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Division of Life Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ 08854
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and c-myc mRNA decay throughout a time course of
T cell activation revealed patterns of regulation that were distinct
from CD154. Similar to the effect on TNF- mRNA, stimulation of T
cells with PMA + ionomycin greatly increased the stability of CD154
message. However, CD154 message stability was only modestly increased
in T cells coactivated with anti-CD3 and anti-CD28 at 5 h
and not increased by costimulation at 24 h. Finally, an analysis
of both mRNA and surface protein expression over a time course of T
cell activation with anti-CD3 revealed a rapid induction of
expression early after activation. This induction was followed by a
more gradual decrease in expression over the next 48 h. Together,
these data support a role for posttranscriptional regulation in the
control and overall expression of CD154 in activated T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies examining the kinetics of CD154 expression have shown maximal levels of surface expression 6–24 h after T cell activation with various stimuli. The amount, as well as the kinetics of CD154 expression over a time course of activation, appear to depend on the type of activation stimuli and on costimulatory interactions provided by B cells or APCs (6, 7, 8, 9, 10, 11, 12, 13, 14, 15). For example, T cell contact with CD40-expressing cells clearly down-regulates CD154 surface expression on activated T cells by increasing receptor-mediated endocytosis (12). But, decreased surface expression through CD40 contact does not correlate with a reduction in the steady-state level of CD154 mRNA (15). Also, costimulation through CD28 appears to augment the expression of CD154, which is accompanied by an increase in CD154 mRNA (11). However, the absolute requirement for costimulation on the induction of CD154 expression is debatable (16, 17, 18). Together, these results point toward CD154 expression being controlled by multiple factors. These factors may be contingent on the process by which T cells become activated and the extent to which the cell has received additional signals through costimulatory and/or adhesion molecules. Also, the time after activation is an important variable in the expression of both CD154 mRNA and protein.
Posttranscriptional control of messenger RNA stability is a particularly important component of the regulation of many human genes, such as cytokines and proto-oncogenes, that are expressed in response to specific cellular signals. Rapid changes in overall mRNA levels can be more easily achieved when both transcription rate and message stability are altered (reviewed in 19). The rapid and transient expression of CD154 during T cell activation suggest that a layer of control may be at the posttranscriptional level.
Several observations suggest that CD154 may be regulated at the level
of message stability. First, the CD154 gene shares considerable
sequence homology with its family member TNF-, which has been shown
to be regulated in part by control of message stability (20, 21, 22).
Second, the CD154 message, like TNF-, contains multiple copies of
the AUUUA sequence in its 3' untranslated region
(3'-UTR)3. This element has
been identified as a sequence motif that affects the message stability
of many mRNAs (23, 24, 25). The mRNA stability of several cytokines is
correlated with RNA-binding activities that selectively bind to AUUUA
multimers in the 3'-UTR of these cytokine messages during T cell
activation (21, 26).
More recent studies have directly demonstrated functional relationships between AU-rich element (ARE)-binding trans-acting factors and the control of mRNA stability. For example, Hel-N1, a protein isolated on the basis of homology to the drosophila embryonic lethal abnormal vision (ELAV) gene, appears to stabilize the glucose transporter (GLUT-1) mRNA when overexpressed in 3T3 cells by binding to AU-rich 3'-UTR sequences (27). Another member of the ELAV-like family, HuR, binds in vitro to ARE found in several mRNAs like IL-3 and c-fos (28). Interestingly, this protein has in vitro RNA-binding specificity to different AU-rich sequences that correlates with the ability of those sequences to direct in vivo mRNA decay (28, 29). Stabilizing or destabilizing RNA-binding factors that recognize AU-rich 3'-UTR sequences could regulate CD154 message stability during T cell activation.
