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*
Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121;
Department of Microbiology and Immunology, University of California, San Francisco, CA 94143; 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 importance of several costimulatory interactions for CD4 T cell responses is well documented (1). Many studies have shown that CD28/B7 and CD40L/CD40 are essential for the initial phases of the naive T cell response (2, 3, 4, 5). CD28 may function by enhancing transcription of IL-2 and altering expression of the bcl family of molecules. In contrast, CD40L interaction with CD40 may function largely at the level of the APC, regulating the expression of costimulatory molecules such as B7-1/-2, and the production of cytokines such as IL-1 and IL-6.
In addition to CD28 and CD40, a number of other costimulatory receptors have been described (1, 6). One in particular, the TNFR family member OX40 (CD134), may possess functions distinct from those described for CD28 and CD40. OX40 was originally described with an Ab that bound to rat CD4 T cells (7, 8), and unlike CD28, is not constitutively expressed, but found on T cells 1–2 days after activation (9, 10, 11, 12). Several groups have shown that OX40L expressed on APC can provide costimulation to CD4 cells (9, 12, 13, 14). OX40L is present on activated APC (13, 15, 16, 17, 18, 19), activated endothelium (20, 21), and activated T cells (22). OX40-positive T cells have been visualized in situ in lymph nodes during the peak of primary T cell responses (23), and at the site of inflammation during the active phases of experimental allergic encephalomyelitis (EAE),3 graft-vs-host disease (GVHD), and rheumatoid arthritis, and on tumor infiltrating lymphocytes (24, 25, 26, 27, 28, 29).
Although the exact function of OX40 has not yet been clarified, several
recent reports highlighted the importance of this molecule in T cell
responses. Blocking OX40 reduced gut inflammation in colitis
(30), suppressed paralysis in EAE (19), and
prevented hyperplasia in GVHD (31). An initial study of
OX40-deficient animals showed that they mounted normal responses to
Leishmania and Nippostrongylus in vivo, but T
cells from these mice proliferated poorly in vitro (22).
Additional studies of OX40-deficient mice also showed that they
generated normal CD8 responses to lymphocytic choriomeningitis virus
(LCMV) and influenza virus, but exhibited reduced primary CD4 responses
to these infections, characterized by lower numbers of
IFN-
-secreting cells and fewer T cells infiltrating the lungs of
infected animals (32). OX40L-deficient mice were also
found to be defective in primary contact hypersensitivity responses to
oxazalone and DNBS in one study, with reduced proliferation and IFN-
secretion seen after in vitro stimulation (33), and in a
separate study, these mice also showed reduced primary Th1 and Th2
responses to keyhole limpet hemocyanin (KLH), the defect in response
being suggested to be related to poor initial T cell priming
(34).
Although the studies with OX40 and OX40L knockout mice demonstrated the critical role of these molecules in CD4 responses, they did not distinguish between an effect on regulating T cell numbers or an effect on regulating T cell activity and differentiation, nor whether the major deficit was related to a lack of OX40 signals to the T cell or a lack of OX40L signals affecting APC function. In addition, there was little data to suggest whether targeting OX40 would affect the development of functional T cell memory, as the primary responses in these studies were only partially impaired.
In the present study, we have addressed the mechanism of action of OX40 and whether this molecule is critical to long-term T cell responses and memory. We had previously proposed that costimulation through OX40 may regulate the ability of CD4 T cells to expand and survive, based on experiments in vitro that showed greatly enhanced T cell proliferation to OX40L expressing APCs in a situation where cell division was normally limited (12, 35). In this report, we present data that support this and show that OX40 regulates the extent of T cell expansion in the primary T cell response and this translates into an ability to persist as a population over time. An agonist Ab to OX40 promoted greater numbers of CD4 T cells to accumulate after the peak of a normal primary response and to survive with time as memory cells. Moreover, CD4 cells from OX40-deficient mice could not sustain IL-2 production and a proliferative response as time progressed, resulting in reduced survival. OX40-deficient mice could not generate normal numbers of Ag-specific T cells in the later stages of a primary response and this led to severely impaired development of memory, again characterized by much lower frequencies of CD4 cells surviving over time. These data support the conclusion that OX40-OX40L regulates the number of T cells that can be generated in a primary response and that persist as memory cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OX40-deficient mice were generated at University of California, San Francisco (UCSF) (22). These were backcrossed four times onto C57BL/6 at UCSF, and a further three times at La Jolla Institute for Allergy and Immunology (LIAI). Wild-type (wt) BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME) or used as OX40+/+ littermates from crossing heterozygous mice. AND TCR transgenic mice were bred on a B10.BR background (36) and wt B10.BR mice were purchased from The Jackson Laboratory.
