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*
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; 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 factors that regulate T cell expansion are just beginning to be elucidated. It is generally accepted that two signals are required for T cell activation, one provided by TCR interaction with peptide/MHC complexes, and another by coreceptor interaction with APC accessory molecules (3, 4). Ligation of CD28 by B7-1 and/or B7-2 has been proposed to be the predominant costimulatory interaction(s), and the majority of studies have focused on these molecules (5, 6, 7, 8, 9, 10). However, recent data suggest that this simple two-signal model may be an oversimplification and should incorporate multiple signals from various sources, all of which synergize with those through the TCR and perhaps with those through CD28 (see Ref. 11 for review). Thus, in isolated systems, other ligand pairs have been shown to costimulate CD4 responses when combined with TCR signals. These are generally molecules in the Ig superfamily, or TNF/TNFR families, and include the interactions of ICAM (-1,-2) with LFA-1, CD40 with CD40L,3 VCAM-1 (CD106) with VLA-4 (CD49d/CD29), HSA (CD24) with an unknown receptor, and CD70 with CD27 (12, 13, 14, 15, 16, 17).
Because of the plethora of accessory molecules that have been implicated in costimulation, it is unclear which interactions are important and whether only some, or all, are essential for generating a T cell response. It is possible that many accessory molecules play identical roles and are therefore redundant much of the time. An alternative possibility, which is more attractive, is that accessory molecules act in concert with one another, and it is the combined action of several interactions that leads to the most effective response. Thus, multiple interactions may be required to initiate the T cell response, and/or other interactions may be needed at different times after the initial events to allow the response to progress efficiently. In this scenario, accessory molecule-coreceptor ligation would occur either concomitantly, or sequentially in a stepwise fashion, and the type of interaction would be dictated by the expression of the molecules on both the T cell and APC surface, and the nature of the APC encountered. In vitro studies that have assessed two molecules simultaneously suggest that an efficient T cell response does require the combined use of several of these ligand-receptor pairs, and synergy has been described between CD40, ICAM-1, and CD70 when combined separately with B7 (12, 15, 18). In vivo data using CD40- and CD40L-deficient mice have shown that the interaction between these molecules is essential for a productive T cell response (19, 20, 21), and similarly, blockade of ICAM/LFA-1 interactions results in deficient immune responses (22, 23).
While many of the above interactions may be important for initiation of T cell responses, with the coreceptors either being constitutively expressed on T cells or up-regulated very shortly after activation, it is likely that other interactions may be necessary for prolonging or propagating the response. In this regard, two members of the TNFR family, namely 4-1BB and Ox-40, have recently gained prominence as costimulatory receptors (24, 25, 26, 27, 28, 29) and are potential candidates for delivering signals that could function during the later stages of T cell responses. Studies with mitogen stimulation have shown that both receptors are induced on T cells several days after initial activation (26, 30), and that their ligands may only be present on previously activated APCs (31, 32). While 4-1BB is expressed on both CD4 and CD8 cells, and may be more important for CD8 responses (33, 34), Ox-40 appears to be predominantly expressed on CD4 cells (35, 36). Ox-40-positive T cells have been detected in situ in several inflammatory states, including experimental autoimmune encephalomyelitis, rheumatoid arthritis, and graft-vs-host disease (36, 37, 38). The clinical importance of Ox-40-expressing T cells has been demonstrated in experimental autoimmune encephalomyelitis, in which disease prevention was achieved by selective depletion with an immunotoxin-conjugated Ab to Ox-40 (36). In addition to a role in costimulation of CD4 cells, recent data suggest that Ox-40/Ox-40L interactions are intimately involved in effector functions. Ox-40L cross-linking has been shown to promote B cell proliferation and Ab secretion (32), and enhance dendritic cell function (39), and blocking this interaction can inhibit both primary and secondary IgG responses (40). Interestingly, both B cell and dendritic cell responsiveness to Ox-40L appear to involve CD40 signaling, again promoting the concept that Ox-40/Ox-40L interactions may primarily function during later phase responses after engagement of one or more other ligand-receptor pairs.
To clarify the role of Ox-40 in primary CD4 responses, we have assessed the capacity of Ox-40L on Ag-presenting fibroblast transfectants, expressed either alone or in combination with B7, to stimulate responses of T cells derived from TCR transgenic animals. Although Ox-40 was readily expressed 24–48 h after Ag stimulation, APCs transfected with Ox-40L had little ability to induce IL-2 secretion or proliferation of naive T cells. In contrast, strong synergy was observed when B7 was coexpressed, resulting in enhanced proliferation that persisted for several days. More striking was the ability of APC expressing Ox-40L to promote secretion of several cytokines, including IL-2, from previously generated effector T cells. This resulted in further extensive proliferation, which was again augmented if CD28 signals were provided. These data show that Ox-40 signals are a potent source of costimulation for a developing primary CD4 response, and that the major action is during the late phase response promoting continued proliferation and expansion of effector cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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AND TCR transgenic mice were bred on a B10.BR background,
as previously described (41, 42), and used as a source of Vß3/V
11
CD4 cells responsive to peptides of pigeon cytochrome c
(PCC) presented on I-Ek.
Ag-presenting cells
Fibroblast cells transfected with I-Ek (originally
generated by Dr. R. Germain, National Institutes of Health, Bethesda,
MD) were used as APCs. Two fibroblast lines were used as before (18, 41), which expressed, or lacked, B7-1 (DCEK.Hi7, referred to as B7;
DCEK, referred to as -/-). These cells do not express ICAM-1, VCAM-1,
VLA-4, B7-2, Ox-40L, 4-1BBL, LFA-1, HSA, or CD48 by FACS
analysis. Both lines were transfected with the hygromycin
resistance-encoding expression vector pREP4 (Invitrogen, San Diego, CA)
into which was inserted cDNA for Ox-40L (a kind gift from Dr. Wayne
Godfrey, Stanford University School of Medicine, Stanford, CA) (25).
