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Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33136
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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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down-regulates CD30 expression on
activated murine T cells; however, CD30 expression does not define the
TH2 subset (9, 10). CD30 is expressed transiently on
activated T cells, which is more pronounced in the CD8 subpopulation
(11) and CD30 expressing activated memory cells produce
IFN- and IL-5 (12).
CD30 belongs to the TNFR family of proteins and CD30L to the TNF family
of ligands (13, 14). The intracellular sequence of CD30
contains TNFR-associated factor (TRAF) domains, allowing it to interact
with adaptor proteins of the TRAF family: TRAF1, TRAF2, and TRAF3
(15, 16). TRAF2 is thought to be responsible for NF-
B
activation and for the antiapoptotic effect mediated by CD30 (17, 18). TRAF2 is regulated by TRAF-interacting protein and by
susceptibility to proteolysis (19, 20).
The primary biological function of CD30 has been difficult to establish
due to the pleiotropic nature of CD30 signals and the transience of
CD30 expression in normal lymphocytes. Mice lacking a functional CD30
gene product have a defect in negative selection of thymocytes
(21), whereas CD30-transgenic mice expressing CD30 in the
thymus have enhanced activity for thymic negative selection
(22). In accordance with this function in negative
selection in the thymus, CD30L is expressed in the Hassal bodies of the
thymus (23). Recently, a function of CD30 in modulating
cytotoxic responses was reported by using TCR-transgenic, autoreactive,
CD30-deficient CD8 T cells in a diabetes model. CD30-deficient T cells
were 
6000 times more active in causing autoimmune diabetes than
their CD30-sufficient counterparts (24, 25). These data
suggested that CD30 is an important negative regulator for cytotoxic
lymphocytes in vivo. We have reported previously that signals emanating
from CD30 down-regulate the cytotoxic activity of the large granular
lymphocyte (LGL) lymphoma line, YT, for B7-expressing target cells
(26). CD30 signals down-regulated CD28, which is required
for recognition and triggering of cytotoxicity by YT
(27).
Even though the signaling pathways of CD30 and the transcription factors activated by CD30 signals are well characterized, little is known about the genes targeted by CD30 for induction or repression. In part this is due to the difficulty of obtaining sufficient numbers of homogeneous lymphocyte populations expressing CD30 that would be suitable for analysis. The YT lymphoma, expressing high levels of CD30 constitutively and endowed with cytotoxic activity, therefore, is an ideal model to further define genes regulated by CD30 signals. As reported below, we find that CD30 down-regulates the expression of major effector molecules for cytotoxicity and represses genes required for proliferation. In addition, CD30 up-regulates molecules critical for lymphocyte homing and increases the expression of proapototic and antiapoptotic molecules. The regulation of the expression of multiple gene products by CD30 can be interpreted as the synergistic suppression of cytotoxic cells by terminating cytotoxicity, diminishing proliferation, redirecting lymphocytes toward lymph nodes rather than inflammatory sites, and rendering them more susceptible to certain proapoptotic signals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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YT cells were cultured in Iscove’s modified Dulbecco’s MEM containing 10% heat-inactivated FBS and were treated with 5 µg/ml of the agonistic anti-human CD30 mAb C10 (26). Treated cells were harvested at different time points and analyzed.
To block TRAF2 signal transmission, YT cells were stably transfected with an expression vector containing truncated, dominant negative, murine dominant negative (DN)-TRAF2 using the Gene Pulser (Bio-Rad, Hercules, CA).
Multiprobe RNase protection assay
Total RNA was extracted from YT cells using the RNeasy Midi kit (Qiagen, Chatsworth, CA). Multiprobe RNase protection assay (PharMingen, San Diego, CA) was performed with 10 µg of total RNA according to the manufacturer’s instruction. Briefly, isolated RNA was hybridized for 17 h at 56oC with 32P-labeled multiprobe template sets and then treated with RNase. Protected RNA fragments were resolved on polyacrylamide gels and radioactive signals were analyzed by a phosphor imager (Bio-Rad). Digitized signals were normalized using as reference the signals of the housekeeping genes L32 or GAPDH. The relative expression levels of the gene products under analysis are presented as percentage to their expression in untreated cells, which is set to 100%.