Adoptive transfers and immunizations
Chimeric mice were produced by injecting 2–3 x
106 Vß3/V
11-positive CD4 cells from AND
transgenic mice i.v. into unirradiated wt B10.BR recipients. After 2
days, these were immunized s.c. in the tail base with peptide 88–103
of moth cytochrome c (MCC) (synthesized at LIAI) emulsified
in CFA (Fischer Scientific, Pittsburgh, PA). For experiments with BL/6
mice, KLH (Calbiochem, La Jolla, CA) was used s.c. emulsified in CFA,
or i.p. precipitated with alum and mixed with 109
Bordetella pertussis organisms (Michigan Public Health
Department, Lansing, MI). Anti-mouse OX40 (rat IgG1) was generated from
the hybridoma OX-86 (11) obtained from the European Cell
Culture Collection (Wiltshire, U.K.). This or an isotype-matched
control rat IgG1 (PharMingen, San Diego, CA) was injected i.p. in PBS 2
days after Ag.
Tracking Ag-specific transgenic T cells
Expansion of MCC-reactive transgenic T cells was assessed in
adoptive recipients using a method similar to that developed by Jenkins
and colleagues (37), by staining with PE-labeled
anti-Vß3, FITC-labeled anti-V11, and cychrome-labeled
anti-CD4 (PharMingen). Controls were with labeled anti-rat
isotype-matched Abs (PharMingen) and analyses conducted on a Becton
Dickinson (Mountain View, CA) FACScan with CellQuest software.
Cell cultures
In vitro cultures were with lymph node or splenic populations depleted of CD8 T cells using anti-CD8 (3.155, in-house) and rabbit complement (Accurate Scientific, Westbury, NY), or with purified CD4 cells isolated using complement and Abs to CD8 (3.155), heat stable Ag (JIID), and class II MHC (M5/114 and CA-4.A12). Irradiated splenocytes from wt mice were added as APCs, either unactivated, or preactivated overnight with LPS and dextran sulfate (DXS; both at 10 µg/ml). Ag was added directly into culture or prepulsed onto the APCs (100 µg/ml). Cultures were set up in 0.2-ml volumes in 96-well plates (Costar, Cambridge, MA) in triplicate. With stimulation from anti-CD3 (2C11, in-house), Ab was added into culture (soluble), or immobilized on plastic by incubating 50 µl in PBS in 96-well plates for 2 h at 37°C.
Proliferation
Cell division was assessed by addition of 1 mCi tritiated
thymidine (ICN Biomedicals, Irvine, CA) to 0.2-ml cultures for 
18 h.
Response was assessed between 72–90 h, 96–114 h, or 120–138
h.
Cytokine secretion
Duplicate supernatants were recovered 20–24 h after T cell
stimulation and assayed after pooling. IL-2 production was determined
by titrating supernatants onto NK.3 cells, in duplicate, in the
presence of anti-IL-4 (11B11) and measuring proliferation 48 h
later (36). IL-4, IL-5, and IFN- were measured by ELISA
as before (36).
Limiting dilution assay
CD8-depleted splenocytes (corrected for CD4 numbers by FACS) were added to 96-well plates in replicates of 36 in the presence of irradiated APCs (2 x 105/well) from wt mice, prepulsed overnight with 100 µg/ml KLH. CD4 cells were plated in 1.5-fold dilutions down to 300 cells per well with at least 11 dilutions used per T cell group. Supernatants were harvested at 24 h and used neat in the NK bioassay to assess IL-2. Wells giving cpm values greater than 2 SDs above the mean of wells containing only T cells or APCs were considered positive. The fraction of negative wells were plotted as a log against the number of CD4 cells, and frequencies calculated using the 37% negative point (38).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the mode of action of OX40, we initially assessed the
T cell response to MCC in an adoptive transfer system, tracking TCR
transgenic T cells in mice given an agonist Ab to OX40. We have shown
the agonist activity of this Ab in vitro, and have not noted any
antagonist ability (41). Vß3/V11 CD4 cells from AND
TCR transgenic mice were adoptively transferred into syngeneic
recipients and these were subsequently immunized with two doses (50 or
5 µg) of MCC in CFA s.c (Fig. 1
). OX40
expression is induced 1–2 days after immunization in vivo, and
down-regulated 3–4 days later (our unpublished observations). To
coincide with the induction of OX40, the Ab was given on day 2 and T
cell responses assessed on day 4 and 8 in comparison to mice receiving
a control Ab.