Ox-40L transfectants were selected, and stable lines were cloned by
limiting dilution (Fig. 1
). APC
populations were treated with mitomycin C (75–100 µg/ml; Sigma, St.
Louis, MO) for 30 min at 37°C before use.
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CD4+ T cells were purified from the spleen of TCR
transgenic mice (41, 42) by nylon wool depletion, followed by
complement treatment with Abs to CD8 (3.155), heat-stable Ag (JIID),
class II MHC (M5/114 and CA-4.A12), macrophages (M1/70), and dendritic
cells (33D1), cross-linked with mouse anti-rat 
(MAR 18.5). Any
residual APC and any in vivo activated T cells were removed by
isolating high density cells spun through a Percoll gradient (45, 53,
62, 80%). The resultant cells were resting (low FSc,
CD69-, CD71-, CD25-) and >95%
CD4+, and >95% of these cells possessed a phenotype
associated with naive CD4 cells (CD45RB+,
CD62L+, CD44low) along with expression of the
Vß3/V11 TCR (41, 42). Effector T cells were derived as in previous
studies by stimulating naive cells for 4 or 5 days in vitro with a
peptide of PCC 88–104 presented on
B7+ICAM+DCEK cells. Cultures were supplemented
with either IL-2 (10 ng/ml) and IFN-
(100 ng/ml) to generate
Th1-like cells secreting predominantly IL-2 and IFN-, or IL-2, IL-4
(20 ng/ml), and anti-IFN- (10 µg/ml) to generate Th2-like
cells secreting predominantly IL-4 and IL-5.
Cell cultures
Cells were cultured in RPMI 1640 (Irvine Scientific, Santa Ana, CA) with penicillin, streptomycin, glutamine, 2-ME, sodium pyruvate, and 7% FCS (HyClone, Logan, UT, and Irvine Scientific, Santa Ana, CA). Cultures were generally set up in 0.2-ml vol in 96-well plates (Costar, Cambridge, MA) in triplicate. Naive and effector CD4 cells were plated at a concentration of 1 x 105/ml with varying numbers of fibroblast APCs that had previously been pulsed with an optimal concentration of PCC peptide (20 µM) at 2 x 106/ml for 2 h at 37°C. In the cases in which cytokine secretion was inhibited, blocking Abs to IL-2 and IL-4 (PharMingen, San Diego, CA) were added at the time of stimulation at 20 µg/ml.
Fluorescence analysis
The phenotype of the DCEK transfectants was confirmed with Abs
to class II MHC (M5/114, rat IgG2b, from American Type Culture
Collection (ATCC), Manassas, VA), B7-1 (IG10, rat IgG2a, from
PharMingen), and Ox-40L (Ox-40.Fc, a human Ig fusion protein with the
extracellular portion of murine Ox-40, from Cantab Pharmaceuticals,
Cambridge, U.K.). Staining was visualized with FITC-labeled mouse
anti-rat (RG7.9), and FITC goat anti-human IgG (Caltag,
Burlingame, CA). Isotype controls were rat IgG and human IgG. T cell
activation was assessed by staining for CD25 (IL-2R) with FITC-labeled
anti-CD25 (rat IgM; PharMingen). Ox-40 expression was measured
using an Ig fusion protein with the extracellular portion of Ox-40L
(Ox-40L.Fc; Cantab Pharmaceuticals), followed by biotin anti-human
IgG (Caltag) and phycoerythrin-streptavidin (PharMingen).
CD4+ T cells were identified using phycoerythrin- or
FITC-conjugated anti-CD4, respectively (PharMingen). FACS analyses
were performed on a FACScan flow cytometer (Becton Dickinson, Mountain
View, CA) with Cellquest software.
Proliferation
Cell division was assessed by addition of 1 µCi of tritiated thymidine (ICN Biomedicals, Irvine, CA) to 0.2-ml cultures for approximately 18 h at the end of culture. Response was assessed at different times depending on the experiment, between either 24 and 42, 48 and 66, 72 and 90, or 96 and 114 h. Values shown represent mean levels from triplicate cultures, and in each case SDs were less than 15% of the means.
Cytokine secretion
Triplicate supernatants were recovered 20–24 h (effector T
cells) and 35–40 h (naive T cells) after stimulation and pooled to
assess cytokine content. IL-2 production was determined as before (18, 42) by titrating pooled replicate supernatants onto NK.3 cells, in
duplicate, in the presence of anti-IL-4 (purified from the 11B11
cell line, ATCC). IL-4, IL-5, and IFN- were measured by ELISA as in
previous studies (42), using the Abs 11B11 and biotinylated
anti-IL-4 (BVD6; PharMingen), TRFK5 and biotin-TRFK4, and R46A-2
and biotin-XMG1.2, respectively. Standard curves were constructed with
purified IL-2, IL-4, IL-5, and IFN- (supernatants from the
respective X63.Ag. cell lines). All values shown are means of
replicates, with SDs in each assay being less than 15% of the means.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of Ox-40 during CD4 T cell responses was analyzed using
cells isolated from Vß3/V11 TCR transgenic mice that are
responsive to peptides of pigeon and moth cytochrome c
presented on I-Ek-expressing APCs (42). Ox-40 expression
was analyzed on naive CD4 cells stimulated with plate-bound
anti-CD3 in the presence or absence of costimulation from
anti-CD28, or with PCC peptide presented on
I-Ek-bearing fibroblast APCs that do or do not express B7-1
(18). In addition, effector T cells generated from naive T cells over 5
days in vitro were also analyzed for Ox-40 expression in response to
Ag. Naive CD4 cells did not express Ox-40, but induction was evident
within 24 h after activation, and similar levels were seen
regardless of the mode of stimulation (Fig. 2a). Interestingly, the
presence of B7-1, or CD28 signaling (anti-CD28), was not required
for induction or maximal expression, even with limiting Ag or APC
number (data not shown). This is in direct contrast to our previous
data on another member of the TNF/TNFR family, CD40L, whose expression
required the presence of B7-1 (41). Ox-40 expression was not evident
within 6 h of activation, but a significant number of naive cells
were positive by 24 h, with maximal expression between this time
and 72 h (Fig. 2b). Ox-40 expression was lost after 4
to 5 days, but reinduction was rapid on the effector cells after
further Ag stimulation, the majority of cells expressing moderate
levels by 4 h. As we have previously shown for several other
facets of T cell activation (43, 44), effector cells were more
responsive to stimulation compared with naive cells, being induced to
express Ox-40 with low numbers of APCs (Fig. 2c).
