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*
Research Service 151, Veterans Administration Medical Center, and
Department of Medicine, University of Tennessee, Memphis, TN 38104
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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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Consistent with this possibility, previous studies have provided
evidence that PGE2 modifies lymphokine production
and proliferation of T cells. It has been demonstrated that
PGE2 inhibits mitogen-stimulated mouse and human
T cell proliferation (8, 9). In 1990, it was reported that
increased intracellular cAMP suppressed IL-2 and proliferation of Th1
cells, but did not affect IL-4 and proliferation of Th2 cells in mice
(10, 11). Also working with murine cells, Betz and Fox
subsequently demonstrated that PGE2 and the
adenylate cyclase activator forskolin inhibited IL-2 and IFN-
production by Th1 clones, but not IL-4 and IL-5 production by Th2
clones (12). In studies using human lymphocytes, it has
been shown that increased intracellular cAMP or
PGE2 modulated T cell lymphokine production and
proliferation in a way similar to its action on murine cells (13, 14).
It is well established in mice that Th1, but not Th2, cells secrete
IL-2 and IFN-, while Th2, but not Th1, cells secrete IL-4, IL-5, as
well as IL-10 (15). In humans, however, T cells with
typical Th1 or Th2 lymphokine secretion patterns account for only a
small proportion of the total population. Most T cells secrete both Th1
and Th2 lymphokines and can be characterized as Th0 type
(16). Therefore, even though the sensitivity of T cell
proliferation in response to PGE2 can be linked
to whether the T cells are of the Th1 or Th2 phenotype, it is not clear
what effect PGE2 has on the activation and
proliferation of the majority of T cells. In addition, it is not known
whether T cells sensitive to PGE2 have a
characteristic phenotype, which has biological significance. The
present study approached these questions by examining the effects of
PGE2 on the proliferation of a large panel of
CD4+ T cell clones. By comparing T cell clones
sensitive to PGE2 with those resistant to
PGE2, as measured by proliferation in response to
anti-CD3 Ab, we discovered that the two groups of T cells
differ greatly in the production of IL-2 and IL-4, both of which are
found to be crucial in supporting T cell activities, especially in the
presence of PGE2. In addition, they are differ in
CD45 isoform expression, which might relate to the
stimulation/activation the cells have experienced.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mononuclear cells were purified from heparinized blood by Ficoll-Hypaque density gradient centrifugation. Cells at the interface were removed, washed three times, and resuspended in RPMI 1640 supplemented with 10% FBS. Cells were cultured at a concentration of 0.5–1 x 106/ml for 24 h in culture plates coated with Ab to CD3. The stimulated cells were then distributed into 96-well microtiter plates with round-bottom wells at an average concentration of 0.5 cell/culture in the presence of 104 irradiated filler cells and 50 U/ml rIL-2 (PeproTech, Rocky Hill, NJ). After 14–18 days, the outgrowing T cell clones were identified by inspection and cultured with irradiated filler cells at 3 x 105 cells/culture and 20 U/ml rIL-2 in 24-well plates. After an additional 7–10 days, the emerging T cell clones were stained with FITC-conjugated Ab to CD4 and PE-conjugated Ab to CD8 (Becton Dickinson, San Jose, CA) and subjected to flow cytometric analysis. Selected T cell clones were maintained by repeated restimulation every 7–10 days in the presence of 10 U/ml exogenous IL-2 and irradiated filler cells.
Ab to CD3 was purified from ascites fluid of nude mice injected with an anti-CD3 producing hybridoma cell line (American Type Culture Collection, Manassas, VA). For anti-CD3 stimulation, the plates were coated with Ab to human CD3 (50 µg/ml in PBS) by incubation overnight at 4°C. After washing twice to remove the unbound Abs, plates were used directly.
The filler cells were EBV transformed human B cells that were irradiated and treated with a combination of neuraminidase and galactose oxidase. The enzyme treatment alters the membrane glycoproteins and enables the human B cell lines to act as mitogens and induce strong T cell proliferative responses. The treatment and its effects have been described previously (17). Briefly, the EBV-transformed B cells were irradiated at 10,000 rad, washed twice with serum-free RPMI, and then suspended in serum-free RPMI at 5 x 106 cells/ml in the presence 0.02 U/ml of neuraminidase (Sigma, St. Louis, MO) and 0.05 U/ml of galactose oxidase (Sigma). The cells were incubated at 37°C for 90 min. After washing twice with RPMI containing 2% FCS and 10 mM galactose (Sigma) and once with wash medium without galactose, the filler cells were resuspended in RPMI complete culture medium and used.
