been found preferentially within the inflammatory compartments of patients and rodents with autoimmune disease and cancer (24, 25). There is little or no expression of OX40 on T cells in the periphery. Thus, it is possible that OX40 is exclusively expressed on Ag-stimulated T cells.
At the effector stage auto-Ag-specific T cells recognize Ag and produce large amounts of cytokines, leading to inflammation within a target organ (26). It has been hypothesized that a low percentage of the effector T cells that recognize Ag and produce cytokines will subsequently differentiate into memory T cells. Because, at this stage, the effector T cells become quite susceptible to activation-induced cell death (AICD) (27). Effector T cells are quite sensitive to OX40-specific costimulation as compared with naive T cells, although the combination of B7 and OX40L signals delivered to naive T cells was found to be synergistic (28). We hypothesized that a signal delivered through OX40 might inhibit AICD during Ag-specific stimulation of effector T cells, thereby increasing the number of effector T cells that survive and become memory cells. To test this hypothesis, we explored the expression of OX40 and the effects of OX40 engagement on effector T cells in a superantigen (SAg) model system, which is known to result in the deletion of SAg-specific effector T cells. The SAg staphylococcal enterotoxin A (SEA) system allows for convenient detection of SAg-specific T cells with an anti-Vß3 TCR Ab. We also examined effector T cell survival in an adoptive T cell transfer model in which peptide-induced deletion has been observed (29).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B10.BR and BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME) or from the National Cancer Institute (Frederick, MD). DO11.10 transgenic mice were generously provided by Drs. Nancy Kerkvliet and Marc Jenkins (Oregon State University, Corvallis, OR and University of Minnesota, Minneapolis, MN, respectively) (30). All mice were maintained at Oregon State University under specific pathogen-free conditions in accordance with federal guidelines.
Reagents, Abs, and flow cytometry
SEA and LPS were purchased from Sigma (St. Louis, MO) and administered to mice as i.p. injections. Chicken OVA (Sigma) was solubilized in balanced salt solution and administered i.p. without adjuvant.
T cells were purified by nylon wool fractionation as described previously (31). Flow cytometry staining was conducted as described previously (8). Briefly, cells were blocked for nonspecific binding and incubated with biotinylated anti-OX40 (33) for 30 min on ice. The cells were washed twice and incubated with anti-CD4-PE (PharMingen, San Diego, CA), anti-TCR Vß3-FITC (KJ25-607.7; see Ref. 32), and RED 613-conjugated streptavidin (Life Technologies, Grand Island, NY). After several washes, the cells were analyzed on an Epics XL flow cytometer (Coulter Electronics, Miami, FL).
Experimental design
The experiment in Fig. 2
was set up as follows: One group was
noninjected (day 0). The remaining groups received SEA and rat IgG
(open circles); SEA and anti-OX40 (filled circles); SEA, LPS, and
rat IgG (open squares); and SEA, LPS, and anti-OX40 (filled
squares). On day 0, mice were given 0.15 µg of SEA and immediately
afterward, an injection of 25 µg of anti-OX40 or rat IgG. On day
+1, mice were given a second injection of anti-OX40 or rat IgG,
followed immediately by 30 µg of LPS. On day +2, mice were given a
final injection of anti-OX40 or rat IgG. The percent and number of
SEA-specific T cells were determined.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Expression of OX40 by Vß3 T cells was examined after mice were
stimulated with SEA. Mice were injected with LPS alone, SEA alone, or
SEA and LPS, and T cells were analyzed at 12, 24, 48, and 72 h
later. SEA induced OX40 expression on the SEA-specific CD4 Vß3 T
cells which peaked at 12 h and declined at 24 and 48 h (Fig. 1 shows 48-h time point). Only a small
percentage of SEA-specific CD8 T cells expressed OX40, and
SEA-unreactive T cells (TCR Vß14) from the same mice showed no
increase (data not shown). We also tested whether or not a danger
signal alone would be capable of enhancing OX40 surface expression on T
cells. Mice were injected with a high dose of LPS and T cells were
analyzed as described above. In the absence of SAg stimulation, OX40
expression was not up-regulated (data not shown and Fig. 1). These data
show that TCR stimulation is sufficient to induce OX40 surface
expression on SAg-stimulated CD4 T cells in vivo.