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To assess the effects of ligating Ox-40, we transfected two of our
existing I-Ek-positive fibroblast lines with cDNA for
Ox-40L to generate APCs that expressed only Ox-40L, or Ox-40L with B7
(see Materials and Methods and Fig. 1
). These APCs and the
parent lines were used to stimulate naive CD4 cells with the cognate
Ag, PCC. Ox-40L expression had no enhancing effect on several markers
of activation such as IL-2R (Fig. 3a) and CD69 expression (not
shown), which we have previously used as a reliable method for
determining the number of T cells activated in culture (2). This was
irrespective of Ag concentration, APC number, time of analysis, and
coexpression of B7 (Fig. 3a and unpublished observations).
Ox-40L expression also had little effect on IL-2 production when
assessed in supernatants taken 40 h after naive T cell stimulation
(Fig. 3, b and c), a time that is usually optimal
for this facet of response (18), and did not augment the low level of
proliferation seen in the absence of Ox-40L (Fig. 3d). This
was in contrast to B7-1, which, as seen in previous studies (18, 41),
induced two- to threefold more IL-2 than APCs without either molecule
(Fig. 3b), and resulted in greater proliferation at early
times (Fig. 3d, and not shown). The presence of Ox-40L did
result in greater levels of IL-2 recovered in supernatants at 64 h
when compared with APCs with B7 or without either molecule (Fig. 3c), but this did not translate into significantly enhanced
proliferation at later times (Fig. 3d).
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, b–d). B7 expressed with Ox-40L resulted in an
APC that could promote similar levels of IL-2 as an APC with B7 alone,
but with ninefold fewer cells, and at optimal numbers resulted in IL-2
secretion that could not be achieved with B7 or Ox-40L alone (Fig. 3b). Significantly, although proliferation at 60 h was
enhanced compared with that with B7 expressing APCs, the main effect of
the combination of B7 and Ox-40L was proliferation that continued at
high levels for 4 days. In the absence of Ox-40L, the proliferative
phase was largely over after 2 days (Fig. 3d). Ox-40L promotes cytokine secretion from both Th1 and Th2 effector cells
Although Ox-40 expression was lost several days after naive T cell
activation, it was rapidly reexpressed on the effector cells after
stimulation (Fig. 2b), suggesting that this molecule may
also regulate responses of Ag-experienced cells, as well as promoting
prolonged naive cell responses. To assess a range of cytokine
responses, we generated short-term, partially polarized, Th1-like, and
Th2-like effector populations over 5 days using standard protocols (see
Materials and Methods). Both populations expressed high
levels of Ox-40 shortly after stimulation, although the IL-4-primed
Th2-like cells did bear somewhat enhanced levels (data not shown).
These cells were restimulated with PCC presented on varying numbers of
fibroblast APCs as before with naive T cells.
As seen in previous studies with effector cells (44, 45), similar
responses were induced with APCs expressing or lacking B7 (Figs. 4 and 5).
In contrast, Ox-40L expression resulted in enhanced IL-2, IL-4, and
IL-5 production compared with the control APCs lacking this molecule,
but had little effect on IFN- production. At least twofold more IL-4
and IL-5 were induced regardless of APC number, with fewer
Ox-40L-expressing cells being required to produce equivalent levels of
these cytokines (Fig. 5). The most striking effect of Ox-40 engagement
was on IL-2 secretion, which was produced from the effector cells at
far higher levels than with Ag presented with B7, and was induced under
limiting APC conditions, in which little or no IL-2 was detected in the
absence of Ox-40L (Fig. 4). Interestingly, even the IL-4-primed
effectors, which did not produce detectable IL-2 with B7 alone, were
induced to secrete some IL-2 with high numbers of Ox-40L-positive APCs
(Fig. 5). Since these effectors are not fully polarized at this stage,
they may contain both Th1- and Th2-like cells, and therefore the
results do not necessarily imply that Ox-40L induces IL-2 production
from IL-4- or IL-5-secreting cells. B7 collaborated with Ox-40L with
all cytokines, but because of the pronounced response to Ox-40L in the
absence of B7, this was not as dramatic as seen with naive T cells.
Again, IL-2 was the cytokine that was augmented to the greatest degree
with both effector populations (Figs. 4 and 5).