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, a and
b, top panels). Anti-OX40 enhanced T cell
expansion compared with controls resulting in 2- to 3-fold increases in
T cell number at 4 days in the draining lymph nodes, and at 8 days in
the spleen. A greater effect was seen with a suboptimal dose of Ag (5
µg), which only produced a weak T cell response alone. With
anti-OX40, the percentage of Ag-specific T cells increased from 2%
to 12% in draining lymph nodes on day 4, and to 5% in spleen on day 8
(Fig. 1a, bottom panels). When converted to total
numbers of T cells, a 34-fold increase was observed in the draining
lymph nodes at day 4, and a 10-fold increase in the spleen at day 8
(Fig. 1b, bottom panels). Nondraining lymph nodes
either showed no difference or a slight increase in numbers of
transgenic T cells after anti-OX40 treatment (data not shown).
These results demonstrate that OX40 signals promote increased
accumulation of CD4 T cells at the sites of Ag exposure, which resulted
from clonal expansion and survival of these cells, rather than simply
altering recruitment of T cells to the site of response.
Anti-OX40 also up-regulated the secretion of IL-2, IFN-, and IL-5,
by 2- to 3-fold over controls, depending on the cytokine and the organ
studied, when assessed in bulk cultures (Fig. 2a, top panels).
Two previous reports had suggested that OX40 ligation preferentially
augmented Th2 cytokines (39, 40), although a recent study
in OX40L knockout mice showed defective Th1 and Th2 responses
(34). We did not see a bias to one particular subset in
vivo with the agonist anti-OX40, and we have seen similar results
in vitro (41). The effect on cytokine secretion was more
dramatically illustrated when responses were recalculated to take into
account the total number of Ag-specific T cells (Fig. 2a,
bottom panels). In this case, cytokine responses were
augmented 4- to 6-fold. Lastly, cytokine secretion per in vitro culture
was normalized for the number of Vß3/V11 cells plated to assess
whether anti-OX40 increased the secretion ability of each
individual T cell generated. By this calculation, there was no
detectable effect on the functional capabilities of each individual
effector T cell, as measured by IL-2 production (Fig. 2b),
or IFN- and IL-5 (data not shown). This suggests that although OX40
signals result in more effector cells being generated and surviving,
and hence more cytokine-secreting cells, each individual effector cell
does not increase their output of cytokines.
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To determine the impact on memory, adoptive transfer experiments
were conducted assessing responses 5 wk after immunization with 50 or 5
µg MCC in CFA (Fig. 3). In control
mice, the total number of Ag-specific cells was significantly elevated
at this time compared with an unimmunized mouse, indicating memory
cells had developed, with anywhere from 5- to 50-fold more cells
present depending on the initial dose of Ag (e.g., in one experiment,
on average 1.1 x 104 Vß3/V11 cells
were found in unimmunized animals, whereas 30 x
104 cells were found 35 days after Ag
immunization). Treatment with anti-OX40 resulted in elevated
percentages (Fig. 3a) and total numbers of Vß3/V11 CD4
cells (Fig. 3b) in the spleen and pooled periaortic and
inguinal lymph nodes compared with control animals, and this effect was
seen at both Ag doses. A larger increase in the number of memory T
cells was observed with 5 µg Ag, correlating with the greater action
of anti-OX40 on the primary response (Figs. 1 and 2). Frequencies
were 4- to 8-fold higher than controls in the spleen, and 2- to 4-fold
in the lymph nodes. Analysis of other lymph nodes again showed similar
numbers of T cells compared with controls, demonstrating that
recruitment could not account for the elevated frequencies (our
unpublished data).
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c).