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). The
levels of OX40 on the SEA-specific T cells was significantly higher at
48 h than with either reagent alone (Fig. 1) and had prolonged
expression compared with SEA (data not shown). As before, staining of
Vß14 T cells showed no evidence of up-regulation of OX40. Thus, we
conclude that a danger signal and TCR stimulation synergized to enhance
OX40 expression on SAg-specific CD4 T cells in vivo. Evaluating the effects of OX40 ligation on SAg-stimulated T cells during clonal expansion
The SAg model in mice has been used to study central and peripheral T cell tolerance. Early after SAg injection into mice, SAg-activated peripheral CD4 and CD8 T cells expand 2- to 5-fold during a 48-h period (34). This expansion is followed by profound deletion of those same T cells. These measurements are possible because unactivated (Vß14) and activated (Vß3) T cells can be detected over time by analyzing the respective cell populations by flow cytometry.
The hypothesis that ligation of OX40 on SEA-activated T cells will
influence peripheral deletion of T cells was tested. Mice were not
injected or injected with SEA with a control IgG (SEA); SEA with LPS
and control IgG (SEA/LPS); SEA with anti-OX40 (SEA/OX40); or SEA
with LPS and anti-OX40 (SEA/LPS/OX40). On days 2, 5, 7, and 12
after SEA injection, the percent and absolute number of LN and spleen
CD4 and CD8 T cells were examined for TCR Vß3 expression (Fig. 2; LN data not shown). As expected, there
was an initial expansion of Vß3+ spleen T cells
in the SEA-injected mice by day 2. However, by day 5, the number of
Vß3 CD4 cells was lower than in noninjected mice, suggesting that
deletion of T cells had occurred. The Vß3 T cells remained low in
number for the duration of the experiment. Vß3 T cells from mice
injected with SEA/LPS or SEA/OX40 had expanded on day 2 to a greater
level in the LN (data not shown) than that observed in mice with SEA
alone. Nevertheless, for splenic T cells, both treatments resulted in
some degree of T cell rescue compared with mice injected with SEA
alone, but there was still profound clonal deletion in all three groups
(Fig. 2). For example, by day 12, 1.12 x
106 and 1.53 x 106
Vß3 splenic T cells were observed in SEA/OX40- and SEA/LPS-treated
mice, respectively, compared with 0.19 x
106 splenic Vß3 T cells in the mice receiving
SEA alone.
SAg plus the combination of danger and OX40 engagement, resulted in
enhanced expansion and a marked inhibition of peripheral T cell
deletion. Instead of the expected decrease in the splenic Vß3 T cells
on day 5, we observed a 12-fold increase in the SEA/OX40/LPS-treated
mice compared with SEA. This was true for both percentage and absolute
number of Vß3 T cells (Fig. 2, A and B,
respectively). The Vß3 population continued to increase on day 7
(28.5-fold; Fig. 2B) with an apparent plateau between days 7
and 12 (Fig. 2B). There was also an increase in the CD8
Vß3 T cell population but not to the same degree as the CD4 T cells,
and no significant changes were observed in a SEA-nonspecific Vß14 T
cell population (data not shown). Collectively, these data show that in
vivo engagement of OX40 in the presence of a danger signal block
SAg-induced peripheral T cell deletion while promoting effector T cell
expansion. There also appeared to be rescue of CD8 T cells even though
their level of OX40 expression was less compared with the CD4 T cells
(Fig. 3). There was a peak of expansion
on day 2, both in terms of percentages and absolute numbers, but
thereafter the response waned. Nevertheless, there was significant CD8
survival when animals were treated with all three signals, which was
somewhat perplexing since there was little OX40 expression on the
SEA-activated CD8 T cells (data not shown).
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To characterize the effects of OX40 engagement during presentation
of peptide Ag, we examined the well-characterized model D011.10 TCR
transgenics for tracking peptide/MHC class II-activated CD4 T cells
(29). T cells from the D011.10 TCR transgenic mice
recognize OVA in the context of Iad and the
OVA-specific T cells can be detected with the anti-idiotypic Ab
KJ1–26. DO11.10 TCR transgenic T cells were transferred into five
groups of mice and thereafter treated with OVA, OVA with anti-OX40
(OVA/OX40), ova with LPS (OVA/LPS), or all three (OVA/OX40/LPS) and
compared with noninjected mice (no OVA). Seven days after Ag exposure,
T cells were analyzed for the absolute number of DO11.10-bearing cells
in the LN and spleen (Table I). Injection
of OVA alone did not increase the number of Ag-specific T cells at day
7 postimmunization. Based on previous experiments, we believe that
inspection of earlier time points would have shown an increase in the
DO11.10 T cell population (data not shown). Coinjection of LPS and OVA
did rescue some of the DO11.10 T cells from deletion compared with the
OVA group, but this effect was minimal compared with the number of
Ag-specific T cells on day 7 in the OVA/OX40 group. There was a
17.7-fold increase in the number of splenic
KJ1-26+ T cells in the OVA/OX40 mice compared
with OVA alone. Furthermore, there was an even greater increase of
DO11.10 T cells in the OVA/LPS/OX40 mice (33.8-fold over the OVA-alone
mice). These observations held true for both splenic and LN T cells,
but the enhancement was greater for the spleen population. Although the
data show that OX40 had a significant effect on T cell survival, there
continues to be additional benefit when LPS and OX40 are combined
during a peptide Ag-specific T cell response.