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Because of the enhanced secretion of IL-2 and IL-4, cytokines that
can be involved in T cell expansion, we analyzed the ability of Ox-40L
to promote proliferation of short-term Th1- and Th2-like effector
cells. Five days after naive T cell activation, the effectors were
restimulated as before with varying numbers of fibroblast
APC-presenting PCC peptide, and proliferation was assessed over time
(Fig. 6). As seen in previous studies
(44), little difference was observed at the effector stage between
responses in the presence or absence of B7. In contrast, APCs
expressing Ox-40L promoted higher levels of proliferation at low APC:T
cell ratios (1:9, 1:3) in both Th1- and Th2-like effector populations,
and appreciably more proliferation when equivalent APC numbers were
used (Fig. 6, a and b). Strong cooperation was
observed between B7 and Ox-40L when fewer APCs were in culture,
resulting in extremely high levels of proliferation, but similar
responses were seen regardless of the presence of B7 with greater
numbers of APCs. The action of Ox-40L was seen most dramatically when
assessing proliferation over time. Interestingly, very similar levels
of response were observed with all APCs when early proliferation was
measured at 42 h (Fig. 6, b and c). In
contrast, both Ox-40L-expressing APCs promoted continued proliferation
at later times (66 and 90 h), while the APCs that expressed B7 or
neither molecule were unable to sustain cell expansion at the level
seen at 42 h. Similar response patterns were seen for both Th1-
and Th2-like effector populations. Blocking studies with naive and Th1
effector T cell populations showed that proliferation was primarily
dependent on IL-2, whereas both IL-2 and IL-4 were responsible for the
extended proliferation seen with Th2 effectors (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously showed that Ag presentation to naive T cells in the
absence of costimulation led to partial activation, i.e., blastogenesis
and expression of several cell surface Ags such as CD69 and IL-2R, but
failed to induce CD40L expression, efficient production of IL-2, and
strong proliferation (2). This resulted in poor long-term cell survival
and hyporesponsiveness, and suggested that induction of CD40L and
production of IL-2 represented key areas that were highly regulated
during naive T cell activation (2). CD40L expression has been shown to
be required for up-regulating B7 expression and costimulatory activity
on all APCs (46, 47, 48), and IL-2 is required for growth and cell
survival; and both in turn are controlled by the interaction of other
accessory molecule-coreceptor pairs (e.g., ICAM-LFA), and at least in
part by CD28 signaling (8, 41, 49). Ox-40 was not present early after
naive T cell activation, only being expressed on a majority of cells
between 24–48 h (Fig. 2). This contrasts with CD28 and LFA-1, which
are constitutively expressed on naive T cells, and CD40L, the
expression of which after Ag stimulation is seen by 3 h, peaks
from 5–8 h, and is generally absent by 15 h (41).
Surprisingly, even though Ox-40 was expressed, Ox-40L in the absence of
B7 resulted in elevated IL-2 levels only at later times, and was
ineffective at inducing proliferation above that induced with the
control APCs lacking both molecules (Fig. 3). In combination with B7,
Ox-40L promoted greatly elevated levels of IL-2 at both early and late
times, enhanced proliferation at early times, and resulted in
proliferation that continued at high levels for several days. Thus,
Ox-40L appears to be a molecule that can promote naive T cell expansion
only after signals through CD28 are received. The interaction between
Ox-40 and Ox-40L may therefore represent an additional event during the
primary CD4 response that is essential for optimal clonal expansion,
acting after the initial interactions between ICAM-LFA, B7-CD28, and
CD40-CD40L have taken place.
The effect of B7 in combination with Ox-40L was reminiscent of our
earlier data with B7 in combination with ICAM-1 (18), again showing
that cooperation/synergy between accessory molecules is required for an
optimal naive T cell response. However, several differences exist
between the action of ICAM and Ox-40L. Ox-40L coexpressed with B7 did
not significantly affect the ability of the fibroblast APCs to activate
naive T cells, as assessed by IL-2R induction (Fig. 3a) and
CD69 induction (not shown), with similar dose-response curves being
seen regardless of the presence of Ox-40L. In contrast, ICAM-1
coexpressed with B7 results in activation of many more naive T cells
under conditions of limiting Ag or APC number, such that the
dose-response curve for IL-2R/CD69 is shifted 10–100-fold lower (50).
Thus, part of the action of ICAM can be attributed to enhanced numbers
of T cells responding, whereas Ox-40L functioned largely by enhancing
production of IL-2 in the absence of an increased number of responding
cells. In addition, Ox-40L under optimal conditions of stimulation
induced sustained IL-2 secretion and proliferation that are also not as
apparent with ICAM in combination with B7, again promoting the concept
that Ox-40L is a molecule that primarily enhances late phase naive T
cell responses.
More striking were the results with effector T cells. As shown
previously (44), and in
Figs. 4–6, these T cells respond fairly well
to Ag presented on APCs lacking molecules such as B7-1 and ICAM-1, and
the presence of B7-1 and ICAM-1 expressed separately has little effect
on the responses induced. Cytokines such as IFN-, IL-4, and IL-5 are
induced efficiently, whereas IL-2 is only weakly produced, which
translates to an early burst of proliferation over 1 to 2 days that
dies quickly (44). Stimulation through Ox-40, particularly under
optimal Ag and APC conditions, resulted in enhanced secretion of IL-2,
IL-4, and IL-5, but not IFN-, and again collaboration with B7 was
also observed. The reason that Ox-40L alone was active on effector T
cells, but not on naive T cells, is unclear. This action was only
apparent with high APC numbers and high dose Ag, with the presence of
B7 being required for enhancing responses under conditions of limited
stimulation. We have shown previously that effector T cells are more
responsive to TCR signals than naive T cells (44, 45), and it is
possible that with sufficient signaling through the TCR, effector cells
do not require additional signals through CD28 to respond to signals
through Ox-40. In contrast, IL-2 secretion from naive T cells is highly
dependent on CD28 signals, regardless of the extent of TCR signaling,
possibly accounting for the lack of effect of Ox-40L expressed alone.
Although IL-4 and IL-5 were up-regulated efficiently, the major effect of Ox-40L appeared to be on IL-2 production by the effector cells. Enhanced IL-2 was evident with those partially polarized to be Th1 like, and was also observed with IL-4-primed cells, a phenomenon that generally does not occur with these Th2-like populations. Correlating with the extent of growth factor production, proliferation was augmented dramatically at late times with Ox-40 ligation, with high levels being maintained up to 4 days after effector T cell restimulation. This contrasts strikingly with the other fibroblast APCs that we have used (including those expressing ICAM-1; see 44 , which are unable to sustain proliferation of either Th1- or Th2-like effector populations. These data therefore support previous observations that showed that an Ab to Ox-40, in combination with anti-CD3, could promote high levels of IL-2 and strong proliferation from a CD4 clone (29).