To investigate whether mRNA stability contributes to the overall regulation of CD154 expression, we have examined CD154 mRNA stability under different conditions of T cell activation. We have found that CD154 message stability in CD4+ T cells is dependent on the pathway and duration of T cell activation. Also, costimulatory signals did not significantly alter the stability of the CD154 message. In relating these findings to CD154 surface expression, CD154 was detected on the surface of purified CD4+ T cells at both early and later times following activation with an anti-CD3 mAb. Together, these findings suggest that the posttranscriptional regulation of mRNA stability plays a role in the control of CD154 expression during T cell activation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD4+ T cells were removed from 50 cc human leukocyte preparations provided by the New Brunswick Affiliated Hospitals Blood Center (New Brunswick, NJ). Briefly, the leukocyte preparation was spun through histopaque (Sigma, St. Louis, MO) to isolate PBMC. CD4+ T cells were removed from total PBMC by biomagnetic separation using anti-CD4-coated magnetic beads, following protocols provided by Dynal (Lake Success, NY). To determine the purity of CD4+ T cell preparations, isolated cells were dual stained with FITC-labeled mouse anti-human anti-CD3 mAb plus R-phycoerythrin-labeled mouse anti-human anti-CD4 mAb (Sigma) and analyzed for two-color fluorescence on an EPICS Profile II flow cytometer (Coulter Electronics, Hialeah, FL).
T cell activation and culture conditions
For stimulation of T cells with an anti-CD3 mAb, 10-cc
tissue culture plates were coated overnight at 4°C with 4 µg/ml of
the anti-CD3 mAb clone HIT3a (PharMingen, San Diego, CA) in 4 ml
1x PBS. After overnight incubations, coating solutions were removed,
and plates were washed gently with 1x PBS to remove unbound Ab.
CD4+ T cells (
4 x 107) were added to
separate Ab-coated plates for 2, 8, 24, or 48 h. After activation,
cells were transferred to new plates and treated with 10 µg/ml of the
transcriptional inhibitor Actinomycin D (Act D; Sigma) for different
lengths of time.
For stimulation with PMA and ionomycin (ion), isolated CD4+ T cells (3 x 107) were cultured with 10 ng/ml PMA and 1 µg/ml ionomycin in 10 ml of RPMI 1640 complete medium. After various times of stimulation, cells were washed once with PBS, resuspended in 10 ml of RPMI 1640 + 10% FCS, 100 U/ml of penicillin, 100 µg/ml streptomycin, 2 mM glutamine (complete) and treated with 10 µg/ml Act D. After various times of Act D treatment, aliquots of cells were removed for RNA isolation.
For experiments assaying the effects of costimulation on CD154 mRNA stability, isolated CD4+ T cells were cultured on 10-cc plates precoated with anti-CD3 mAb as above and 4 µg/ml of the anti-CD28 mAb clone 9.3 (a gift from Dr. Carl June, Uniformed Armed Services University, Bethesda, MD) for 5 or 24 h. For stimulation with soluble anti-CD28, the 9.3 mAb (4 µg/ml) was added directly to the T cells that were being cultured on anti-CD3-coated plates. After incubation, cells were treated with Act D, as described above.
Analysis of steady-state levels of RNA were conducted on 4 x
107 CD4+ T cells at each indicated time point.
Cells were incubated either on anti-CD3-coated plates or with
PMA/ion for the indicated period of time. Cells were then removed and
frozen for RNA.
RNA isolation and Northern blot analysis
Total RNA was isolated from 5 x 106 to 1 x 107 cells using the Trizol reagent (Life Technologies, Gaithersburg, MD). RNA (6–15 µg) were run in 1.2% agarose/formaldehyde gels and transferred to supported nitrocellulose. Membranes were hybridized to random-primed 32P-labeled probes overnight at 42°C and then washed three times at 68°C for 15 min with 2x SSC + 0.5% SDS. After hybridization with the 28S rRNA probe, membranes were washed three times at 68°C for 15 min with 1x SSC + 0.5% SDS, followed by a single wash for 1 h at 68°C with 0.1x SSC + 0.1% SDS. Membranes were exposed to XAR-film or scanned using the Storm PhosphorImager system (Molecular Dynamics, Sunnyvale, CA) for signal quantification.
DNA and RNA probes
The human CD154 cDNA, isolated from the D1.1 Jurkat T cell line
(7, 30) was used as a probe on Northern blots. For the analysis of
TNF- expression, a 1.1-kb human TNF- cDNA was excised from the
pE4 plasmid clone (American Type Culture Collection, Manassas, VA). For
the analysis of c-myc expression, a 1.6-kb human genomic
fragment was isolated from a plasmid containing the 3' half of the
v-myc gene from the avian myelocytomatosis virus. All
probes were generated by random-primer labeling according to standard
protocols. The human 28S rRNA-specific probe was generated by in vitro
transcription of the pTri28S plasmid (Ambion, Austin, TX) in the
presence of [32P]rUTP.