Lymphokine analyses
For lymphokine analysis, resting T cells were cultured at a
concentration of 1 x 105 cells/culture in
RPMI with 10% FBS in flat-bottom 96-well microtiter plates coated with
Ab to CD3. In some cultures PGE2 (Sigma) was
added to assess the effects of PGE2 on lymphokine
secretion. Cultures in wells without Ab to CD3 were set up in parallel
to assess background lymphokine secretion. Supernatants were harvested
after 24 h. The cells and debris were removed from the supernatant
by centrifugation. Interferon-, IL-2, IL-4, IL-5 and IL-10 were
measured in duplicate using commercially available ELISA kits (Endogen,
Cambridge, MA; and R&D Systems, Minneapolis, MN).
Proliferation assays
For proliferation analysis, T cells were cultured at a concentration of 3–4 x 104 cells/well in RPMI 1640 with 10% FBS in flat-bottom 96-well plates coated with anti-CD3 in duplicate. After 48 h, each of the cultures was pulsed with 1 µCi of [3H]thymidine. After an additional 12 h, cells were harvested onto glass-fiber filters and counted on a Matrix 96 direct ionization beta counter (Packard, Meridian, CT). Proliferation responses were assessed by the mean [3H]thymidine incorporation.
CD45RA and CD45RO expressions
The T cells were stained with PE-conjugated Ab to CD45RA or
FITC-conjugated Ab to CD45RO (PharMingen, San Diego) and analyzed by
flow cytometry. For each sample a control Simultest Control 1/2
(Becton Dickinson, San Jose, CA) was used. CD45RA and CD45RO
expressions were assessed by mean fluorescent intensity.
Statistical analysis
Statistical evaluation of differences among multiple groups of data was performed using one-way repeated measures ANOVA. When the normality test failed, Friedman’s repeated measures ANOVA on ranks was used. The analyses were followed by Dunnett’s multiple comparison test. For differences between two groups of data the unpaired t test was used. When the normality test failed, the Mann-Whitney rank sum test was used. Data were judged statistically significant when p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 37 CD4+ T cell clones were
isolated for use in this study. On the average,
PGE2 inhibited proliferation of these cells in a
dose-dependent manner. In the presence of PGE2 at
concentrations of 10-8,
10-7, 10-6, and
10-5 M, [3H]thymidine
incorporation by the 37 T cell clones decreased from the average
control value of 53,110 by 7, 41, 62, and 78%, respectively (Fig. 1
). However, the effect of
PGE2 on the responses of individual T cell clones
differed substantially, as evidenced by the large SDs.
PGE2 strongly inhibited proliferation in some
clones, but exerted only minimal effects on others. Examples of clones
that were strongly inhibited and minimally affected are shown in Fig. 2.
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The ability of PGE2 to affect lymphokine
secretion was tested in 11 clones (Fig. 4). Five cytokines were chosen for
analysis, including IFN-, IL-2, IL-4, IL-5, and IL-10. In general,
at concentrations between 10-8 and
10-5 M, PGE2 inhibited
lymphokine production in a dose-dependent manner. However, there were
substantial differences among lymphokines. Of the five lymphokines
tested, IL-2 production was most sensitive to inhibition. It was
strongly suppressed by PGE2 at concentrations as
low as 10-8 M and was almost completely
inhibited by PGE2 at a concentration of
10-7 M. IL-10, IFN-, and IL-4 production were
also sensitive to the effects of PGE2, although
inhibition required doses that were about 10- to 1000-fold higher than
that for IL-2. IL-5 was relatively resistant to
PGE2 and was even enhanced by
PGE2 at low concentrations. To confirm the data,
all 37 CD4+ T cell clones were tested in the
presence of PGE2 at a concentration of
10-6 M. The results were consistent (Table I).