Overall, the data therefore suggest that costimulation through Ox-40 is a major pathway that acts after the initial activation events and results in prolonged naive and primary effector cell responses. These results complement the recent observations from Stuber et al. (32, 40) and Ohshima et al. (39), which showed that Ox-40L signaling to both B cells and dendritic cells could synergize with CD40 signals to enhance activity of these APCs. All studies promote the concept that Ox-40/Ox-40L interactions transduce critical signals for downstream T cell-APC responses, and may contribute to the massive expansion that is seen during a primary CD4 response in vivo (1). Attention has recently been focused on the need for an inflammatory event to elicit a productive, nontolerizing, CD4 response, as has been demonstrated many times by priming with protein Ags in the presence or absence of adjuvant. The reasons for this requirement are not clear, but it has been proposed that inflammatory signals may help ensure that either costimulatory molecules such as B7-1 and B7-2 are induced efficiently, or that cytokines such as IL-6 and IL-1 are produced, all of which may contribute to cell expansion and/or survival (51, 52). We suggest that the interaction between Ox-40 and Ox-40L represents a major signaling pathway that occurs after the initial T cell-APC activation events, and will ensure that weak transient responses are not induced, and that tolerance does not result. We additionally propose that Ox-40L and Ox-40 may be targets for adjuvant action, with their efficient expression being necessary to generate sufficient secondary signals to keep the primary T cell response going.
The results presented in this work and elsewhere also substantiate the notion that Ox-40/Ox-40L interactions are pivotal to productive T cell/B cell collaboration. Generally, it is thought that naive T cell activation occurs on dendritic cells, which are present in the T cell zones of spleen and lymph nodes, and that subsequent interactions take place with B cells in the outer T zones and in the follicles (53, 54). Studies with B cell-deficient mice (55, 56, 57) suggest that these later interactions may play a major role in promoting efficient T cell expansion as well as effector function. As Ox-40L is predominantly expressed on activated B cells, and appears to require CD40 signaling for induction, the absence of Ox-40L and signaling through Ox-40 represents one component that may contribute to the weak T cell priming seen when animals are depleted of B cells. As well as the generation of primary T cell responses, an additional aspect that may be highly relevant to the findings in this study is the generation of memory T cell responses. It is largely accepted that efficient primary T cell responses, and especially a high level of expansion of naive cells specific for the particular Ag are necessary for a strong memory response. It may therefore be predicted that the Ox-40/Ox-40L interaction will contribute to the development of memory, and in support of this, recent data have shown that Ox-40L.Fc, as a T cell costimulus, can enhance tumor immunity in a model involving CD4 cells (A. D. Weinberg, unpublished observations).
Although Ox-40L is obviously a potent costimulatory molecule, its
mechanism of action is largely unknown. As Ox-40 is a member of the
TNFR family, it utilizes several of the TRAF family of molecules
(2 and 3) and nuclear factor-B (58), and thus should produce signals
distinct from those generated through CD28. We have demonstrated that a
dominant action is in driving cytokine secretion and proliferation
(this article and 29 , with clonal expansion being largely
dependent on IL-2, with IL-4 also playing a role with Th2-like cells.
Additionally, it is possible that Ox-40 signals are antiapoptotic and
promote short-term cell survival, although assessment of cell
recoveries over an extended period suggests that other signals may be
required for long-term survival (unpublished observations). Potential
mechanisms of action, other than promoting cytokine transcription,
could include up-regulation of members of the bcl family of
proteins, inhibition of Fas or FasL expression or function, or
overcoming down-regulatory signals through CTLA4, and we are initiating
investigations of these aspects of T cell regulation by Ox-40L.
Regardless of the mechanisms involved, the studies reported in this
work suggest that Ox-40 and Ox-40L may be a major ligand-receptor pair
that is not only crucial for induction of efficient APC activity, but
is also intimately involved in development of this T cell effector
function and in initiating long-lived T cell responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael Croft, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121. E-mail address:
3 Abbreviations used in this paper: CD40L, CD40 ligand; Ox-40L, Ox-40 ligand; PCC, pigeon cytochrome c.
Received for publication February 12, 1998. Accepted for publication August 13, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B. Mol. Cell. Biol. 18:558.This article has been cited by other articles:
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  M. Walch, S. K. Rampini, I. Stoeckli, S. Latinovic-Golic, C. Dumrese, H. Sundstrom, A. Vogetseder, J. Marino, D. L. Glauser, M. van den Broek, et al. Involvement of CD252 (CD134L) and IL-2 in the Expression of Cytotoxic Proteins in Bacterial- or Viral-Activated Human T Cells J. Immunol., June 15, 2009; 182(12): 7569 - 7579. [Abstract] [Full Text] [PDF]
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M. Klinger, J. K. Kim, S. A. Chmura, A. Barczak, D. J. Erle, and N. Killeen Thymic OX40 Expression Discriminates Cells Undergoing Strong Responses to Selection Ligands J. Immunol., April 15, 2009; 182(8): 4581 - 4589. [Abstract] [Full Text] [PDF]
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 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]
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B. E. Burrell, G. Lu, X. C. Li, and D. K. Bishop OX40 Costimulation Prevents Allograft Acceptance Induced by CD40-CD40L Blockade J. Immunol., January 1, 2009; 182(1): 379 - 390. [Abstract] [Full Text] [PDF]