Bulk cultures showed up to 12-fold increases in IL-2 (Fig. 3c, left panel), and this was reflected when
values were normalized based on total T cell numbers with 4- to 8-fold
more IL-2 from anti-OX40 treated animals (Fig. 3c,
middle). Again, when evaluated as IL-2 production per
transgenic cell, there was little difference between control and
anti-OX40 groups (Fig. 3c, right). We found
little evidence of other cytokines secreted from the memory cells
(IL-4, IFN-, not shown), implying that OX40 signals had not resulted
in the preferential development of Th1- or Th2-like memory. Therefore, these results demonstrate that OX40 signals can enhance development of CD4 memory. Again, the major action is to determine the number of memory cells that survive over time, rather than increase their activity on a per cell basis.
CD4 cells from OX40-deficient animals are impaired in their ability to sustain a proliferative response and to survive over time
Next, we analyzed the responses of CD4 T cells from mice made deficient in OX40 (22). We initially assessed responses of CD8-depleted populations in vitro. APCs were not removed so they could provide a source of OX40L. In some cases, activated syngeneic APCs from wt mice were additionally added to further provide OX40L costimulation. Equivalent results were obtained with OX40-/- APCs, showing we were analyzing a selective defect in OX40, and that any reduced responses were due to lack of costimulation from OX40L.
Significantly, little difference was observed in proliferation after 3
days with a low concentration of plate-bound anti-CD3, whereas
after 5 days OX40-/- T cells were proliferating
at levels greater than 50% lower than those of wt T cells (Fig. 4a, top graphs).
Similar results were obtained with the weaker stimulus of soluble
anti-CD3, except slightly reduced proliferation was evident at 3
days (60% of wt), but again much less at 5 days (30% of wt).
When analyzing T cell survival, comparable results to proliferation
were seen in that nearly identical numbers of cells were recovered from
OX40-/- cultures after 4 days with 2 µg/ml
plate-bound anti-CD3 (Fig. 4b, middle
graphs). Subsequently, survival of T cells was markedly reduced in
the OX40-/- cultures (averaging 50% of
wt), although the rate of death/survival over time, shown by the slope
of the curves, was fairly equivalent to that seen in wt cultures. With
soluble anti-CD3, somewhat reduced T cell survival was evident by 4
days (65% of wt) and numbers declined with increasing time (30%
of wt by day 10), in this case the rate of death/survival being greater
in the absence of OX40. We have recently reproduced the latter effect
with T cells from OX40-/- mice bred to AND
transgenics and responding to peptide in vitro (P. R. Rogers and
M.C., unpublished observations), suggesting that OX40 may regulate both
clonal expansion and the ability of the expanded T cells to
survive.
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c, bottom graphs). Because
OX40-negative T cells were proliferating equivalently or less than wt T
cells, it is unlikely that the lower IL-2 levels reflected increasing
consumption by the responding cells.
Therefore, these results complement our in vivo data with anti-OX40
and show that OX40 signals regulate the ability of CD4 cells to sustain
cell division during the later phases of the primary T cell response,
and are required for continued survival of high numbers of cells over
time. Interestingly, with a high dose of immobilized anti-CD3 (Fig. 4, left graphs), OX40-deficient T cells behaved identically
to wt T cells with respect to proliferation, IL-2, and cell survival,
suggesting that OX40 signals can be bypassed if there is a sufficiently
strong antigenic/TCR stimulus.
Primary and memory CD4 responses are impaired in OX40-deficient mice
Functional responses of OX40-/- mice were
assessed using KLH given i.p. in alum/B. pertussis. The
primary effector response was analyzed 7 days after immunization, and
development of memory at 35 days (Fig. 5). At 7 days,
OX40-/- CD4 cells proliferated at levels
significantly below those of wt T cells when restimulated in vitro with
KLH (25–35% of wt), and produced lower levels of all cytokines
measured (<30% of wt), including IL-2, IFN-, IL-5, and IL-4 (Fig. 5a). These results are similar to previous data obtained
with primary KLH responses in OX40L-deficient mice (34).
Importantly, we also demonstrated the novel finding that the extent of
memory was lower in the OX40-/- mice with
proliferation reduced by 70–80%, and IL-2 reduced by 80%, when
assessed 35 days after immunization (Fig. 5b). Again, IL-2
was the major cytokine detected in memory T cell cultures, and if other
cytokines were seen, these were universally reduced in the
OX40-/- cultures, suggesting no preferential
control of a particular T cell subset (not shown). These data directly
correlate with, and complement, our earlier results with the agonist Ab
to OX40 and confirm that OX40 signals are integral to the effective
development of a memory CD4 response.