RT-PCRs
One microgram of total RNA was used to synthesize cDNA using the SuperScript Preamplification System (Life Technologies, Rockville, MD). For PCR, 1/200 of the volume of the first-strand cDNA sample was used for amplification of c-myc, CCR7, or ß-actin. The primers used for PCR were as follows: CCR7 (sense) 5'-TGGTGGCTCTCCTTGTCATT-3', CCR7 (antisense) 5'-GCTGATGCAAAGAAGTAGGA-3'; c-myc (sense) 5'-ACTGCGACGAGGAGGAGAAC-3', c-myc (antisense) 5'-AAGCCGCTCCACATACAGTC-3'; ß-actin (sense), 5'-TCTGGCACCACACCTTCTAC-3', ß-actin (antisense) 5'-GAAGGAAGGCTGGAAGAGTG-3'. The PCR products were resolved on agarose gels, visualized by ethidium bromide staining and quantitated using the Molecular Analyst software (Bio-Rad). ß-actin was used as internal standard for normalization and relative expression levels of c-myc and CCR7 were expressed as percentage of untreated cells set to 100%.
Western blotting
YT cells were lysed in 150 mM NaCl, 1.0% Nonidet P-40, 0.5% sodium deoxycholate, 0.1% SDS, 50 mM Tris (pH 8.0), with 1 µg/ml of each inhibitor, aprotinin, leupeptin, pepstatin, and 1 mM PMSF. A total of 50 µg of the whole-cell lysate protein was analyzed on 10% SDS-polyacrylamide gels and blotted with antihuman TRAF1, TRAF2, and TRAF3 antiserum, respectively (Santa Cruz Biotechnology, Santa Cruz, CA). Abs were detected by chemiluminescence (enhanced chemiluminescence; Amersham Pharmacia Biotech, Piscataway, NJ).
Flow cytometry
YT cells were cultured with or without C10 for 24 h, and 1 x 106 cells of each sample were stained with FITC conjugated anti-human Fas Ab or anti-human CD28 (PharMingen) and analyzed on a FACScan flow cytometer (Becton Dickinson, Franklin Lakes, NJ).
Chromium release (cytotoxicity) assay
P815 or P815-Fas cells were labeled with 51Cr for 2 h and washed three times with PBS. Cytotoxicity of YT cells against P815 or P815-Fas cells was examined in 6-h assays in triplicate in 96-well microtiter plates at 1:1, 3:1, 10:1, and 30:1 E:T ratios. Results are expressed as percent specific lysis relative to HCl-lysed controls by subtracting the values of spontaneous Cr release, ranging between 5 and 12%.
Gene microarray analysis
Human UniGem Microarrays (Genome Systems, St. Louis, MO) containing cDNAs of 4000 named genes and an equal number of expressed sequence tags (ESTs) were used to analyze the induction or suppression of mRNAs by CD30 signals. mRNA was extracted from untreated and C10-treated (17 h) YT cells according to the manufacturer’s instructions. After conversion to cDNA and differential fluorescent labeling, the fluorescent probes of C10-treated and untreated YT cells were mixed and hybridized to the gene microarrays. Differential binding of the two probes to the arrays is analyzed by the manufacturer and normalized according to known reference markers on the gene chip. A ratio of binding of one of the two probes indicates no change in gene expression due to CD30 signals. The data are given as percent induction or suppression of gene products by CD30 signals relative to untreated YT cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD30 signals are transmitted through adaptor proteins of the TRAF
family, resulting in the activation of transcription factors including
NF-B and Jun N-terminal kinase. The target genes addressed by CD30
signals through these and other transcription factors remain largely
undefined. Because few lymphocytes express CD30 under physiological
conditions and CD30 expression is usually transient, it is difficult to
obtain information about genes regulated by CD30. Using the YT cell
line (28), a LGL lymphoma with cytotoxic activity
constitutively overexpressing CD30, we generated CD30 signals using an
agonistic anti-CD30 Ab, C10 (26), and studied the
regulation of several groups of genes by CD30 signals.
We have published previously that CD30 signals induced the loss of YT cytotoxicity toward B7-expressing targets (26). Loss of cytotoxicity correlated with the down-regulation of CD28, which is known to be required for YT killing of B7-expressing target cells (27). In the current study, we investigated whether cytotoxic effector molecules and other gene products expressed by YT were regulated by CD30. YT cells contain cytolytic granules containing perforin and granzyme B and express functional Fas-L. To obtain reliable data on several groups of genes, the analyses combined the results of RNA expression with protein expression and with functional data. RNA expression data were obtained by several methods: RNase protection assays, RT-PCR assays, or gene microarray assays. Protein products were assayed by Western blot, flow cytometry, or by functional assays. In all cases, CD30 signals were examined by incubating YT cells with 5 µg/ml of the agonistic C10 Ab for various periods of time followed by the analysis of RNA levels, protein levels, or function.