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W. Duan, T. So, and M. Croft Antagonism of Airway Tolerance by Endotoxin/Lipopolysaccharide through Promoting OX40L and Suppressing Antigen-Specific Foxp3+ T Regulatory Cells J. Immunol., December 15, 2008; 181(12): 8650 - 8659. [Abstract] [Full Text] [PDF]
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Z. J. Kraus, J. S. Haring, and G. A. Bishop TNF Receptor-Associated Factor 5 Is Required for Optimal T Cell Expansion and Survival in Response to Infection J. Immunol., December 1, 2008; 181(11): 7800 - 7809. [Abstract] [Full Text] [PDF]
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S. F. Mousavi, P. Soroosh, T. Takahashi, Y. Yoshikai, H. Shen, L. Lefrancois, J. Borst, K. Sugamura, and N. Ishii OX40 Costimulatory Signals Potentiate the Memory Commitment of Effector CD8+ T Cells J. Immunol., November 1, 2008; 181(9): 5990 - 6001. [Abstract] [Full Text] [PDF]
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X. Xiao, A. Kroemer, W. Gao, N. Ishii, G. Demirci, and X. C. Li OX40/OX40L Costimulation Affects Induction of Foxp3+ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo J. Immunol., September 1, 2008; 181(5): 3193 - 3201. [Abstract] [Full Text] [PDF]
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 W. Elyaman, P. Kivisakk, J. Reddy, T. Chitnis, K. Raddassi, J. Imitola, E. Bradshaw, V. K. Kuchroo, H. Yagita, M. H. Sayegh, et al. Distinct Functions of Autoreactive Memory and Effector CD4+ T Cells in Experimental Autoimmune Encephalomyelitis Am. J. Pathol., August 1, 2008; 173(2): 411 - 422. [Abstract] [Full Text] [PDF]
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J. Song, T. So, and M. Croft Activation of NF-{kappa}B1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival J. Immunol., June 1, 2008; 180(11): 7240 - 7248. [Abstract] [Full Text] [PDF]
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C. E. Ruby, R. Montler, R. Zheng, S. Shu, and A. D. Weinberg IL-12 Is Required for Anti-OX40-Mediated CD4 T Cell Survival J. Immunol., February 15, 2008; 180(4): 2140 - 2148. [Abstract] [Full Text] [PDF]
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 F. Reggeti, C. Ackerley, and D. Bienzle CD134 and CXCR4 expression corresponds to feline immunodeficiency virus infection of lymphocytes, macrophages and dendritic cells J. Gen. Virol., January 1, 2008; 89(1): 277 - 287. [Abstract] [Full Text] [PDF]
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 E. N. M. Nolte-'t Hoen, E. P. J. Boot, J. P. A. Wagenaar-Hilbers, J. H. M. van Bilsen, G. J. A. Arkesteijn, G. Storm, L. A. Everse, W. van Eden, and M. H. M. Wauben Identification and monitoring of effector and regulatory T cells during experimental arthritis based on differential expression of CD25 and CD134 J. Leukoc. Biol., January 1, 2008; 83(1): 112 - 121. [Abstract] [Full Text] [PDF]
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W. L. Redmond, M. J. Gough, B. Charbonneau, T. L. Ratliff, and A. D. Weinberg Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist J. Immunol., December 1, 2007; 179(11): 7244 - 7253. [Abstract] [Full Text] [PDF]
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I. R. Humphreys, A. Loewendorf, C. de Trez, K. Schneider, C. A. Benedict, M. W. Munks, C. F. Ware, and M. Croft OX40 Costimulation Promotes Persistence of Cytomegalovirus-Specific CD8 T Cells: A CD4-Dependent Mechanism J. Immunol., August 15, 2007; 179(4): 2195 - 2202. [Abstract] [Full Text] [PDF]
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S.-J. Lee, R. J. Rossi, S.-K. Lee, M. Croft, B. S. Kwon, R. S. Mittler, and A. T. Vella CD134 Costimulation Couples the CD137 Pathway to Induce Production of Supereffector CD8 T Cells That Become IL-7 Dependent J. Immunol., August 15, 2007; 179(4): 2203 - 2214. [Abstract] [Full Text] [PDF]
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 K. C. Beier, T. Kallinich, and E. Hamelmann T-cell co-stimulatory molecules: novel targets for the treatment of allergic airway disease Eur. Respir. J., August 1, 2007; 30(2): 383 - 390. [Abstract] [Full Text] [PDF]
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T. So and M. Croft Cutting Edge: OX40 Inhibits TGF-beta- and Antigen-Driven Conversion of Naive CD4 T Cells into CD25+Foxp3+ T cells J. Immunol., August 1, 2007; 179(3): 1427 - 1430. [Abstract] [Full Text] [PDF]
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Y. Tone, Y. Kojima, K. Furuuchi, M. Brady, Y. Yashiro-Ohtani, M. L. Tykocinski, and M. Tone OX40 Gene Expression Is Up-Regulated by Chromatin Remodeling in Its Promoter Region Containing Sp1/Sp3, YY1, and NF-{kappa}B Binding Sites J. Immunol., August 1, 2007; 179(3): 1760 - 1767. [Abstract] [Full Text] [PDF]
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C. A. Williams, S. E. Murray, A. D. Weinberg, and D. C. Parker OX40-Mediated Differentiation to Effector Function Requires IL-2 Receptor Signaling but Not CD28, CD40, IL-12Rbeta2, or T-bet J. Immunol., June 15, 2007; 178(12): 7694 - 7702. [Abstract] [Full Text] [PDF]
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K. C. Beier, T. Kallinich, and E. Hamelmann Master switches of T-cell activation and differentiation Eur. Respir. J., April 1, 2007; 29(4): 804 - 812. [Abstract] [Full Text] [PDF]
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Q. Chen, G. Sen, and C. M. Snapper Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine J. Immunol., November 1, 2006; 177(9): 6044 - 6051. [Abstract] [Full Text] [PDF]
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L. A. Beck, B. Tancowny, M. E. Brummet, S. Y. Asaki, S. L. Curry, M. B. Penno, M. Foster, A. Bahl, and C. Stellato Functional Analysis of the Chemokine Receptor CCR3 on Airway Epithelial Cells. J. Immunol., September 1, 2006; 177(5): 3344 - 3354. [Abstract] [Full Text] [PDF]
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 G. Bamias, M. Mishina, M. Nyce, W. G. Ross, G. Kollias, J. Rivera-Nieves, T. T. Pizarro, and F. Cominelli From the Cover: Role of TL1A and its receptor DR3 in two models of chronic murine ileitis PNAS, May 30, 2006; 103(22): 8441 - 8446. [Abstract] [Full Text] [PDF]
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P. Soroosh, S. Ine, K. Sugamura, and N. Ishii OX40-OX40 Ligand Interaction through T Cell-T Cell Contact Contributes to CD4 T Cell Longevity J. Immunol., May 15, 2006; 176(10): 5975 - 5987. [Abstract] [Full Text] [PDF]