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Lastly, we assessed the frequency of KLH-specific T cells that developed in OX40 knockout mice. Frequencies of primary effector cells and memory cells were measured by limiting dilution 5–7 days and 35 days after immunization, respectively. As a measure of the T cell frequency, we assessed IL-2 production, firstly because this cytokine is produced by both subsets, and secondly because the bioassay for IL-2 is the most sensitive way of determining T cell responsiveness that we have.
Fig. 6 shows the primary effector and
memory responses of three individual mice per group. In all cases, the
frequency of KLH-specific T cells was substantially reduced in the
OX40-deficient animals, regardless of the time of assay or method of
immunization. With CFA immunization, there was on average a 7-fold
difference in the frequency in the primary response, and an 11-fold
difference once memory had developed. With alum/B.
pertussis, a 40-fold lower frequency of KLH-responsive T cells was
detected in the OX40-/- mice during the primary
response, and a 24-fold lower frequency at the memory stage. Thus, OX40
signals regulate the number of Ag-specific CD4 cells that develop in
the primary response, and the number that survive over time as memory
cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The importance of OX40 in primary CD4 but not CD8 responses was shown
in initial studies of OX40 and OX40L knockout mice (22, 32, 33, 34), highlighting the requirement for this molecule in T
cell priming. Our previous results demonstrated that OX40L transfected
APCs dramatically enhanced CD4 proliferation in vitro, several days
after initial stimulation, in a situation where cell division had begun
to diminish (12), implying that a major action was to
prolong clonal expansion. This was similarly implied in the study of
OX40-/- mice responding to LCMV, where a 3- to
4-fold reduction in the number of IFN--secreting cells was detected
by FACS analyses 15 days after infection (32). The
experiments here with an agonist Ab to OX40, and with OX40-deficient T
cells, conclusively show that clonal expansion in the primary CD4
response is regulated by OX40 ligation. As well as regulating T cell
expansion, our data also show that OX40 can impact on T cell survival.
Thus, frequencies of Ag-specific cells were dramatically lower 35 days
after priming OX40-/- animals, and they were
significantly higher after treatment with anti-OX40. Overall, the
data therefore suggest that a major action of OX40 is to regulate the
number of T cells that are expanded in primary responses and thus
survive through to memory. These results appear to be consistent with
recent data assessing the impact of OX40-OX40L interactions on germinal
center (GC) reactions. In one study, transgenic expression of OX40L on
dendritic cells resulted in greater numbers of CD4 cells in B cell
follicles (43), and in a second study, an inhibitory
OX40.Fc fusion protein reduced GC size, and T cell numbers in GCs
(44).
Although we have focused on the effects of OX40 signaling to the T cell, it is possible that defects in the OX40 knockout animals were also related to a lack of OX40L signaling to various APCs. Previous studies showed that both primary and secondary IgG responses could be inhibited with a polyclonal antiserum to OX40 (23), implying that OX40 and/or OX40L signals regulated B cell responses, but not distinguishing this from an effect on inhibiting T cell expansion. Although we did not assess B cell responses in the studies here, separate analyses of OX40 knockout animals did not reveal any major defects in the B cell response to several Ags including TNP-KLH, NP-CGG, Leishmania, and Nippostrongylus (22), or VSV, LCMV, and influenza (32). These results are therefore at variance with the earlier studies with the antiserum (23), and suggest that OX40/OX40L does not have a dominant role in B cell responses in vivo. It was also recently proposed, from in vitro experiments with an agonist Ab, that OX40L could signal dendritic cells to promote secretion of inflammatory cytokines such as IL-1, TNF, and IL-6 (17). Our results in the OX40 knockout animals could then be interpreted as a requirement for OX40L to enhance dendritic cell action, which in turn would have regulated the T cell response, rather than a direct effect of OX40 signaling to the T cell. This then would be comparable to the CD40-CD40L interaction which many people regard as largely affecting the APC rather than a requirement for CD40L signals for the T cell. However, the fact that similar conclusions were derived with anti-OX40 in vivo, and that anti-OX40 also promotes T cell growth and survival in vitro (41), suggests that the main deficiency in T cell responses in OX40 knockout mice were related to a lack of signals to the T cell. It remains to be determined whether OX40L signals are critical to APC function.
Whether OX40 signals directly regulate T cell survival is not clear.