To study regulation of Fas-L and a group of other gene products
involved in regulating apoptosis by CD30, RNA protection assays were
used (Figs. 1
and 2). The images of radiolabeled,
hybridized, protected RNA fragments were quantitated and normalized by
reference to housekeeping genes (L32 and GAPDH) using the phosphor
imager. Agonistic anti-CD30 treatment of YT completely
down-regulated Fas-L expression within 6 h. In contrast, TRAIL,
Fas, and death receptor 3 (DR3) were up-regulated from 2- to 4-fold by
CD30 signals. DR3 is only weakly expressed by YT whereas TRAIL showed a
somewhat higher level of expression. The expression of other gene
products such as caspase 8, Fas-associated factor, Fas-associated death
domain protein, TNFR1, TNFR-associated death domain protein, and
receptor-interacting protein, involved in signaling for apoptosis, was
not significantly affected by CD30 signals (Figs. 1 and 2). It is
evident from these regulatory effects that CD30 signals are highly
specific for selected gene products rather than globally affecting
transcriptional activity of proapoptotic and antiapoptotic genes.
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To determine whether the TRAF2-dependent pathway was used by CD30
signals for the regulation of death receptor and ligand genes, YT cells
were transfected with the DN mutant of TRAF2 (Fig. 2
). DN-TRAF2
protein, after selection in G418, was expressed at a high level in
bulk-transfected, uncloned YT, as seen in Western blots (Fig. 2A). The presence of DN-TRAF2 blocked CD30-mediated
down-regulation of Fas-L by >50%. Similarly, DN-TRAF2 inhibited the
up-regulation of Fas to the same degree (Figs. 2 and 3C). CD30 signals regulating
the expression of death receptors and ligands, therefore, use primarily
the TRAF2 pathway. These analyses were repeated in three independent
experiments with essentially identical results. The effects of CD30
signals were also detected at the protein level or by functional
assays.
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A) are indeed
lysed by YT in 6-h assays, proving the use of Fas-L for the lytic
activity. Treatment of YT with anti-CD30 Ab (C10) for 16 h
completely abolished lysis of P815-Fas by YT, indicating that Fas-L
protein in addition to its mRNA is down-regulated by CD30 signals. In
DN-TRAF2-transfected YT in contrast, P815-Fas lysis was not inhibited
by C10 treatment of YT cells (Fig. 3B).
In accord with the RNase protection assay, CD30 signals up-regulated
Fas protein expression by YT about 3-fold as measured by the increase
in fluorescence intensity in the flow cytometer, whereas CD28
expression, as reported previously (26), decreased 3-fold.
Both effects were blocked by the presence of DN-TRAF2 in YT (Fig. 3, C–F).
CD30 signals down-regulate perforin and granzyme B expression
We next determined whether the effector molecules perforin and
granzyme B, expressed by YT cells, were regulated by CD30 similar to
Fas-L. YT cells do not express granzyme A. The analysis was conducted
by RNase protection assay and by hybridization to gene microarrays of
fluorescently labeled cDNAs obtained from untreated YT and from cells
treated for 17 h with C10, respectively. The microarray analysis
gives information about the absolute level of gene expression (Table I, right column) and relative changes
following CD30 signaling. For validation, the results of the microarray
analysis were confirmed for the relevant genes by independent assays
for RNA expression (Table I). Quantitative analysis of normalized
expression of perforin and granzyme B mRNA after CD30 signaling
revealed a 2-fold suppression from 100 to about 50% of the RNA levels
for both gene products in both microchip assays and by RNase protection
assay (Table I and Fig. 4). Cathepsin C
mRNA, coding for a lysosomal protease related to granzyme B, was also
suppressed. Signals from CD30 thus down-regulate the two major
cytotoxic pathways of lymphocytes; the apoptotic pathway important for
lymphocyte homeostasis by down-regulating Fas-L and the cytolytic
pathway important for immune defense by suppressing perforin and
granzyme B expression. Since granzymes and perforin are stored in
cytoplasmic granules, the effect of decreased mRNA levels will have
only a delayed effect on the corresponding protein levels.