Determination of mRNA half-lives
mRNA t1/2 were determined by the linear regression of semilogarithmic plots of fraction mRNA remaining after Act D addition vs time after Act D addition according to previously described methods (31). Fractions of mRNA remaining were normalized to levels of the 28S rRNA to control for loading error.
Determination of CD154 surface expression
After various periods of stimulation with plate-bound
anti-CD3 mAb, 0.5 x 106 cells were stained
with either a FITC-labeled anti-human CD154 mAb (Ancell, Bayport,
MN) or a corresponding FITC-labeled mouse IgG1 isotype control
(Ancell). After activation, cells were washed once with 1x PBS and
incubated with a 1:50 dilution of either Ab. Cells were incubated for
45 min at 4°C and, after washing once with 3.5 ml of FACS wash (MEM +
12 mM HEPES (pH 7.2), 0.2% NaHCO2), were fixed in 1%
paraformaldehyde. Fluorescence was measured using an EPICS
Profile II flow cytometer, and the percent CD154 positive cells at each
time point was determined after subtracting the percent positive with
the isotype control.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNAs show similar kinetics of
up-regulation in response to T cell activation
To establish the kinetics of CD154 mRNA expression in response to
conditions of anti-CD3 mAb, purified CD4+ T cells were
positively selected and stimulated over a time course of activation. In
multiple experiments, the purity of the selected population was >97%
CD3+/CD4+ and <1%
CD19+/IgM+ cells (Fig. 1
A, and data not shown). This
level of purity in the T cell population insured that the analysis of
CD154 expression was being conducted virtually in the absence of other
cell types. When the kinetics of CD154 mRNA expression were analyzed,
we found that expression was maximal 1–3 h postactivation, followed by
a gradual decrease in expression over the next 2 days. In addition, a
comparison of CD154 and TNF- mRNA expression in activated T cells
showed very similar kinetics except for a more gradual decline in CD154
mRNA levels after 2 h of stimulation (Fig. 1B).
Together, these results demonstrate a highly regulated pattern of CD154
mRNA expression over a time course of T cell activation that is very
similar to the expression of TNF- mRNA over the same course of
stimulation.
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To determine how mRNA stability influences the overall control of
CD154 expression during a time course of T cell activation, purified
CD4+ T cells were stimulated for different lengths of time
(2, 8, or 24 h) with plate-bound anti-CD3. Message stability
was analyzed by treating cells with the transcriptional inhibitor, Act
D, from 1–4.5 h. Under these conditions of transcriptional activation
and inhibition, we found that the CD154 message was very unstable after
2 and 8 h of contact with anti-CD3 (Fig. 2A). This finding was very
similar to results obtained for both the TNF- and c-myctranscripts at these time periods postactivation (Fig. 2, A and B). Surprisingly, when we assayed CD154
message stability after 24 h of continuous activation with
anti-CD3 mAb, we found that the stability of the CD154 transcript
had markedly increased. Under identical conditions and throughout a
time course of T cell activation, both the TNF- and c-myc
mRNA decay rates remained relatively unchanged and very unstable
compared with the CD154 transcript (Fig. 2, A and
B).
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As a consequence of the rapid decay of the CD154 mRNA by 1 h
of Act D treatment, we were unable to establish an mRNA
t1/2 in our initial experiments. Therefore, to
determine the t1/2 of the CD154 message after
several periods of anti-CD3 stimulation (2, 8, 24, and 48 h),
CD4+ T cells were treated with a shorter time course of Act
D treatment (0, 15, 30, and 60 min). Again, we found that the CD154
message became measurably more stable after 24 h of anti-CD3
stimulation compared with 2 h poststimulation with
t1/2 of 84 min vs 40 min, respectively (Fig. 3A and Table I). This time course of activation also
allowed us to assess CD154 mRNA stability beyond 24 h of
anti-CD3 stimulation. At 48 h, the CD154 mRNA became
increasingly stable with a calculated t1/2 of
132 min (Fig. 3A and Table I). The Northern blot
analysis data was normalized to the 28S rRNA signals and
presented graphically in Fig. 3B. This representation
reveals the clear difference in stability between the CD154 and TNF-
mRNAs at later times postactivation. The t1/2
value of the c-myc message remained relatively unchanged
after prolonged anti-CD3 signaling (Fig. 3A).