OX40 can bind TRAFs 2, 3, and 5, and this results in NF-
B activation
(45, 46), consistent with the notion of a survival effect.
Our data demonstrate a major difference in the frequencies of memory
cells if OX40 is ligated and if OX40 is lacking. However, because
frequencies were also different during the peak of the primary
response, and the relative difference between the frequency from the
primary effector to the memory stage was similar regardless of the
presence or absence of OX40 signals (see Fig. 6), it could be argued
that OX40 does not intrinsically provide a survival advantage on an
individual cell basis, only at the population level. Thus, OX40 may
largely regulate clonal expansion in the primary response, and because
of the increased numbers at this stage, more cells will persist through
to memory by default. However, other recent data, under potentially
tolerizing conditions with soluble superantigen, have shown a dramatic
difference in T cell survival over time when LPS is combined with the
agonist OX40 Ab (47), a phenomenon presumably brought
about by suppressing activation induced cell death. OX40 may therefore
synergize with, or regulate, signals from other surface molecules or
cytokines, rather than being a bona fide survival factor. Regardless,
from the data with anti-OX40 and OX40 knockout animals, it is clear
that OX40 signals can have a major impact on the frequency of T cells
that form the memory pool. As such, these studies suggest that agonist
reagents to OX40 may be useful therapeutically in enhancing T cell
memory, and antagonist reagents may limit long-term detrimental immune
responses such as those which occur in many autoimmune states.
The data from OX40 and OX40L knockout animals predict that OX40 signals
will be required during development of functional T cell populations in
most immune responses. As mentioned before, inhibition of OX40-OX40L
interaction reduced inflammatory responses in proteolipid
protein-induced EAE, trinitrobenzene sulfonic acid-induced colitis, and
in GVHD (19, 30, 31), and more recently an anti-OX40L
Ab suppressed the Th2 response in Leishmania-infected BALB/c
mice (48). Preliminary results with myelin oligodendrocyte
glycoprotein in OX40-deficient mice also show reduced severity and
incidence of EAE (A.D.W., unpublished data). However,
H2b OX40 knockout mice are resistant to
Leishmania major, and can mount normal responses to
Nippostrongylus brasiliensis (22). Because of
the latter results, it is therefore not clear what ultimately governs
the use of OX40. It was originally suggested that OX40 may only control
Th2 responses (39, 49), which could have partially
explained these results. However, the data in OX40-deficient mice with
LCMV and influenza (32), and with KLH (this paper), and in
OX40L-deficient mice with DNBS (33) and KLH
(34), clearly show that IFN- is also regulated by these
molecules. A more attractive idea, therefore, is that the use of OX40
is dependent upon the magnitude of the antigenic insult. Significantly,
in vitro, we saw normal responses of OX40-/- T
cells to a high dose of immobilized anti-CD3, but defective
responses when the apparent strength of T cell signaling was reduced
(Fig. 4). Thus, much like CD28 (50, 51), a requirement for
OX40 may be bypassed if sufficient signals can be provided by Ag to the
TCR, or via other costimulatory receptors.
In conclusion, the results of our study show that OX40-OX40L interactions regulate clonal expansion of primary CD4 T cells. Because of the ability to control T cell numbers in the primary response, OX40 signals therefore determine the extent of memory that develops. We propose the following scenario. Initial activation of a naive CD4 T cell is controlled solely by Ag/TCR signals. These result in CD40L expression, which in turn promotes APC activation and induction of B7-1 and/or B7-2. Signals through CD28 regulate the early events in the T cell, and up-regulate IL-2 production, and drive cell cycle progression and initial expansion. One to two days into the response, OX40 is induced on the T cell and OX40L on APCs. These secondary interactions then promote sustained IL-2 production, continued T cell expansion, and suppression of cell death, and result in the high frequencies of T cells characteristic of primary responses and memory. Although we stress the importance of OX40 in this paper, it is likely that OX40 is not the only molecule which functions in this regard. Two other ligand-receptor pairs of the TNFR-TNF family may also perform similar functions, namely 4–1BB-4–1BBL (52, 53, 54) and CD27-CD70 (14, 55, 56). There is insufficient data at present to compare the merits of one to the other, but it could be envisioned that different antigenic stimuli may invoke their relative involvement to different degrees, or alternatively that there may be preferential use depending on whether the responding cell is a CD4 or a CD8 T cell. Together, these molecules may determine the vigor of the primary T cell response and consequently have a critical role in establishing effective T cell memory.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint request to Dr. Michael Croft, Division of Immunochemistry, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121.
