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,
*
Department of Pathology,
Committee on Immunology, and
Department of Medicine, University of Chicago, Chicago, IL 60637; and
Department of Surgery, University of Wisconsin, Madison, WI 53792
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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TCR
ligand. Moreover, JNK activation was also detected in
2C/RAG2-/- T cells stimulated with P815 cells that
express the relevant alloantigen Ld whether or not B7-1 was
coexpressed. However, IL-2 production by both Th1 clones and
CD28+/+ 2C/RAG2-/- T cells was detected only
upon TCR and CD28 coengagement. Thus, CD28 coligation is not necessary,
and stimulation through the TCR is sufficient, for JNK activation in
normal murine T cells. The concept that JNK mediates the costimulatory
function of CD28 needs to be reconsidered. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD28 is constitutively expressed on naive and differentiated T cells, and is believed to be the principal costimulatory molecule in T cell activation (3). The role of CD28 is best described with respect to the functional outcomes of its coligation with the TCR complex. CD28 costimulation results in increased production of several cytokines, although IL-2 production is particularly CD28 dependent. Augmented cytokine production results both from increased transcription and enhanced mRNA stability (4, 5). CD28 has also been described to promote T cell survival, which was observed to correlate with up-regulation of Bcl-xL (6), and to prevent the induction of anergy in Th1 T cell clones (7). Consistent with these observations, blockade of CD28 in vivo is immunosuppressive and can in some cases result in Ag-specific tolerance (8, 9, 10).
Although much is known about the biochemical consequences of TCR ligation, and several events resulting from CD28 engagement have been described, it is not clear which CD28–induced signals are required to promote IL-2 production. It has been reported that signal integration through these two receptors may occur at the level of the c-Jun N-terminal kinase (JNK)3 (11). In the Jurkat model system, JNK activity was observed upon stimulation with anti-CD3 in combination with anti-CD28, but ligation of either receptor alone failed to activate JNK. Because JNK activation correlated with combined stimulation through the TCR and CD28, it has been suggested that JNK may mediate the costimulatory function of CD28. In addition, the observation that JNK activation is blunted in anergic Th1 clones has reinforced the correlation between JNK activity and IL-2-producing capability (12, 13).
JNK is a mitogen-activated protein (MAP) kinase that phosphorylates c-Jun and other related transcription factors (14). Phosphorylated c-Jun then heterodimerizes with Fos proteins to form the transcription factor AP-1, which has been shown to be important for IL-2 gene transcription (5). In one recent set of studies, JNK1-deficient T cells as well as JNK1+/-JNK2+/- T cells were shown to be hyporesponsive to stimulation, proliferating less and producing less IL-2 compared with wild-type counterparts (15). However, in an independent report, T cells deficient in both JNK1 and JNK2 showed increased proliferation upon TCR/CD28 coligation (16, 17, 26), suggesting that JNK proteins may actually negatively regulate acute T cell activation. Thus, the precise role of JNK in T cell signaling through the TCR and/or CD28 remains unclear.
We sought to readdress the question of whether CD28 costimulation was necessary for activation of JNK, using normal murine T cells. For this purpose, we used two model systems: CD4+ Th1 and Th2 clones and CD28+/+ or CD28-/- TCR transgenic T cells. Strikingly, JNK activity was readily induced in CD28-/-/2C TCR transgenic/recombinase-activating gene 2 (RAG2)-/- T cells stimulated with anti-CD3 mAb or with Ld/peptide dimers, although significant IL-2 production was not detected in the absence of CD28 ligation. These results suggest that the concept of JNK activation as the critical point of integration of signaling through the TCR and CD28 needs to be reconsidered.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The 2C TCR transgenic mice were developed as described
previously (18), and obtained from D. Loh (Washington
University School of Medicine, St. Louis, MO). The 2C
(H2-Kb) T cells are specific for the alloantigen
Ld complexed with the octapeptide p2Ca, derived
from the ubiquitously expressed -ketoglutarate dehydrogenase. These
mice were intercrossed with RAG2-deficient mice to obtain
2C/RAG2-/- mice, which in turn were bred to
CD28-deficient mice to obtain
2C/RAG2-/-/CD28-/-
animals. DBA/2 mice were purchased from The Jackson Laboratory (Bar
Harbor, ME). All mice were housed in a specific pathogen-free barrier
facility at the University of Chicago (Chicago, IL).