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myc Expression correlates with cell proliferation and is known to
regulate Fas-L expression in activated T cells via TGF-ß
(29). Since Fas-L mRNA was completely down-regulated by
CD30 signals, we investigated whether c-myc expression was also
suppressed (Table I and Fig. 5). Using
gene microarray analysis and RT-PCR, c-myc was found to be
significantly suppressed by CD30 signals, despite the finding that
proliferation was not significantly affected at that time (data not
shown). In timed RT-PCR analysis, CD30 signals completely
down-regulated c-myc expression in YT within 24 h. Suppression of
c-myc by CD30 therefore appears to be responsible for the suppression
of down stream Fas-L. ß-actin used as control in the RT-PCR analysis
was not affected by CD30 signals.
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). The microarray allows one to obtain a
global overview of gene regulation in addition to the assessment at the
individual gene level. In a global analysis of the microarray assay,
CD30 signals up-regulated many more gene products than were
down-regulated by CD30. We used as threshold for significant regulation
a 2-fold or greater change of gene expression induced by CD30 (Table II). Of the 8000 gene products
analyzed by microarray analysis, 750 were up-regulated >2-fold by
CD30, including ESTs, whereas only 90 gene products, including ESTs,
were down-regulated to a similar extent (Table II). The remaining gene
products were either not expressed by YT or not significantly regulated
by CD30 signals. Twenty-four of the most highly induced or suppressed
gene products by CD30 signals are given in Tables III and IV.
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). CCR7 mRNA was induced by CD30 signaling
almost 3-fold within 24 h above the level of unstimulated YT as
measured by PCR. Expression of CCR7 during the next 72 h slowly
decreased (Fig. 5). According to microarray analysis, CCR5 and CCR6 are
also expressed by YT cells but not affected by CD30 signals, whereas
CCR1 and CCR2 and CXCR1 are not expressed. CD30 signals induce TRAF1 and cellular inhibitor of apoptosis 2 (cIAP2) in a TRAF2-independent pathway
TRAF proteins are important signal-transducing adaptors for
members of the TNFR family. TRAF1 is up-regulated by TNFR signals. CD30
signals likewise strongly induced TRAF1 mRNA (Fig. 6, A and B) and
protein (Fig. 6C) within 6 h to about 12-fold above the
level of unstimulated cells as measured by RNase protection assay.
TRAF1 levels subsequently slowly decreased over 72 h to 6-fold
above that in control cells. TRAF2 and TRAF4 levels did not change upon
CD30 signaling; TRAF3 was not expressed by YT. The apoptosis inhibitor
cIAP2, which can block activation of caspase 3, 7, and 8, was induced
to a similar extent and with similar kinetics as TRAF1. In Western
blots, TRAF1 protein was also induced in accordance with the results of
RNase protection assay, whereas TRAF2 protein remained unchanged during
the entire time course of CD30 signaling (Fig. 6C). TRAF3
was not detected in Western blots (data not shown). The presence of
DN-TRAF2 in YT had little effect on TRAF1 and cIAP2 induction by CD30
in YT, in contrast to its effect on Fas-L, suggesting that these genes
are induced independent of the participation of TRAF2 (Fig. 6D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most direct effect of CD30 on cytotoxic activity is mediated via the complete down-regulation of Fas-L, eliminating the ability of YT to lyse P815-Fas. Regulation of Fas-L expression by CD30 is a novel finding and has important implications in the homeostatic regulation of lymphocytes. CD30 also down-regulates perforin and granzyme B. Since perforin and granzyme B are storage proteins, the effect of transcriptional regulation on protein levels depends on the half-life of the cytotoxic proteins and may take several days to become detectable. CD30 thus suppresses the granule-dependent and granule-independent cytotoxic pathways of cytolytic lymphocytes. A similar effect of CD30 signals on cytotoxic lymphocytes infiltrating tissues in vivo, that may be mediated by local CD30L expression on monocyte/macrophages or activated T cells, is likely to substantially dampen cytotoxic activity in situ.
Down-regulation of Fas-L by TGF-ß is mediated by c-myc; the DN c-myc mutant has been shown to block TGF-ß-mediated Fas-L down-regulation (32). CD30 signals, as shown here, completely down-regulate c-myc in addition to Fas-L supporting the link between c-myc and Fas-L expression. The down-regulatory signal for c-myc and Fas-L is traveling via TRAF2, because DN-TRAF2, the DN mutant, blocks the effect of CD30 signaling on Fas-L down-regulation. The down-regulation of c-myc by CD30 may also be responsible for the diminished proliferative capacity of CD30-expressing Ag-specific CTL in tissues (24).