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and tested for DO11.10-bearing T cells 62 days
after exposure to Ag (Table II). Our data
show that Ag stimulation followed by OX40 engagement enhanced growth
and long-term survival of the DO11.10 T cells. The addition of LPS
further enhanced this effect. A 12.3-fold increase was observed with Ag
and OX40 engagement as compared with Ag alone, and a striking 59.8-fold
increase in long-term surviving T cells was observed when both
anti-OX40 and LPS were used to stimulate the OVA-specific T cells.
Phenotypic analysis of the OVA-specific T cells
(KJ1-26+) in the OVA/LPS/OX40 mice revealed that
they were small, resting memory cells as assessed by low forward
scatter and up-regulation of CD44 expression (Fig. 4). In contrast, the
KJ1-26- cells had a broad range of CD44
expression (4-fold lower in mean channel fluorescence) than that
observed for the OVA-specific T cells. Therefore, we conclude that the
optimal development of long-lived memory T cells required three signals
during effector T cell stimulation: Ag, OX40 costimulation, and danger
(LPS).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data clearly show that two signals are better than one and that
three signals are better than two. Nevertheless, what is key is that
they are three different signals. Of course Ag is signal 1, signal 2 is
a growth signal such as that observed with OX40, and signal 3 is a
danger signal, which in this study is LPS. Although signals 2 and 3 are
somewhat interchangeable, they seem to synergize when activated
concomitantly during an antigenic response. For example, LPS can
enhance growth at high doses (37), and OX40 can certainly
increase survival without LPS (see Table II); but when combined the
greatest amount of long-term survival is observed. One important
difference between costimulatory or growth signals and danger signals
is that LPS alone can induce shock at very low doses, whereas high
doses of anti-OX40 alone does not (our unpublished observations).
These data suggest that CD4 T cell memory development can be obtained
by more than one set of parameters.
We show that optimal T cell memory acquisition requires three signals
at refined doses, but nevertheless suboptimal survival was obtained
without LPS or without OX40 stimulation (Fig. 3 and Table II).
Additionally, it is clear that LPS can synergize with CD40 stimulation
to generate profound SAg-specific T cell survival; however, each signal
individually with SAg is far less effective (our unpublished data).
This latter model is totally dependent on CD28/B7 ligation for growth
(8). Interestingly, two costimulatory signals through OX40
and CD40 (B7/CD28) were not sufficient to block peripheral deletion of
SAg-stimulated T cells (data not shown), which strongly suggests that
two costimulatory signals are not sufficient to substitute for one
survival signal.
It is clear from our data that survival was not limited to CD4 T cells.
For example we show that CD8 T cells can also be rescued from deletion
even though OX40 expression was far less on activated CD8 T cells than
that observed on activated CD4 T cells (Fig. 3). One possibility is
that OX40 ligation and Ag stimulation prime CD4 T cells to secrete
large quantities of cytokines which activate bystander CD8 T cells to
survive. Alternatively, it is possible that the low levels of OX40 on
the surfaces of CD8 T cells were in enough quantity to be ligated and
thereby promote rescue. Nevertheless, this is a very complex problem
that is currently being investigated.
A role for cytokines in this system is likely to be paramount to the
rescuing process. It was previously shown that LPS could rescue T cells
from SAg-induced deletion through the action of TNF- and a minor
role for IFN-
(20). It is still unclear how these
cytokines promote long-term survival, especially in light of the fact
that TNF- has also been implicated in driving T cell death
(38). This also seems to be the case for CD95 which has
been shown to be a very important death signal in a variety of systems
(39), but has also been shown to promote growth in others
(40). Therefore, it is likely that the cytokine
environment influences activated T cells to respond with a survival or
death response depending on the variety and balance of cytokines. This
has been clearly observed in other systems including Th1 and Th2
skewing.