T cell clones
Two I-Ad-restricted, OVA-specific CD4+ T cells clones were used: the Th1 clone, PGL10, and the Th2 clone, PL104. Clones were cultured in DMEM (Life Technologies, Gaithersburg, MD) supplemented with 5% FCS and incubated at 37°C in an 8% CO2 atmosphere. They were maintained by weekly passage with irradiated DBA/2 splenocytes (2000 rad), OVA (200 µg/ml; Sigma, St. Louis, MO), and human rIL-2 (12.5 U/ml; Chiron, Emeryville, CA), as described (19). Before use in experiments, T cells were purified by centrifugation over Ficoll-Hypaque.
Cell lines and transfectants
P815 mastocytoma cells were cultured in DMEM supplemented with 10% FCS and incubated at 37°C in an 8% CO2 atmosphere. P815 cells transfected with murine B7-1 (P815.B7-1) were derived and maintained as described (20). Both cells express the alloantigen Ld recognized by 2C T cells.
Purification and in vitro priming of 2C/RAG2-/-/CD28+/+ and 2C/RAG2-/-/CD28-/- T cells
All experiments were performed with primed CD8+ T cells. CD8+ T cells were isolated from spleen using a negative enrichment protocol based on a magnetic separation system (Stem Cell Technologies, Vancouver, Canada). Priming of 2C/RAG2-/-/CD28+/+ T cells was achieved by stimulation with P815.B7-1 cells. Cultures were initiated by admixing 2C/RAG2-/- T cells (5 x 104) with mitomycin C-treated P815.B7-1 cells (3.5 x 105) in 24-well Linbro tissue culture plates (ICN Biomedicals, Emeryville, CA). Mitomycin C treatment was performed as described (20). In experiments in which 2C/RAG2-/-/CD28+/+ and CD28-/- T cells were directly compared, priming was performed with mitomycin C-treated P815 cells in the presence of human rIL-2 (20 U/ml). After 5–6 days in culture, cells were harvested and purified by centrifugation over Ficoll-Hypaque for use in experiments.
Stimulation of T cells for biochemical analysis and lymphokine production
T cells were stimulated with beads coated with varying concentrations of anti-CD3 mAb (145-2C11) in the presence or absence of an anti-CD28 mAb (PV1). The Abs were immobilized onto sheep anti-mouse-coated beads (Dynal, Oslo, Norway) by overnight incubation at 4°C in bead-binding buffer (0.5% BSA (Sigma) in Ca2+/Mg2+-free Dulbecco’s PBS (DPBS; Life Technologies)) with the desired amount of Ab. Beads were rinsed twice with bead-binding buffer and resuspended in stimulation medium (DMEM containing 1 mM MOPS). For stimulation, a 5:1 bead:T cell ratio was used. T cells (3 x 106) were incubated with the Ab-coated beads (15 x 106) for 20 min at 37°C, after which the reaction was stopped by addition of ice-cold Ca2+/Mg2+-free DPBS. The cells were then either lysed and analyzed by Western blotting, or lysed and analyzed for JNK kinase activity.
For experiments in which T cells were stimulated with H2-Ld dimers, Ld dimers were prepared as described (21) and coated onto sheep anti-mouse beads (Dynal) at the specified concentrations. Coating was performed overnight at 4°C in Ca2+/Mg2+-free DPBS containing the appropriate concentration of Ld dimer loaded with QL9 peptide. Before stimulation, beads were washed once with Ca2+/Mg2+-free DPBS containing QL9 peptide (1 nM) and then resuspended in stimulation buffer. Stimulations were done as described above, followed by analysis by Western blotting or in vitro kinase assay.