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; GVHD, graft-vs-host disease; LCMV, lymphocytic choriomeningitis virus; KLH, keyhole limpet hemocyanin; wt, wild type; MCC, moth cytochrome c; DNBS, dinitrobenzenesulfonic acid; GC, germinal center.
Received for publication April 17, 2000. Accepted for publication June 28, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B activation. J. Biol. Chem. 273:5808.B. Mol. Cell Biol. 18:558.This article has been cited by other articles:
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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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 B. Rhodes and T. J. Vyse The genetics of SLE: an update in the light of genome-wide association studies Rheumatology, November 1, 2008; 47(11): 1603 - 1611. [Abstract] [Full Text] [PDF]
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 M. J. Gough, C. E. Ruby, W. L. Redmond, B. Dhungel, A. Brown, and A. D. Weinberg OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor Cancer Res., July 1, 2008; 68(13): 5206 - 5215. [Abstract] [Full Text] [PDF]
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M. C. Wheeler, M. Rizzi, R. Sasik, G. Almanza, G. Hardiman, and M. Zanetti KDEL-Retained Antigen in B Lymphocytes Induces a Proinflammatory Response: A Possible Role for Endoplasmic Reticulum Stress in Adaptive T Cell Immunity J. Immunol., July 1, 2008; 181(1): 256 - 264. [Abstract] [Full Text] [PDF]
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 S. Piconese, B. Valzasina, and M. P. Colombo OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection J. Exp. Med., April 14, 2008; 205(4): 825 - 839. [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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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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P. Soroosh, S. Ine, K. Sugamura, and N. Ishii Differential Requirements for OX40 Signals on Generation of Effector and Central Memory CD4+ T Cells J. Immunol., October 15, 2007; 179(8): 5014 - 5023. [Abstract] [Full Text] [PDF]
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S. J. Jenkins, G. Perona-Wright, A. G. F. Worsley, N. Ishii, and A. S. MacDonald Dendritic Cell Expression of OX40 Ligand Acts as a Costimulatory, Not Polarizing, Signal for Optimal Th2 Priming and Memory Induction In Vivo J. Immunol., September 15, 2007; 179(6): 3515 - 3523. [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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 A. Valujskikh and X. C. Li Frontiers in Nephrology: T Cell Memory as a Barrier to Transplant Tolerance J. Am. Soc. Nephrol., August 1, 2007; 18(8): 2252 - 2261. [Full Text] [PDF]
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T. Kallinich, K. C. Beier, U. Wahn, P. Stock, and E. Hamelmann T-cell co-stimulatory molecules: their role in allergic immune reactions Eur. Respir. J., June 1, 2007; 29(6): 1246 - 1255. [Abstract] [Full Text] [PDF]
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I. R. Humphreys, C. de Trez, A. Kinkade, C. A. Benedict, M. Croft, and C. F. Ware Cytomegalovirus exploits IL-10-mediated immune regulation in the salivary glands J. Exp. Med., May 14, 2007; 204(5): 1217 - 1225. [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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M. MacLeod, M. J. Kwakkenbos, A. Crawford, S. Brown, B. Stockinger, K. Schepers, T. Schumacher, and D. Gray CD4 memory T cells survive and proliferate but fail to differentiate in the absence of CD40 J. Exp. Med., April 17, 2006; 203(4): 897 - 906. [Abstract] [Full Text] [PDF]
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A. Crawford, M. MacLeod, T. Schumacher, L. Corlett, and D. Gray Primary T Cell Expansion and Differentiation In Vivo Requires Antigen Presentation by B Cells J. Immunol., March 15, 2006; 176(6): 3498 - 3506. [Abstract] [Full Text] [PDF]
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 A. Fukushima, T. Yamaguchi, W. Ishida, K. Fukata, H. Yagita, and H. Ueno Roles of OX40 in the Development of Murine Experimental Allergic Conjunctivitis: Exacerbation and Attenuation by Stimulation and Blocking of OX40 Invest. Ophthalmol. Vis. Sci., February 1, 2006; 47(2): 657 - 663. [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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 J. Endl, S. Rosinger, B. Schwarz, S.-O. Friedrich, G. Rothe, W. Karges, M. Schlosser, T. Eiermann, D. J. Schendel, and B. O. Boehm Coexpression of CD25 and OX40 (CD134) Receptors Delineates Autoreactive T-cells in Type 1 Diabetes Diabetes, January 1, 2006; 55(1): 50 - 60. [Abstract] [Full Text] [PDF]
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L. Serghides, J. Bukczynski, T. Wen, C. Wang, J.-P. Routy, M.-R. Boulassel, R.-P. Sekaly, M. Ostrowski, N. F. Bernard, and T. H. Watts Evaluation of OX40 Ligand as a Costimulator of Human Antiviral Memory CD8 T Cell Responses: Comparison with B7.1 and 4-1BBL J. Immunol., November 15, 2005; 175(10): 6368 - 6377. [Abstract] [Full Text] [PDF]