Proinflammatory cytokines are not the only cytokines that promote T
cell survival. Several ligands specific to members of the common
chain family of receptors have also been implicated in mediating T cell
survival (41, 42). Of these, IL-4, which is clearly not
proinflammatory, can block Ag-induced death and spontaneous death of
nonactivated "fresh" T cells. Oddly enough TNF- does not seem to
block death in vitro of these same cell types (data not shown). These
data argue that the mechanism of survival induction is different
between TNF- and IL-4. IL-4-induced T cell survival is definitely
dependent on the common chain for rescue (data not shown), whereas
it is not clear whether TNF- rescues Ag-activated T cells directly.
For example, under the appropriate circumstances, activated T cells may
bind TNF-, which in turn may inhibit an activated death program.
Alternatively, it is possible that TNF- induces other factors to
block various death pathway(s).
Of particular interest in this regard is IL-6. IL-6 is involved in
acute phase responses, B cell stimulation, T cell activation,
hematopoiesis, and many other functions (43). In
particular, however, IL-6 has been shown to block spontaneous death on
resting T cells (44). This result is consistent with the
fact that IL-6-/- mice have a diminished number of peripheral T cells
(45). Therefore, it is possible that a cytokine like IL-6,
which is induced by TNF-, may mediate survival. Preliminary studies
have shown that IL-6 does not block activation-induced death in vitro
(data not shown), and others have shown that IL-6 administration in
vivo only minimally affects T cell rescue from deletion
(46). Once again, it may be that a mixture of cytokines in
the right proportions can influence memory acquisition. Therefore,
individually they are ineffective but in combination are substantially
effective.
Other cytokines induced by TNF- are also possibilities and include
IL-1ß and IL-12. By itself, IL-1ß has been shown to block deletion
(47), but it is not known whether this cytokine directly
inhibits death by binding to T cells or inhibits deletion by an
indirect method. Previous reports have shown that IL-12 can stimulate
Th1 differentiation during a tolerogenic response but does not block
deletion by itself (46, 48). Furthermore, it has been
firmly established that OX40 stimulation potentiates cytokine
production on effector T cells (27). Specifically, it has
been shown that Th1 and Th2 cytokine production can be enhanced by
cross-linking OX40 on Ag-stimulated T cells (23, 49).
Finally, it is clear that resolving the survival mechanism in vivo will
certainly involve cytokines and chemokines, surface receptors, non-T
cells, and possibly factors from the endocrine system.
These data show that peptide-specific T cells are very responsive to OX40 ligation in combination with a danger signal, suggesting that this treatment may significantly improve the efficacy of vaccines designed to activate T cells. A major limiting factor in vaccine development has largely been the identification of a practical adjuvant that is efficient. Because most adjuvants would be too toxic for human use, due to massive inflammatory reactions, it is likely that a more refined targeted treatment will be necessary. The OX40 protein is an excellent target because it is expressed only on recently activated Ag-specific cells, which are primarily found at the site of inflammation (24, 50). Perhaps the danger mechanism described in this study (i.e., up-regulation of OX40 expression on Ag-activated T cells by LPS) helps explain the positive effects adjuvants exert on activated T cells and may lead to more defined approaches for vaccination protocols.
Collectively, these data suggest that costimulation in the absence of
danger can lead to Ag-dependent clonal expansion, but does not elicit
the same magnitude of long-term T cell survival when compared with the
same response elicited in the presence of a danger signal. These data
may help explain why B7 transgenic mice do not develop autoimmune
diseases spontaneously, and why the same mice crossed with TNF-
transgenic mice develop autoimmune disease (9).
Additionally, it is widely accepted that TNF- is an important
effector molecule in the development of EAE (51).
Recently, it has also been shown that OX40 and OX40-ligand expression
is found on T cells and activated macrophages, respectively, within the
inflamed tissue of rodents with clinical signs of EAE (our unpublished
data). Thus, it is possible that inflammatory cytokines like TNF-
promote the appropriate activation of autoreactive memory T cells via
OX40 up-regulation.
Our data support a new model of T cell activation that incorporates three definable signals. In this study, we suggest that one set of optimal conditions for long-term survival of Ag-specific T cells requires three signals, which include an antigenic stimulus, OX40 stimulation, and activation by LPS.