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Since it has previously been reported that Th1 cells are sensitive
to the effects of increased intracellular cAMP and
PGE2 whereas Th2 cells are not (11, 14), we attempted to correlate the sensitivity of proliferation
to PGE2 with the lymphokine secretion profile of
the T cell clones. To achieve this, we compared anti-CD3-induced
IFN-, IL-2, IL-4, IL-5, and IL-10 production of 10 T cell clones
sensitive to PGE2 as measured by proliferation
with that of 10 T cell clones resistant to PGE2
(Table II). As reported by other investigators, T cell clones that were
resistant to PGE2 in proliferation secreted
higher levels of IL-4 and IL-5 than clones that were sensitive to
PGE2 (11, 14). However, most of the
resistant clones also secreted high amounts of IL-2. A stronger
correlation was found between PGE2 resistance and
the secretion of IL-2, IL-4, or both than with Th phenotype. While T
cell clones resistant to PGE2 uniformly secreted
high levels of IL-2, IL-4, or both, all the T cell clones
sensitive to PGE2 secreted low amounts of both
IL-2 and IL-4. In contrast, both PGE2-sensitive
and PGE2-resistant groups contained clones that
were high and low producers of IFN- and IL-10, suggesting that
these two lymphokines have little, if any, correlation with the
sensitivity of T cell proliferation in response to
PGE2.
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IL-2 or IL-4 could restore the proliferative response of PGE2-sensitive T cell clones
To understand the correlation between IL-2 and IL-4 secretion and
the sensitivity of the T cell proliferation to
PGE2, the concentrations of the lymphokines
inhibited by PGE2 were measured. It was found
that in the presence of PGE2 at
10-6 M, the IL-2 and IL-4 secreted by T cell
clones with low lymphokine production usually disappeared. In
comparison, those secreted by T cell clones with high lymphokine
production were greatly inhibited, but usually still present in the
cultures (data not shown). These data suggest that both IL-2 and IL-4
might be crucial in supporting T cell proliferation, especially in the
presence of PGE2. To obtain direct evidence,
experiments were performed in which exogenous IL-2 or IL-4 was added to
two PGE2-sensitive T cell clones, H41 and H64.
Proliferation of both these T cell clones was almost completely
inhibited by PGE2 at
10-6M. Neither of the clones secreted detectable
IL-2 or IL-4 upon anti-CD3 stimulation. The experiments from both T
cell clones showed similar results. Although IL-2 was more effective,
either exogenous IL-2 or IL-4 was able to promote T cell proliferation
in the presence of PGE2. The results from T cell
clone H41 are shown in Fig. 5. In
contrast to the effects of IL-2 and IL-4, IL-10 was not capable of
restoring proliferation inhibited by PGE2.
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the sensitivity of
proliferation of the T cell clones to PGE2 could
also be correlated with IL-5 secretion. We, therefore, tested IL-5 at
concentrations of 0.2–20 ng/ml for its ability to up-regulate the
proliferation of two sensitive T cell clones in the presence of
PGE2 at 10-6 M in separate
experiments. No enhancement of proliferation by IL-5 was identified
(data not shown), suggesting that the observed correlation was not
caused by the biological effects of IL-5. Down-regulation of proliferation of PGE2-resistant T cell clones by Abs against IL-2 and/or IL-4
We further investigated the role of IL-2 or IL-4 in supporting the
proliferative response of Th1, Th2, and Th0 like cells in the presence
of PGE2 using Abs to IL-2, IL-4, or both. Abs
were added to three PGE2-resistant T cell clones,
and the clones were stimulated by Ab to CD3 in the presence of
10-6M PGE2. H62 was a
Th1-like clone that secreted 5671 pg/ml of IL-2 and 136 pg/ml of IL-4
(Table II). These levels were reduced to
682 and 52 pg/ml, respectively, by PGE2. H37 was
a Th2-like clone that secreted no detectable IL-2, but secreted 4676
pg/ml of IL-4. These levels were reduced to 867 pg/ml by
PGE2. H40 was a Th0-like clone that secreted 2377
pg/ml of IL-2 and 4864 pg/ml of IL-4, which were reduced to 21 and 4185
pg/ml, respectively, by PGE2. The proliferation
of the Th1-like clone H62 could be inhibited by
PGE2 in the presence of Ab to IL-2, while Ab to
IL-4 had only a slight effect. In contrast, the proliferation of the
Th2-like clone H37 could be inhibited by PGE2
only in the presence of Ab to IL-4, while Ab to IL-2 had no effect. For
the Th0-like clone H40, Ab to either IL-2 or IL-4 was partially
effective in inhibiting T cell proliferation in the presence of
PGE2, and the combination of both Abs was
additive (Fig. 6). These results
indicated that in the presence of PGE2,
proliferation of Th1-like cells depended on IL-2, that of Th2-like
cells depended on IL-4, and that of Th0-like cells depended on both
IL-2 and IL-4.