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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]
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S. Colombetti, V. Basso, D. L. Mueller, and A. Mondino Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin. J. Immunol., March 1, 2006; 176(5): 2730 - 2738. [Abstract] [Full Text] [PDF]
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Q. Yu, F. Y. Yue, X. X. Gu, H. Schwartz, C. M. Kovacs, and M. A. Ostrowski OX40 Ligation of CD4+ T Cells Enhances Virus-Specific CD8+ T Cell Memory Responses Independently of IL-2 and CD4+ T Regulatory Cell Inhibition J. Immunol., February 15, 2006; 176(4): 2486 - 2495. [Abstract] [Full Text] [PDF]
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 L. Myers, S. W. Lee, R. J. Rossi, L. Lefrancois, B. S. Kwon, R. S. Mittler, M. Croft, and A. T. Vella Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells Int. Immunol., February 1, 2006; 18(2): 325 - 333. [Abstract] [Full Text] [PDF]
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M. D. Vu, M. R. Clarkson, H. Yagita, L. A. Turka, M. H. Sayegh, and X. C. Li Critical, but Conditional, Role of OX40 in Memory T Cell-Mediated Rejection J. Immunol., February 1, 2006; 176(3): 1394 - 1401. [Abstract] [Full Text] [PDF]
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S. Murata, B. H. Ladle, P. S. Kim, E. R. Lutz, M. E. Wolpoe, S. E. Ivie, H. M. Smith, T. D. Armstrong, L. A. Emens, E. M. Jaffee, et al. OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen J. Immunol., January 15, 2006; 176(2): 974 - 983. [Abstract] [Full Text] [PDF]
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 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]
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J. Hendriks, Y. Xiao, J. W. A. Rossen, K. F. van der Sluijs, K. Sugamura, N. Ishii, and J. Borst During Viral Infection of the Respiratory Tract, CD27, 4-1BB, and OX40 Collectively Determine Formation of CD8+ Memory T Cells and Their Capacity for Secondary Expansion J. Immunol., August 1, 2005; 175(3): 1665 - 1676. [Abstract] [Full Text] [PDF]
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J. Mestas, S. P. Crampton, T. Hori, and C. C. W. Hughes Endothelial cell co-stimulation through OX40 augments and prolongs T cell cytokine synthesis by stabilization of cytokine mRNA Int. Immunol., June 1, 2005; 17(6): 737 - 747. [Abstract] [Full Text] [PDF]
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Y. K. Chou, D. M. Edwards, A. D. Weinberg, A. A. Vandenbark, B. L. Kotzin, A. P. Fontenot, and G. G. Burrows Activation Pathways Implicate Anti-HLA-DP and Anti-LFA-1 Antibodies as Lead Candidates for Intervention in Chronic Berylliosis J. Immunol., April 1, 2005; 174(7): 4316 - 4324. [Abstract] [Full Text] [PDF]
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B. Valzasina, C. Guiducci, H. Dislich, N. Killeen, A. D. Weinberg, and M. P. Colombo Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR Blood, April 1, 2005; 105(7): 2845 - 2851. [Abstract] [Full Text] [PDF]
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E. Biagi, G. Dotti, E. Yvon, E. Lee, M. Pule, S. Vigouroux, S. Gottschalk, U. Popat, R. Rousseau, and M. Brenner Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor-reactive cytotoxic T lymphocytes Blood, March 15, 2005; 105(6): 2436 - 2442. [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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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]
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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]
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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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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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K. A. Papadakis, J. L. Prehn, C. Landers, Q. Han, X. Luo, S. C. Cha, P. Wei, and S. R. Targan TL1A Synergizes with IL-12 and IL-18 to Enhance IFN-{gamma} Production in Human T Cells and NK Cells J. Immunol., June 1, 2004; 172(11): 7002 - 7007. [Abstract] [Full Text] [PDF]
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 S. Andarini, T. Kikuchi, M. Nukiwa, P. Pradono, T. Suzuki, S. Ohkouchi, A. Inoue, M. Maemondo, N. Ishii, Y. Saijo, et al. Adenovirus Vector-Mediated in Vivo Gene Transfer of OX40 Ligand to Tumor Cells Enhances Antitumor Immunity of Tumor-Bearing Hosts Cancer Res., May 1, 2004; 64(9): 3281 - 3287. [Abstract] [Full Text] [PDF]
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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]
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 M. Shimojima, T. Miyazawa, Y. Ikeda, E. L. McMonagle, H. Haining, H. Akashi, Y. Takeuchi, M. J. Hosie, and B. J. Willett Use of CD134 As a Primary Receptor by the Feline Immunodeficiency Virus Science, February 20, 2004; 303(5661): 1192 - 1195. [Abstract] [Full Text] [PDF]
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G. Demirci, F. Amanullah, R. Kewalaramani, H. Yagita, T. B. Strom, M. H. Sayegh, and X. C. Li Critical Role of OX40 in CD28 and CD154-Independent Rejection J. Immunol., February 1, 2004; 172(3): 1691 - 1698. [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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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]
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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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B. R. Blazar, A. H. Sharpe, A. I. Chen, A. Panoskaltsis-Mortari, C. Lees, H. Akiba, H. Yagita, N. Killeen, and P. A. Taylor Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients Blood, May 1, 2003; 101(9): 3741 - 3748. [Abstract] [Full Text] [PDF]
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 T. Totsuka, T. Kanai, K. Uraushihara, R. Iiyama, M. Yamazaki, H. Akiba, H. Yagita, K. Okumura, and M. Watanabe Therapeutic effect of anti-OX40L and anti-TNF-alpha MAbs in a murine model of chronic colitis Am J Physiol Gastrointest Liver Physiol, April 1, 2003; 284(4): G595 - G603. [Abstract] [Full Text] [PDF]