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Acknowledgments |
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Footnotes |
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2 J.M. and A.W. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Anthony T. Vella, Department of Microbiology, 220 Nash Hall, Oregon State University, Corvallis, OR 97331. E-mail address:
4 Abbreviations used in this paper: EAE, experimental autoimune encephalomyelitis; SAg, superantigen or peptide antigen; SEA, staphylococcal enterotoxin A; LN, lymph node.
Received for publication August 5, 1999. Accepted for publication October 14, 1999.
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References |
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 Y.-J. Kim, T. M. Stringfield, Y. Chen, and H. E. Broxmeyer Modulation of cord blood CD8+ T-cell effector differentiation by TGF-{beta}1 and 4-1BB costimulation Blood, January 1, 2005; 105(1): 274 - 281. [Abstract] [Full Text] [PDF]
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W. Dawicki, E. M. Bertram, A. H. Sharpe, and T. H. Watts 4-1BB and OX40 Act Independently to Facilitate Robust CD8 and CD4 Recall Responses J. Immunol., November 15, 2004; 173(10): 5944 - 5951. [Abstract] [Full Text] [PDF]
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S.-J. Lee, L. Myers, G. Muralimohan, J. Dai, Y. Qiao, Z. Li, R. S. Mittler, and A. T. Vella 4-1BB and OX40 Dual Costimulation Synergistically Stimulate Primary Specific CD8 T Cells for Robust Effector Function J. Immunol., September 1, 2004; 173(5): 3002 - 3012. [Abstract] [Full Text] [PDF]
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M. Wojtasiak, C. M. Jones, L. C. Sullivan, A. C. Winterhalter, F. R. Carbone, and A. G. Brooks Persistent expression of CD94/NKG2 receptors by virus-specific CD8 T cells is initiated by TCR-mediated signals Int. Immunol., September 1, 2004; 16(9): 1333 - 1341. [Abstract] [Full Text] [PDF]
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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]
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S. K. Lathrop, C. A. Huddleston, P. A. Dullforce, M. J. Montfort, A. D. Weinberg, and D. C. Parker A Signal through OX40 (CD134) Allows Anergic, Autoreactive T Cells to Acquire Effector Cell Functions J. Immunol., June 1, 2004; 172(11): 6735 - 6743. [Abstract] [Full Text] [PDF]
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 M. Y. Mapara and M. Sykes Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance J. Clin. Oncol., March 15, 2004; 22(6): 1136 - 1151. [Abstract] [Full Text] [PDF]
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I. Takeda, S. Ine, N. Killeen, L. C. Ndhlovu, K. Murata, S. Satomi, K. Sugamura, and N. Ishii Distinct Roles for the OX40-OX40 Ligand Interaction in Regulatory and Nonregulatory T Cells J. Immunol., March 15, 2004; 172(6): 3580 - 3589. [Abstract] [Full Text] [PDF]
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E. M. Bertram, W. Dawicki, B. Sedgmen, J. L. Bramson, D. H. Lynch, and T. H. Watts A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo J. Immunol., January 15, 2004; 172(2): 981 - 988. [Abstract] [Full Text] [PDF]
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 A. Ladanyi, B. Somlai, K. Gilde, Z. Fejos, I. Gaudi, and J. Timar T-Cell Activation Marker Expression on Tumor-Infiltrating Lymphocytes As Prognostic Factor in Cutaneous Malignant Melanoma Clin. Cancer Res., January 15, 2004; 10(2): 521 - 530. [Abstract] [Full Text] [PDF]
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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]
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J. R. Maxwell, R. J. Rossi, S. J. McSorley, and A. T. Vella T Cell Clonal Conditioning: A Phase Occurring Early after Antigen Presentation but before Clonal Expansion Is Impacted by Toll-Like Receptor Stimulation J. Immunol., January 1, 2004; 172(1): 248 - 259. [Abstract] [Full Text] [PDF]
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R. A. Prell, D. E. Evans, C. Thalhofer, T. Shi, C. Funatake, and A. D. Weinberg OX40-Mediated Memory T Cell Generation Is TNF Receptor-Associated Factor 2 Dependent J. Immunol., December 1, 2003; 171(11): 5997 - 6005. [Abstract] [Full Text] [PDF]
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 I. R. Humphreys, G. Walzl, L. Edwards, A. Rae, S. Hill, and T. Hussell A Critical Role for OX40 in T Cell-mediated Immunopathology during Lung Viral Infection J. Exp. Med., October 20, 2003; 198(8): 1237 - 1242. [Abstract] [Full Text] [PDF]