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CD45 is a TCR-linked protein tyrosine phosphatase that is
present in several isoforms. Although its exact function is not clearly
understood, it is known that naive cells express the CD45RA isoform,
and after activation some cells express the CD45RO isoform. It has been
suggested that CD45RO is a marker for memory T cells (18).
To determine whether there was a correlation between CD45 isoform
expression and sensitivity to PGE2,
PGE2-sensitive and -resistant clones were
analyzed by flow cytometry for CD45 isoform expression. These studies
were conducted soon after the clones were established to minimize the
effects of repeated in vitro restimulation. The mean intensity of
CD45RA expression in the sensitive clones ranged from 0.5 to 2.3, which
was significantly lower than that of the resistant clones, which ranged
from 6.3 to 19.0 (mean, 1.2 ± 0.6 vs 7.8 ± 5.7;
p = 0.001). In contrast, CD45RO expression in the
PGE-sensitive clones ranged from 36.2 to 78.4, which was significantly
higher than that of resistant clones, which ranged from 9.4 to 45.1
(mean, 55.7 ± 15.1 vs 33.4 ± 12.9; p =
0.02; Table III). As examples, the
results of a PGE2-sensitive T cell clone (H63)
and a PGE2-resistant T cell clone (H37) are shown
in Fig. 7. Data are shown for seven
resistant and six sensitive clones that were analyzed simultaneously.
The other three of the 10 sensitive and four of the 10 resistant clones
were also tested in the same way, but in a different experiment, and
gave comparable results, although the precise level of staining was
variable (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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to PGE2 inhibition.
The reason for the inconsistency is not clear. One reason may be that
we studied randomly selected T cell clones, while other groups used
PBLs or representative T cell clones with typical Th patterns.
Our data suggest that in the presence of PGE2,
IL-2 can support the proliferation of Th1 cells, IL-4 can support that
of Th2 cells, while either IL-2 or IL-4 can support that of Th0 cells.
Because IL-2 is much more sensitive to inhibition than IL-4, it is not
surprising that, on the average, proliferation of Th1 cells was more
sensitive to inhibition by PGE2 than was that of
Th2 cells (11, 14). Consistent with this, we also observed
that proliferation of Th1 clones that secreted moderate levels of IL-2
was usually more sensitive to PGE2, in contrast
to that of Th2 clones that secreted moderate levels of IL-4 (data not
shown). However, our overall results do not fully support the concept
that the proliferation of Th1 cells is sensitive to
PGE2 inhibition whereas that of Th2 cells is not.
As examples of important exceptions, we have shown that the
proliferation of some Th1-like clones that secrete high levels of IL-2,
such as H43 and H62 was resistant to PGE2. In
addition, the proliferation of some Th2-like clones that secrete low
levels of IL-4, such as H52, was sensitive to
PGE2 (see Table II).
It has been reported that a class of cytokines, including the T cell
lymphokines IL-2 and IL-4, use a shared receptor-signaling component
that forms the -chain of the IL-2R (19). Any lymphokine
whose effect is mediated through the shared pathway will support cell
proliferation (20, 21). Our studies showed that in the
presence of PGE2, IL-2 and/or IL-4 secretion by
resistant T cell clones was diminished, but usually still present. The
reduced levels of lymphokines were apparently sufficient to maintain
cell proliferation. This explanation is strongly supported by
additional experiments in which the IL-2 and/or IL-4 concentration in
the culture was increased by the additional exogenous lymphokines or
was decreased by Abs against the lymphokines. However, this might not
be the whole story. We have found that PGE2 could
still, to some extent, inhibit the T cell proliferation of sensitive T
cell clones even in the presence of a high amount of exogenous IL-2
(data not shown), suggesting that other mechanisms of suppression might
also exist. Further study of the effects of PGE2
on the regulation of genes relating to T cell activation/proliferation
and the interaction between IL-2R -chain signaling and the gene
regulation in PGE2-resistant and -sensitive T
cell clones might help us to understand more about the mechanisms of
PGE2 inhibition.