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or c-myc transcripts does not
significantly change over the same time period under the identical
conditions of activation (Table I
). CD28 costimulation does not significantly affect the stability of the CD154 transcript
The difference in the pattern of mRNA stability between the CD154
transcript at early and late times post anti-CD3 activation led us
to examine whether this pattern of regulated instability was a
consequence of costimulatory signals working in combination with
anti-CD3-responsive pathways. CD154 surface expression and
associated "helper" activity for B cells has previously been shown
to increase in response to costimulatory interactions in the presence
of CD3 signaling (11, 17). Also, in the presence of costimulation there
is a significant increase in the stability of the TNF- transcript
(20). As shown above, our population of CD4+ T cells was
very homogeneous. However, it was possible that costimulatory
interactions between T cells or with a small number of contaminating B
cells or macrophage were influencing CD154 message stability at later
times postactivation. Alternatively, a lack of costimulation might lead
to a stabilization of mRNA that is associated with the anergic state of
the T cells. Therefore, to establish if CD28-mediated signals are
influencing CD154 mRNA stability at early or late times postactivation,
we costimulated purified CD4+ T cells with anti-CD3 mAb
in the presence or absence of immobilized anti-CD28 mAb.
CD4+ T cells were activated according to previously
described conditions for the stabilization of the TNF- transcript
(20) at time points that corresponded to an unstable (5 h) or stable
(24 h) CD154 transcript. Decay of CD154 mRNA was analyzed by Act D
treatment over a 1-h period.
After CD154 mRNA expression was normalized to 28S rRNA expression, we
observed a modest increase in CD154 mRNA stability from 45 to 52 or 54
min with immobilized anti-CD28 at 5 h postactivation (Fig. 4A). We observed a similar
level of stabilization when T cells were costimulated by soluble
anti-CD28 mAb (Table I, and data not shown). This level of increase
correlated with the level of stabilization we observed for the TNF-
transcript under the same conditions (Table I). Similarly, when T cells
were activated for 24 h in the presence or absence of
costimulation, we observed no significant difference in the decay
pattern of CD154 mRNA (Fig. 4B). To insure that, under our
conditions of activation, costimulatory signals were being transduced
in response to CD28 contact, steady-state levels of CD154 and IL-2 mRNA
were analyzed in the presence and absence of costimulation. In
accordance with previous findings (11, 32, 33), we found IL-2 and CD154
mRNA expression to be up-regulated in response to costimulatory signals
(10-fold and 2-fold, respectively). Therefore, costimulatory signals
were being actively transduced to CD4+ T cells under the
conditions of our assay. However, signaling resulted in only an 20%
increase in CD154 mRNA stability at 5 h and no measurable increase
in stability at 24 h. These data suggest that the regulated decay
of CD154 mRNA throughout T cell activation is uncoupled to the process
of T cell costimulation by CD28 signaling.