The strong up-regulation of CCR7 by CD30 was an unexpected finding resulting from gene microarray analysis. CCR7 expression allows cells to enter lymph nodes via secondary lymphoid tissue chemokine expressed on high endothelial venules (29, 30, 31). CCR7-expressing, central memory T cells have reduced effector function, including sharply diminished cytokine production (31). Our studies show that CD30 signals can strongly up-regulate CCR7, coincident with the loss of cytotoxic function. CD30L signals delivered to CD30 expressed on tissue-infiltrating cytotoxic cells, therefore, have the potential to shut off cytotoxicity within the tissue and redirect CTL to the draining lymph node.
CD30 signals can up-regulate Fas and DR3, making cells potentially more susceptible to apoptotic signals by Fas-L or the DR3-L. It is possible that cells that are redirected to lymph nodes via CCR7 expression, reencounter APCs and undergo activation-induced cell death due to the increased level of Fas and DR3 expression. The concurrent up-regulation by CD30 of antiapoptotic genes like TRAF1 and cIAP2 on the other hand, which is associated with resistance to TNF-induced apoptosis and to caspase 3, 7, and 8 activation, may render the cells more resistant to specific apoptotic signals (33, 34). Among CD4 cells, CCR7 is expressed exclusively on TH1 cells (29). Reentry into lymph nodes of CCR7-positive memory cells triggered by CD30 and expression of antiapoptotic molecules, therefore, may serve to provide TH1 helper function for the generation of additional effector cells. Further studies will be needed to understand the role of CD30 regulating lymphocyte traffic and apoptosis in vivo.
The importance of TRAF2 in mediating CD30 signals is well documented (18, 20). As shown here, TRAF2 is used by CD30 for up- or down-regulating many genes on YT including Fas-L, CD28, and Fas. Interestingly, however, the up-regulation by CD30 of TRAF1 and cIAP2 is not dependent on TRAF2 since the DN mutant was unable to block the induction of these genes. It has been reported previously, and is confirmed here, that TRAF-independent signaling can emanate from CD30 (35). However, the molecular nature of that signaling pathway remains to be defined.
The analysis of gene products modulated by CD30 signals on an LGL lymphoma allows the formulation of the hypothesis that CD30 terminates cytotoxic lymphocyte responses by several synergistic pathways. The molecular mechanisms appear to comprise a synergistic pattern for suppression of cytotoxicity by decreasing the expression of cytotoxic effector molecules, down-regulating costimulatory CD28, slowing down proliferation, potentially redirecting lymphocyte traffic, and increasing lymphocyte susceptibility to apoptosis. It remains to be established that these molecular mechanisms occur in T cells in vivo due to local CD30L expression. The reported finding that CD30 dampens cytotoxic activity of CTL in a diabetes model in mice (24) provides strong support for this hypothesis. Moreover, in our own initial studies, CD30L-deficient mice show increased in vivo CTL activity supporting the role of CD30 as a negative regulator of cytotoxic lymphocytes.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Eckhard R. Podack, P.O. Box 016960 (R138), Miami, FL 33101.
3 Abbreviations used in this paper: CD30L, CD30 ligand; TRAF, TNFR-associated factor; TRAIL, TNF-related apoptosis-inducing ligand; EST, expressed sequence tag; DR3, death receptor 3; DN, dominant negative; cIAP2, cellular inhibitor of apoptosis 2; LGL, large granular lymphocyte; Fas-L, Fas ligand.
Received for publication June 12, 2000. Accepted for publication August 2, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. J. Immunol. 158:2090.[Abstract]
and IL-5 and exhibit enhanced B cell helper activity. J. Immunol. 153:2861.[Abstract]
B activation and binding specificity. Proc. Natl. Acad. Sci. USA 93:9699.B by the CD30 receptor is mediated by TRAF1 and TRAF2. Mol. Cell. Biol. 17:1535.[Abstract]
B activation. J. Exp. Med. 185:1275.B and c-Jun N-terminal kinase. J. Biol. Chem. 274:19368.B antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c- IAP2 to suppress caspase-8 activation. Science 281:1680.B activation. Int. Immunol. 10:203.This article has been cited by other articles:
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