For experiments in which APCs were used as acute stimulators, P815 and P815.B7-1 cells were first mitomycin C treated as described above, then washed extensively before mixing with T cells. A 2:1 T cell:stimulator cell was used in all experiments, and both T cells and stimulator cells were resuspended in stimulation medium. T cells (3 x 106) were incubated with stimulator cells (1.5 x 106) for 20, 60, and 120 min at 37°C, after which the reaction was stopped by addition of ice-cold Ca2+/Mg2+-free DPBS. The cells were then lysed and analyzed by Western blotting for phospho-JNK. For the 0-min time point, 2C/RAG2-/- CD8+ T cells and stimulator cells were lysed individually, and the lysates were combined.
Parallel stimulations for measuring cytokine production were performed
as follows. T cells (1 x 105) were
stimulated with either Ab- or Ld dimer-coated
beads (5 x 105) in triplicate cultures in
96-well Costar plates (Corning, Cambridge, MA), in a final volume of
250 µl. When using APCs, T cells (1 x
105) were stimulated with either mitomycin
C-treated P815 or P815.B7-1 cells (0.5 x
105) in triplicate cultures in 96-well Costar
plates, in a final volume of 200 µl. Supernatants were removed at
16–24 h and assessed for IL-2 and IFN-
content by ELISA using Ab
pairs obtained from BD PharMingen (San Diego, CA).
SDS-PAGE and Western immunoblotting
The lysis buffer used in all experiments consisted of 50 mM Tris-HCl, pH 7.6, 5 mM EDTA, 150 mM NaCl, 1 mM Na3VO4, 10 µg/ml leupeptin, 10 µg/ml aprotinin, 10 µg/ml soybean trypsin inhibitor, 1 mM benzamidine, 25 mM p-nitrophenyl p-guanidinebenzoate, 1 mM PMSF, 1 mM sodium fluoride, pH 7.4, and 0.5% Triton X-100. Cells were lysed for 30 min on ice, after which the lysates were centrifuged for 10 min at 12,000 x g. The supernatants were transferred to a new tube containing 5x reducing sample buffer (250 mM Tris-HCl, pH 6.8, 500 mM DTT, 10% SDS, 50% glycerol, 0.5% bromophenol blue, 2% 2-ME). Samples were heated for 5 min at 95°C and separated using 10% SDS-PAGE. After transferring onto a polyvinylidene difluoride membrane (Millipore, Bedford, MA), Western blotting was performed as described (22). Anti-phospho-extracellular signal-related kinase (ERK) and anti-phospho-JNK were obtained from Promega (Madison, WI). The anti-JNK1 mAb used for immunoblotting for total JNK1 was obtained from BD PharMingen, and total ERK was detected using anti-ERK mAb (Zymed, South San Francisco, CA).
JNK kinase assays
JNK kinase assays were performed as described (23).
Briefly, T cells (2 x 106) were stimulated
with either Ab- or Ld dimer-coated beads (10
x 106) for 20 min at 37°C, after which the
reaction was stopped by addition of ice-cold
Ca2+/Mg2+-free DPBS. The
cells were then lysed in lysis buffer (20 mM Tris, pH 7.6, 0.5%
Nonidet P-40, 250 mM NaCl, 3 mM EDTA, 3 mM EGTA, 10 µg/ml aprotinin,
2 mM DTT, 0.1 mM Na2VO4).
Endogenous JNK was immunoprecipitated from T cell extracts with an
anti-JNK mAb (BD PharMingen). The activity of the immune complex
was assayed at 30°C for 30–60 min in 30 µl kinase buffer in the
presence of 10 µM ATP/10 µCi [32P]ATP
(10 Ci/mmol; ICN Biomedicals) with GST-c-Jun 1–79(1–79) as substrate. The
reactions were terminated with 5x reducing sample buffer. The proteins
were resolved by 12% SDS-PAGE, followed by autoradiography. Coomassie
blue staining was performed as a loading control.