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X. Yuan, A. D. Salama, V. Dong, I. Schmitt, N. Najafian, A. Chandraker, H. Akiba, H. Yagita, and M. H. Sayegh The Role of the CD134-CD134 Ligand Costimulatory Pathway in Alloimmune Responses In Vivo J. Immunol., March 15, 2003; 170(6): 2949 - 2955. [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. 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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L. Taylor, M. Bachler, I. Duncan, S. Keen, R. Fallon, C. Mair, T. T. McDonald, and H. Schwarz In vitro and in vivo activities of OX40 (CD134)-IgG fusion protein isoforms with different levels of immune-effector functions J. Leukoc. Biol., September 1, 2002; 72(3): 522 - 529. [Abstract] [Full Text] [PDF]
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K. W. Chan, C. D. Hopke, S. M. Krams, and O. M. Martinez CD30 Expression Identifies the Predominant Proliferating T Lymphocyte Population in Human Alloimmune Responses J. Immunol., August 15, 2002; 169(4): 1784 - 1791. [Abstract] [Full Text] [PDF]
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D. V. R. Prasad, V. V. Parekh, B. N. Joshi, P. P. Banerjee, P. B. Parab, S. Chattopadhyay, A. Kumar, and G. C. Mishra The Th1-Specific Costimulatory Molecule, M150, Is a Posttranslational Isoform of Lysosome-Associated Membrane Protein-1 J. Immunol., August 15, 2002; 169(4): 1801 - 1809. [Abstract] [Full Text] [PDF]
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S. Ronchetti, G. Nocentini, C. Riccardi, and P. P. Pandolfi Role of GITR in activation response of T lymphocytes Blood, June 17, 2002; 100(1): 350 - 352. [Abstract] [Full Text] [PDF]
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C. Chirathaworn, J. E. Kohlmeier, S. A. Tibbetts, L. M. Rumsey, M. A. Chan, and S. H. Benedict Stimulation Through Intercellular Adhesion Molecule-1 Provides a Second Signal for T Cell Activation J. Immunol., June 1, 2002; 168(11): 5530 - 5537. [Abstract] [Full Text] [PDF]
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W. Ise, M. Totsuka, Y. Sogawa, A. Ametani, S. Hachimura, T. Sato, Y. Kumagai, S. Habu, and S. Kaminogawa Naive CD4+ T Cells Exhibit Distinct Expression Patterns of Cytokines and Cell Surface Molecules on Their Primary Responses to Varying Doses of Antigen J. Immunol., April 1, 2002; 168(7): 3242 - 3250. [Abstract] [Full Text] [PDF]
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 A. Yamada, A. D. Salama, and M. H. Sayegh The Role of Novel T Cell Costimulatory Pathways in Autoimmunity and Transplantation J. Am. Soc. Nephrol., February 1, 2002; 13(2): 559 - 575. [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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H.-C. Wang and J. R. Klein Multiple Levels of Activation of Murine CD8+ Intraepithelial Lymphocytes Defined by OX40 (CD134) Expression: Effects on Cell-Mediated Cytotoxicity, IFN-{gamma}, and IL-10 Regulation J. Immunol., December 15, 2001; 167(12): 6717 - 6723. [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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M. Kelleher and P. C. L. Beverley Lipopolysaccharide Modulation of Dendritic Cells Is Insufficient to Mature Dendritic Cells to Generate CTLs from Naive Polyclonal CD8+ T Cells In Vitro, Whereas CD40 Ligation Is Essential J. Immunol., December 1, 2001; 167(11): 6247 - 6255. [Abstract] [Full Text] [PDF]
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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]
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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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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]
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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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A. G.-H. Jember, R. Zuberi, F.-T. Liu, and M. Croft Development of Allergic Inflammation in a Murine Model of Asthma Is Dependent on the Costimulatory Receptor OX40 J. Exp. Med., February 5, 2001; 193(3): 387 - 392. [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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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]
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R. Pankow, H. Durkop, U. Latza, H. Krause, U. Kunzendorf, T. Pohl, and S. Bulfone-Paus The HTLV-I Tax Protein Transcriptionally Modulates OX40 Antigen Expression J. Immunol., July 1, 2000; 165(1): 263 - 270. [Abstract] [Full Text] [PDF]
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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]
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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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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]
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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]
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J. R. Maxwell, A. Weinberg, R. A. Prell, and A. T. Vella Danger and OX40 Receptor Signaling Synergize to Enhance Memory T Cell Survival by Inhibiting Peripheral Deletion J. Immunol., January 1, 2000; 164(1): 107 - 112. [Abstract] [Full Text] [PDF]
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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]
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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]
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J. L. Cannons, K. P. Hoeflich, J. R. Woodgett, and T. H. Watts Role of the Stress Kinase Pathway in Signaling Via the T Cell Costimulatory Receptor 4-1BB J. Immunol., September 15, 1999; 163(6): 2990 - 2998. [Abstract] [Full Text] [PDF]
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A. D. Weinberg, K. W. Wegmann3, C. Funatake, and R. H. Whitham Blocking OX-40/OX-40 Ligand Interaction In Vitro and In Vivo Leads to Decreased T Cell Function and Amelioration of Experimental Allergic Encephalomyelitis J. Immunol., February 1, 1999; 162(3): 1818 - 1826. [Abstract] [Full Text] [PDF]
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M. Gerloni, S. Xiong, S. Mukerjee, S. P. Schoenberger, M. Croft, and M. Zanetti From the Cover: Functional cooperation between T helper cell determinants PNAS, November 21, 2000; 97(24): 13269 - 13274. [Abstract] [Full Text] [PDF]
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