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 S. P Hickman and L. A Turka Homeostatic T cell proliferation as a barrier to T cell tolerance Phil Trans R Soc B, September 29, 2005; 360(1461): 1713 - 1721. [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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A. Song, X. Tang, K. M. Harms, and M. Croft OX40 and Bcl-xL Promote the Persistence of CD8 T Cells to Recall Tumor-Associated Antigen J. Immunol., September 15, 2005; 175(6): 3534 - 3541. [Abstract] [Full Text] [PDF]
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B. Y. Ma, S. A. Mikolajczak, A. Danesh, K. A. Hosiawa, C. M. Cameron, A. Takaori-Kondo, T. Uchiyama, D. J. Kelvin, and A. Ochi The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T cells Blood, September 15, 2005; 106(6): 2002 - 2010. [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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E. Y. Kim and H.-S. Teh Critical Role of TNF Receptor Type-2 (p75) as a Costimulator for IL-2 Induction and T Cell Survival: A Functional Link to CD28 J. Immunol., October 1, 2004; 173(7): 4500 - 4509. [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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 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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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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P. Bansal-Pakala, B. S. Halteman, M. H.-Y. Cheng, and M. Croft Costimulation of CD8 T Cell Responses by OX40 J. Immunol., April 15, 2004; 172(8): 4821 - 4825. [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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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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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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Q. Tang, K. J. Henriksen, E. K. Boden, A. J. Tooley, J. Ye, S. K. Subudhi, X. X. Zheng, T. B. Strom, and J. A. Bluestone Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells J. Immunol., October 1, 2003; 171(7): 3348 - 3352. [Abstract] [Full Text] [PDF]
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F. G. Lakkis and M. H. Sayegh Memory T Cells: A Hurdle to Immunologic Tolerance J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2402 - 2410. [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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P.-J. Linton, B. Bautista, E. Biederman, E. S. Bradley, J. Harbertson, R. M. Kondrack, R. C. Padrick, and L. M. Bradley Costimulation via OX40L Expressed by B Cells Is Sufficient to Determine the Extent of Primary CD4 Cell Expansion and Th2 Cytokine Secretion In Vivo J. Exp. Med., April 7, 2003; 197(7): 875 - 883. [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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A. Curti, M. Parenza, and M. P. Colombo Autologous and MHC class I-negative allogeneic tumor cells secreting IL-12 together cure disseminated A20 lymphoma Blood, January 15, 2003; 101(2): 568 - 575. [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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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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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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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. Mestas and C. C. W. Hughes Endothelial Cell Costimulation of T Cell Activation Through CD58-CD2 Interactions Involves Lipid Raft Aggregation J. Immunol., October 15, 2001; 167(8): 4378 - 4385. [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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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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 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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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) or control IgG (
) was given i.p. Memory development was
assessed at 5 wk. All results represent mean values ± SEM from
three individual mice per group. Similar responses were seen in two
separate experiments. a, Percentage (%) of Vß3/V
) and wt
mice (
) were primed in groups of three with 100 µg KLH given
either s.c. in CFA (a) or i.p. in alum/pertussis
(b). T cell frequencies were determined by limiting
dilution assay as described in experimental procedures. The frequency
of primary effector T cells was determined on day 5 with CFA and day 7
with alum/pertussis, and the frequency of memory T cells was determined
on day 35 in both cases. Frequencies with CFA for both primary and
memory were performed on mice immunized at the same time. Memory
frequencies with alum/pertussis were derived from separate
immunizations.