Proliferation assays
Proliferation assays were performed as described (20). Briefly, 2C/RAG2-/- T cells (3 x 105) were stimulated with an equivalent number of mitomycin C-treated P815 or P815.B7-1 cells in 96-well Costar plates (Corning). After a 72-h incubation, cells were pulsed with 0.5 µCi [3H]thymidine (ICN Biomedicals) for 8 h, at which time the plates were frozen and thawed, and the wells were harvested for determination of [3H]thymidine incorporation using a Packard cell harvester and plate reader (Packard, Meriden, CT).
For measuring proliferation of 2C/RAG2-/- T cells stimulated with Ld dimers, T cells (1 x 105) were stimulated with Ld/peptide dimer-coated beads (5 x 105) in triplicate cultures in 96-well Costar plates (Corning), in a final volume of 200 µl. Cultures were pulsed at 72 h, and proliferation was determined as described above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To begin to examine whether JNK activation depended upon CD28
ligation, CD4+ Th1 and Th2 clones were stimulated
with varying doses of anti-CD3 mAb alone, or anti-CD3 and
anti-CD28, and induction of phospho-JNK was assessed by Western
blot analysis. As shown in Fig. 1
, whereas a low concentration of anti-CD3 (1 µg/ml) failed to
induce detectable phosphorylation of JNK1/JNK2 in Th1 and Th2 clones,
the addition of anti-CD28 mAb cooperatively promoted JNK
phosphorylation in both cell subsets. ERK1/ERK2 phosphorylation showed
a different behavior, being promoted even by a low-dose anti-CD3
alone. These data were consistent with previous reports
(11). However, a higher dose of anti-CD3 mAb (10
µg/ml) was sufficient to promote JNK phosphorylation even in the
absence of anti-CD28 mAb.
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). However, T cells stimulated with
anti-CD3 and anti-CD28 produced IL-2 at all concentrations of
anti-CD3 examined. The extent of JNK phosphorylation varied between
experiments, but was always detected with higher doses of anti-CD3
mAb alone. In contrast to IL-2, production of IFN- was observed in
response to anti-CD3 mAb even without anti-CD28, confirming
that ligation of the TCR complex did have a functional consequence
(data not shown). These results indicated that JNK activation was not
sufficient for IL-2 production.
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It was conceivable in the above experiments that CD28 may have
been ligated by B7 expressed by contaminating APCs or by the T cells
themselves. Therefore, we examined JNK activation in primed T cells
from wild-type and CD28-deficient 2C TCR transgenic T cells
(2C/RAG2-/- and
2C/RAG2-/-CD28-/- T
cells, respectively). Upon stimulation with anti-CD3 mAb alone,
phosphorylated JNK1 was detected in cell lysates of both
2C/RAG2-/- and
2C/RAG2-/-CD28-/- T
cells (Fig. 3A), supporting
the notion that JNK phosphorylation did not require CD28. Although the
extent of JNK phosphorylation varied between experiments, phospho-JNK
was reproducibly detected following TCR ligation in
2C/RAG2-/-CD28-/- T
cells.