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S. Salek-Ardakani, J. Song, B. S. Halteman, A. G.-H. Jember, H. Akiba, H. Yagita, and M. Croft OX40 (CD134) Controls Memory T Helper 2 Cells that Drive Lung Inflammation J. Exp. Med., July 21, 2003; 198(2): 315 - 324. [Abstract] [Full Text] [PDF]
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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]
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 L. Myers, C. Takahashi, R. S. Mittler, R. J. Rossi, and A. T. Vella Effector CD8 T cells possess suppressor function after 4-1BB and Toll-like receptor triggering PNAS, April 29, 2003; 100(9): 5348 - 5353. [Abstract] [Full Text] [PDF]
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G. Gri, E. Gallo, E. Di Carlo, P. Musiani, and M. P. Colombo OX40 Ligand-Transduced Tumor Cell Vaccine Synergizes with GM-CSF and Requires CD40-Apc Signaling to Boost the Host T Cell Antitumor Response J. Immunol., January 1, 2003; 170(1): 99 - 106. [Abstract] [Full Text] [PDF]
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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]
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P. Bansal-Pakala and M. Croft Defective T Cell Priming Associated with Aging Can Be Rescued by Signaling Through 4-1BB (CD137) J. Immunol., November 1, 2002; 169(9): 5005 - 5009. [Abstract] [Full Text] [PDF]
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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]
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P. P. Banerjee, D. S. Vinay, A. Mathew, M. Raje, V. Parekh, D. V. R. Prasad, A. Kumar, D. Mitra, and G. C. Mishra Evidence That Glycoprotein 96 (B2), a Stress Protein, Functions as a Th2-Specific Costimulatory Molecule J. Immunol., October 1, 2002; 169(7): 3507 - 3518. [Abstract] [Full Text] [PDF]
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J. L. Cannons, E. M. Bertram, and T. H. Watts Cutting Edge: Profound Defect in T Cell Responses in TNF Receptor-Associated Factor 2 Dominant Negative Mice J. Immunol., September 15, 2002; 169(6): 2828 - 2831. [Abstract] [Full Text] [PDF]
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J. R. Maxwell, C. Ruby, N. I. Kerkvliet, and A. T. Vella Contrasting the Roles of Costimulation and the Natural Adjuvant Lipopolysaccharide During the Induction of T Cell Immunity J. Immunol., May 1, 2002; 168(9): 4372 - 4381. [Abstract] [Full Text] [PDF]
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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]
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D. E. Evans, R. A. Prell, C. J. Thalhofer, A. A. Hurwitz, and A. D. Weinberg Engagement of OX40 Enhances Antigen-Specific CD4+ T Cell Mobilization/Memory Development and Humoral Immunity: Comparison of {alpha}OX-40 with {alpha}CTLA-4 J. Immunol., December 15, 2001; 167(12): 6804 - 6811. [Abstract] [Full Text] [PDF]
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J. Kjaergaard, L. Peng, P. A. Cohen, J. A. Drazba, A. D. Weinberg, and S. Shu Augmentation Versus Inhibition: Effects of Conjunctional OX-40 Receptor Monoclonal Antibody and IL-2 Treatment on Adoptive Immunotherapy of Advanced Tumor J. Immunol., December 1, 2001; 167(11): 6669 - 6677. [Abstract] [Full Text] [PDF]
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J. L. Cannons, P. Lau, B. Ghumman, M. A. DeBenedette, H. Yagita, K. Okumura, and T. H. Watts 4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy J. Immunol., August 1, 2001; 167(3): 1313 - 1324. [Abstract] [Full Text] [PDF]
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V. Malmstrom, D. Shipton, B. Singh, A. Al-Shamkhani, M. J. Puklavec, A. N. Barclay, and F. Powrie CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice J. Immunol., June 1, 2001; 166(11): 6972 - 6981. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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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]
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); SEA and anti-OX40 (•);
SEA, LPS and rat IgG (
); and SEA, LPS, and anti-OX40 (
). On
days 2, 5, 7, and 12 after SEA injection, the spleen and LNs (data not
shown) were removed from three mice per group. Purified T cells were
counted, stained with Abs against CD4 and Vß3, and analyzed by flow
cytometry. Each point represents the mean percentages
(A) and numbers (B) ± SEM from at
least three mice from one representative experiment of four
performed.