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Previous analyses revealed that TNF- expression is regulated at
the level of mRNA stability during T cell activation and that stability
is increased after PMA/ion activation (20, 21, 22, 34, 35). Because of the
structural and regulatory similarities between the two genes, it seemed
quite possible that CD154 mRNA stability was also altered in response
to PMA/ion induction. In comparing the steady-state level of CD154 mRNA
in either PMA/ion or anti-CD3-activated CD4+ T cells
over a time course of activation, we found that the overall expression
level was significantly greater with PMA/ion at all time points tested
(Figs. 5A). This finding
correlates with previous reports showing that surface expression of
CD154 protein is considerably higher in PMA/ion-activated T cells
compared with anti-CD3-activated T cells (6, 14, 36). To establish
whether the disparity in mRNA expression levels could be explained, in
part, by a change in mRNA stability, purified T cells were activated
with PMA/ion for different lengths of time, and decay rates were
measured by Act D treatment. We found that the CD154 mRNA was very
stable between 1 and 16 h postactivation with
t1/2 between 17.8 and 4.3 h (Fig. 5B, and Table I). We also confirmed that the TNF-, but
not the c-myc, transcript is also stabilized by PMA/ion
signaling (Fig. 5B, and Table I). This result suggests that
one possible factor effecting the elevated steady-state expression of
CD154 mRNA and protein in PMA/ion-activated T cells is the extremely
stable message at all times after activation. Also, because the decay
rate of the CD154 mRNA does not drop below 4 h over an extended
period of time, the decrease in steady-state mRNA beyond 8 h is
possibly a result of down-regulating transcription. This finding places
the CD154 transcript within a class of cytokine and growth factor mRNAs
that are highly stabilized in response to PMA/ion signaling (34, 35, 37, 38, 39, 40, 41).
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Several mRNAs require translation to "activate" the
destabilization element involved in rapid decay pathways (42, 43, 44, 45, 46). In
light of this mechanism, one possible explanation for the regulated
increase in CD154 mRNA stability at later times postactivation is that
the CD154 mRNA is not actively being translated. To rule out this
possibility and to relate changes in message stability and mRNA levels
to the overall regulation of CD154 expression, we examined the kinetics
of CD154 surface expression on T cells activated with anti-CD3 mAb.
CD4+ T cells were stimulated as described above and stained
with either a FITC-labeled anti-CD154 mAb or a FITC-labeled isotype
control mAb. As seen in Fig. 6 and in
confirmation of others’ findings (6, 14, 36), the overall expression
of CD154 on anti-CD3-stimulated T cells is relatively low with peak
expression occurring between 8 and 24 h of stimulation. By 48
h, there is a noticeable reduction in expression, but the level is
still slightly above unstimulated cells. Since the turnover rate of
CD154 protein in anti-CD3-activated T cells has been shown to be
10 h with prolonged stimulation (8), at 48 h the translation of
surface CD154 protein would have occurred when the CD154 mRNA is
already stabilized. Therefore, the change in CD154 mRNA stability does
not appear to be related to a block in translation. The pattern of
increased CD154 mRNA stability at later time points after activation
corresponds to a gradual reduction or maintenance of CD154 surface
expression during this same time period.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several novel findings with respect to the regulation of CD154 mRNA
stability are reported. First, activation of T cells with either
PMA/ion or anti-CD3 produces distinct effects on CD154 message
stability. Also, the stability of the CD154 message, but not the
TNF- or c-myc mRNAs, changes during T cell activation
with anti-CD3, and this change does not appear to be related to
costimulatory signals. Finally, changes in CD154 mRNA stability in
anti-CD3-activated T cells occur during a time period when the
levels of both mRNA and protein levels are declining less rapidly.
The instability of the CD154 message in response to early T cell activation with anti-CD3 is a pattern observed with several cytokine and proto-oncogene mRNAs (reviewed in 47). This pattern of mRNA decay, during the time period when CD154 message levels are at their highest, is consistent with CD154 expression being highly dependent on transcriptional mechanisms at early times postactivation.
In contrast to the rapid induction of CD154 mRNA immediately after anti-CD3 stimulation, we find that message levels steadily decline (to 50% maximal levels) by 8 h after activation and then more gradually decrease to 20% maximal levels over the next 40 h. This biphasic pattern of mRNA expression may be explained, in part, by an increase in CD154 message stability during this same time period. Increased CD154 mRNA stability during anti-CD3 activation may not necessarily result in an absolute increase in steady-state mRNA levels or surface expression, but may affect the rate of decline of the message and protein after activation. Our analysis of CD154 surface expression revealed measurable levels of protein expression 24–48 h postactivation with anti-CD3, which is consistent with previous studies (6, 14, 18, 36). Therefore, after extended T cell activation, message stabilization may allow for CD154 surface expression at a time when the steady-state levels of CD154 mRNA are relatively low. Our data, showing minor to no changes in CD154 mRNA stability with costimulation at both early and late times after activation, suggests that the "regulated decay" pathway is independent of the anergized state of the T cells and argues for a physiological role for this process in CD154 expression.