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B, increasing concentrations of anti-CD3
mAb induced comparable JNK kinase activity in both
CD28+/+ and CD28-/- 2C T
cells, in a dose-dependent manner (Fig. 3B). However,
significant IL-2 production was only observed in the
CD28+/+ T cells, and only when anti-CD28 mAb
was included, although IFN- production was induced at comparable
levels in both populations (data not shown). These results demonstrate
that JNK kinase activity can be activated in the absence of CD28
following CD3 ligation alone. JNK kinase activity is induced in 2C/RAG2-/-/CD28-/- T cells by Ld/peptide dimers
We examined whether ligation of the TCR complex by natural
ligands also could promote JNK activation in the absence of CD28. This
type of experiment was enabled by the use of TCR
transgenic/CD28-deficient T cells. The 2C TCR recognizes the
alloantigen Ld complexed to a peptide called p2Ca
derived from the ubiquitously expressed protein, -ketoglutarate
dehydrogenase. A high affinity peptide, designated QL9, has been
generated by the inclusion of an N-terminal glutamine in the native
sequence (24). To examine JNK activation in response to a
physiologic TCR ligand, we used QL9 peptide-loaded recombinant
Ld dimers immobilized to beads for stimulating 2C
T cells. MHC molecules rendered dimeric via fusion to an Ig backbone
have been shown to activate Ag-specific T cells, resulting in TCR
down-modulation, cytokine production, and proliferation
(25).
Ld dimers were loaded with QL9 peptide and used
to stimulate 2C/RAG2-/- and
2C/RAG2-/-/CD28-/- T
cells. As shown in Fig. 4A,
activation of JNK, measured using either phospho-specific JNK Abs or in
vitro kinase assay, was detected at similar levels in both wild-type
and CD28-deficient 2C T cells stimulated with Ld
dimers. Similar to the results obtained with anti-CD3, IFN- was
detected in response to Ld dimer stimulation in a
dose-dependent fashion, but IL-2 was not (data not shown).
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B). Ld dimers plus anti-CD28
stimulation resulted in IL-2 production at all concentrations of dimer
analyzed, and were also capable of inducing proliferation in a
dose-dependent fashion (data not shown). Similar levels of IFN- were
detected in cells stimulated with Ld dimer with
and without anti-CD28 (data not shown). Collectively, these results
suggest that JNK is activated following stimulation with a direct
TCR ligand in the absence of CD28 coligation, although it is not
sufficient for IL-2 production. JNK activation is equivalently induced in 2C/RAG2-/- T cells stimulated with P815 and P815.B7-1 cells
We finally investigated whether APCs could stimulate JNK
activation in the absence of CD28 coligation. P815 cells either
untransfected (P815) or transfected with B7-1 (P815.B7-1) were used to
stimulate 2C/RAG2-/- T cells. This experiment
was complicated by the contribution of proteins from the P815 cells
that resulted in background binding by the phospho-JNK Ab. Nonetheless,
as shown in Fig. 5A, JNK1
phosphorylation could be distinguished from this background, and
comparable levels of phosphorylated JNK1 were detected in 2C cells
stimulated with P815 and P815.B7-1 cells. Consistent with all our
previous observations, IL-2 production and proliferation were only
detected in response to B7-1 costimulation (Fig. 5B). Thus,
with each experimental model used, including stimulation with APCs, JNK
activation was observed in the absence of CD28 coligation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, the precise role of JNK activation in IL-2 production is unclear. Sabapathy and colleagues (15) reported that JNK1-/- and JNK2-/- T cells, as well as JNK1+/-JNK2+/- T cells, exhibited hypoproliferation and reduced IL-2 production upon stimulation, arguing for similar positive roles of JNK1 and JNK2 in T cell activation. However, others have reported that T cells from JNK1-/- mice hyperproliferated in response to stimulation with either anti-CD3 or anti-CD3 plus anti-CD28 (16, 17). Moreover, Dong and colleagues (26) reported that, using three different model systems, JNK was not necessary for T cell activation. In their experiments, T cells from mice expressing a dominant-negative JNK1 and deficient for JNK2 showed increased IL-2 production and proliferation in response to TCR ligation. Similar results were obtained with T cells deficient for both JNK1 and JNK2, and T cells deficient for MAP kinase kinase (MKK) 7, an upstream activator of JNK. Despite lack of a positive effect on IL-2 production, JNK-deficient T cells did show preferential differentiation toward a Th2 lineage during in vitro priming, arguing for a role in effector cell differentiation. Reconciling these various results may require an alternative approach for eliminating JNK function selectively in postthymic cells.