Although the present study addressed the roles of IL-2 and IL-4 in T
cell activation and proliferation in the presence of
PGE2, it does not exclude the possibility that
other lymphokines may also be involved. Lymphokines that use the IL-2R
common -chain and support T cell activities include not only IL-2
and IL-4, but also IL-7, IL-9, and IL-15 (19, 20, 21). T cells
do not produce IL-7 and IL-15 (22, 23, 24). Therefore, these
lymphokines are unlikely to have been involved in the experimental
system we used. However, they may be important in preventing T cell
activities from being inhibited by PGE2 in vivo,
especially in some inflammation sites. IL-9 is a T cell lymphokine that
is preferentially expressed in CD4+ Th2
cells (25). It is possible that this lymphokine may also
be involved in the experimental system we used. It is likely, however,
that IL-9 secretion would parallel IL-4 in much the same way that IL-5
does. In any case, the presence of IL-9 would not alter the observation
that PGE2 sensitivity is not dependent upon Th
classification.
Our data suggested that sensitivity to PGE2 is not determined by the Th1 or Th2 phenotype. To determine whether the sensitivity to PGE2 is related to the activation states of T cells, we analyzed the cell lines for activation markers. Although several markers were tested, we report here on our findings with CD45. CD45 is a member of a family of molecules that appear to play a role in activation through the TCR. CD45 isoforms are expressed on various cells, and the pattern of expression varies with the stage of development and antigenic stimulation. CD45RA is the high m.w. form of CD45, while CD45RO is a lower m.w. form. Both forms act as protein tyrosine phosphatases. However, the precise functions of CD45 isoforms remain incompletely understood (26, 27, 28).
It was previously believed that CD45RA and CD45RO are markers of virgin and memory T cells, respectively (18). This was based on the in vitro observations that CD45RO is expressed after activation, and cells that express it respond more vigorously to recall responses (29, 30, 31). These cells also express a combination of early and late activation markers and several adhesion molecules (18, 32). However, subsequent in vivo studies have shown that cells can revert to expression of CD45RA (33, 34, 35). Therefore, although the correlation between the expression of CD45 isoforms and the sensitivity to PGE2 found in the present study relates the sensitivity to PGE2 to the memory status of T cells, it is still unclear whether the cells with distinct sensitivity to PGE2 represent a unique subset of cells.
Of course, the cells used in these experiments have all been stimulated in culture, so we were unable to measure the response of a truly naive cell. All the cell lines in these experiments had some level of CD45RO expression. To minimize the effects of repeated stimulation, all cells were tested soon after isolation (all were stimulated three or four times), so all had experienced a similar number of doublings during our cloning procedure. In addition, the proliferative responses and the sensitivity to PGE2 of 11 clones and the IL-2 and IL-4 secretion of eight clones were successively tested two or three times. All measurements appear relatively stable. However, with continued long term culture of the PGE2-resistant cell lines we have observed an increase in sensitivity to PGE2 that is associated with decreased CD45RA and increased CD45RO expression (data not shown).
It has been reported that naive CD4+ T cells produce only IL-2 and IL-3, whereas memory cells can be induced to secrete a range of T cell cytokines (18). It seems, therefore, that although naive T cells are limited in their ability to produce lymphokines, after a few cycles of stimulation they become potent lymphokine producers. Based on our findings, at this stage they would be resistant to the effects of PGE2. Cells that were CD45RO in vivo and had been restimulated and expanded in vitro may have reduced overall lymphokine production and become PGE2 sensitive.
In conclusion, our present study has correlated sensitivity to
PGE2 with the secretion of IL-2R -chain
signaling cytokines and the activation status of
CD4+ cells. Our data do not fully support the
differential regulation of Th1- and Th2-mediated responses. Cells that
express high levels of IL-2 or IL-4 are resistant to
PGE2. This is most likely due to the inability of
PGE2 to completely suppress cytokine production,
as confirmed by altering the response by addition of exogenous
cytokines or absorptive Abs. These data suggest the possibility that
the down-regulation of IL-2R -chain signaling cytokines in T
cell-mediated inflammatory diseases, especially those with chronic
recurrence, may lead to enhanced sensitivity of the T cells to
PGE2 inhibition and diminished inflammatory
responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Xiaowen He, Research Service 151, Veterans Administration Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104. E-mail address:
3 Abbreviation used in this paper: PGE, PG of the E series.
Received for publication December 18, 1998. Accepted for publication September 17, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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c chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266:1042.-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xS) gene expression. Eur. J. Immunol. 26:294.[Medline]
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