One possible model for the regulation of CD154 mRNA stability during T cell activation is that TCR engagement initially leads to the transient induction of a factor that binds to elements of the CD154 mRNA, resulting in message destabilization. Subsequent loss of this destabilizing RNA-binding activity after 24–48 h of anti-CD3 stimulation would lead to the observed increase in CD154 message stability. The gain and loss of an RNA-binding activity has been previously demonstrated in the regulation of several mRNAs. For example, GM-CSF mRNA destabilization after anti-CD3 stimulation of T cells correlates with increased binding of the factor AU-B to ARE elements in the 3'-UTR region (25). Also, GM-CSF mRNA stabilization induced by PMA costimulation correlates with the loss of AU-B binding (25).
Our observation of a highly stable CD154 message after PMA/ion activation could reflect a rapid loss of a destabilizing RNA-binding activity. Alternatively, the CD154 mRNA destabilizing factor may be induced by CD3-mediated signal transduction pathways that are bypassed during PMA/ion activation. Recent data showing increased CD154 mRNA stability in PMA-stimulated mononuclear cells suggests that activation of PKC-mediated pathways has a stabilizing effect on the CD154 message (48).
Differences in the regulation of CD154 and TNF- mRNA stability
during T cell activation with anti-CD3 may be attributed to
variations in mRNA sequence motifs or the RNA-binding factors that
recognize these sequences. It has been previously suggested that the
organization of ARE elements in the 3'-UTR region and the specificity
of RNA-binding factors could account for differences between cytokine
and c-myc message stability during T cell activation (49).
ARE-sequence elements (AUUUA), which have been implicated in the
control of mRNA stability, are dispersed throughout the CD154 3'-UTR
(50). In contrast, these elements are tandemly arranged in the TNF-
mRNA and other cytokine messages (25). Therefore, message-specific
RNA-binding factors could recognize distinct AU-rich sequences in the
3'-UTR region, or other RNA sequence motifs, in the CD154 and TNF-
mRNAs.
In summary, our results indicate that the CD154 gene is specifically regulated at the level of mRNA stability and that this regulation influences the overall control of CD154 expression during T cell activation. How this pattern might be altered or influenced by interactions with other cells in an immune response is currently being investigated. Recent studies indicate that CD154 may have critical functions in anti-tumor immune responses (51, 52), the development of autoimmune disease, and transplant rejection (reviewed in 53). Therefore, an increased understanding of factors that control CD154 expression will enhance our general knowledge of both its biological role in the regulation of immunity as well as in other clinical and disease processes.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Lori R. Covey, Division of Life Sciences, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854. E-mail address:
3 Abbreviations used in this paper: UTR, untranslated region; ARE, AU-rich elements; ion, ionomycin; Act D, actinomycin D.
Received for publication June 30, 1998. Accepted for publication December 28, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in murine T cell clones activated through the TCR. J. Immunol. 152:4336.[Abstract]
mRNA accumulation in human milo-monocytic cell lines: role of transcriptional regulation by DNA sequence motifs and mRNA stabilization. J. Immunol. 147:2047.[Abstract]
and phorbol myristate acetate. Blood 84:2632. mRNA in a cytolytic T cell clone: Ca2+-induced transcription followed by mRNA stabilization through activation of protein kinase C or increase in cAMP. Eur. J. Immunol. 25:889.[Medline]
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P. J. Blair, J. L. Riley, D. M. Harlan, R. Abe, D. K. Tadaki, S. C. Hoffmann, L. White, T. Francomano, S. J. Perfetto, A. D. Kirk, et al. Cd40 Ligand (Cd154) Triggers a Short-Term Cd4+ T Cell Activation Response That Results in Secretion of Immunomodulatory Cytokines and Apoptosis J. Exp. Med., February 21, 2000; 191(4): 651 - 660. [Abstract] [Full Text] [PDF]
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W. F. C. Rigby, M. G. Waugh, and B. J. Hamilton Characterization of RNA Binding Proteins Associated with CD40 Ligand (CD154) mRNA Turnover in Human T Lymphocytes J. Immunol., October 15, 1999; 163(8): 4199 - 4206. [Abstract] [Full Text] [PDF]
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