It has been suggested that signal integration of TCR and CD28 pathways can be traced upstream of JNK to other proteins reported to participate in the JNK pathway, such as MKK4. As with JNK, there is conflicting evidence from MKK4-deficient T cells, with one report observing spontaneous lymphoadenopathy and polyclonal T cell expansion, and another study observing hyporesponsiveness to TCR and CD28 stimulation (27, 28). However, as mentioned above, data from MKK7-/- T cells support the notion that absence of the JNK pathway renders T cells hypersensitive to TCR stimulation.
In our current study, we report that JNK activation is observed in the absence of CD28 coligation, both in CD4+ and in CD8+ T cell systems. Th1 and Th2 CD4+ T cell clones activated JNK in response to ligation of CD3 alone. Although high-dose anti-CD3 mAb is sufficient to induce anergy in this Th1 clone as well as in other similar clones (12, 29), this observation suggests that JNK activation is unlikely to be sufficient to prevent anergy induction. In addition, because JNK phosphorylation was detected equivalently in both Th1 and Th2 cells, the latter of which fail to make IL-2, these results also suggest that JNK activation is unlikely to be sufficient to enable IL-2 production. JNK activation was detected in CD28-/-/2C TCR transgenic T cells in response to either anti-CD3 stimulation alone or Ld dimers alone. Furthermore, JNK phosphorylation was detected in 2C/RAG2-/- T cells stimulated with P815 cells expressing Ld, even without B7. Thus, in both model systems and under all stimulation conditions tested, CD28 coligation was not necessary for JNK activation.
Our data are, on the surface, contradictory to those reported by Su et al. (11). The differences in our findings most likely result from the experimental systems used. Previous reports used Jurkat cells stimulated with a single dose of anti-TCR mAb, whereas we have used nontransformed T cells, a range of doses of anti-CD3 mAb, and more physiologic TCR ligands. In our current study, the fact that strong JNK activation could be detected in the absence of IL-2 production, and that IL-2 production could be observed under conditions of minimal JNK activity questions the notion that JNK mediates the costimulatory function of CD28, at least with respect to IL-2 production.
Our studies clearly confirm the importance of CD28 costimulation for
IL-2 production, both by CD4+ and
CD8+ T cells. However, although JNK activation
could be detected in the absence of CD28 coligation, it was not
sufficient for IL-2 production. We have observed that production of
IFN- by Th1 cells, as well as production of IL-4 by Th2 cells, was
induced at high levels in response to TCR ligation alone. In addition,
cytolytic activity by cells having lytic potential is not dependent
upon CD28 ligation (2). Thus, our studies cannot rule out
a role for JNK in these other T cell functions that are CD28
independent. JNK activity has been reported to contribute to the
stabilization of cytokine mRNA (30). Although our data
cannot argue against a role of JNK in IL-2 message stabilization, they
suggest that JNK activity is not sufficient for IL-2 protein expression
in the absence of CD28 coligation. In conclusion, our results suggest
that the ability of CD28 costimulation to promote the production of
IL-2 is unlikely to be mediated through JNK.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas F. Gajewski, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. E-mail address: tgajewsk{at}medicine.bsd.uchicago.edu
3 Abbreviations used in this paper: JNK, c-Jun N-terminal kinase; DPBS, Dulbecco’s PBS; ERK, extracellular signal-related kinase; MAP, mitogen-activated protein; RAG2, recombinase-activating gene 2; MKK, MAP kinase kinase.
Received for publication June 13, 2001. Accepted for publication July 5, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production. J. Exp. Med. 179:299. in immune regulation. III. Differential selection of TH1 and TH2 murine helper T lymphocyte clones using recombinant IL-2 and recombinant IFN-. J. Immunol. 143:15.[Abstract]
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