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,
* Division of Neuroimmunology, Department of Neurology, and
Division of Rheumatology/Clinical Immunology, Department of Medicine, Charité University Hospital, and
Deutsches Rheuma-Forschungszentrum, Berlin, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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/IL-4 production, and
proliferation. These effects were independent of APC, Ag specificity,
and Th differentiation, and no differences were detected between
healthy donors and multiple sclerosis patients. TRAIL affected neither
the expression of the cell cycling inhibitor
p27Kip1 nor the capacity of T cells to produce
IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor
does not induce T cell anergy. Instead, the TRAIL-induced
hypoproliferation could be attributed to the down-regulation of the
cyclin-dependent kinase 4, indicating a G1 arrest of the
cell cycle. Thus, although it does not contribute to mechanisms of
peripheral T cell tolerance such as clonal anergy or deletion by
apoptosis, TRAIL can directly inhibit activation of human T cells via
blockade of calcium influx. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, it was shown to
rapidly induce apoptosis in susceptible cells upon trimerization of its
receptors and subsequent activation of the caspase cascade leading to
fragmentation of DNA (1, 2). TRAIL can interact with five different receptors. Of these, only TRAIL receptor 1 (also referred to as DR4) (3) and TRAIL receptor 2 (DR5) (4) are capable of transmitting a death signal, whereas the transmembrane TRAIL receptor 3 (DcR1) and TRAIL receptor 4 (DcR2) do not contain a functional death domain. The latter two are considered to act as decoy receptors because their overexpression was shown to inhibit TRAIL-induced apoptosis (3, 4). The soluble receptor osteoprotegerin is reported to block TRAIL-mediated apoptosis by competitive inhibition of TRAIL binding to TRAIL receptors 1 and 2 (5). Although TRAIL and its receptors were shown to be constitutively expressed by a variety of cell types including human (auto)antigen-specific T cells (6), the physiologic relevance of the TRAIL system and its potential role in inflammatory processes are not completely understood.
Previous studies emphasized a certain selectivity of TRAIL to induce apoptotic cell death in tumor cells (7, 8, 9, 10). However, this view has been challenged because TRAIL was also reported to induce massive apoptosis in normal human hepatocytes (11) and human brain cells (12), indicating a species difference between rodents and man.
Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector function. Systemic neutralization by TRAIL receptor 2 was demonstrated to exacerbate collagen-induced arthritis (13) and experimental autoimmune encephalomyelitis (14).
We have recently shown that human T cells, although expressing the death-inducing TRAIL receptors 1 and 2, are not killed by soluble leucine-zipper TRAIL in vitro (6). Therefore, we asked whether in the human immune system TRAIL might exhibit immunoregulatory effects other than clonal deletion by induction of apoptosis. Our results show that TRAIL is capable of inhibiting T cell activation, subsequent cell cycle progression, and cytokine production in human autoreactive and foreign Ag-specific T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The human recombinant soluble TRAIL used together with an
enhancer Ab for multimerization, and the human recombinant protein
consisting of the extracellular domain of TRAIL receptor 2 fused to the
Fc portion of human IgG1 (rhTRAIL-R2:Fc fusion protein; Alexis, San
Diego, CA) were used for the functional analysis of the TRAIL system. T
cells were activated, independent of Ag, by anti-CD3 Ab (OKT3;
American Type Culture Collection, Manassas, VA) and anti-CD28 Ab
(Ancell, Bayport, MN). FITC-conjugated rat anti-human IFN-
(XMG1.2; BD PharMingen, San Diego), PE-conjugated rat anti-mouse
IL-4 (11B11; BD PharMingen), and FITC-/PE-labeled rat IgG1 isotype
control Abs (R3-34; BD PharMingen) were used for the intracellular
cytokine staining by flow cytometry. Monoclonal mouse
anti-p27Kip1 (Santa Cruz Biotechnology,
Heidelberg, Germany), polyclonal rabbit anti-cyclin-dependent
kinase (CDK)4 (Santa Cruz Biotechnology), and monoclonal
anti-
-actin (Sigma-Aldrich, Steinheim, Germany) were used for
the Western blotting experiments.
Jurkat T lymphoma and CTLL-2 cells (kindly provided by Dr. M. Walden, Department of Dermatology, Charité University Hospital, Berlin, Germany) were cultured in RPMI supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, and 10% FCS.
Human Ag-specific T cell lines
Ag-specific activation. Ag-specific CD4+ T cell lines were established using a modified "split-well" protocol (15). Briefly, 2 x 105 PBMC were seeded in 200 µl medium (RPMI supplemented with 2 mM L-glutamine, 100 U/ml penicillin, 100 µg/ml streptomycin, and 5% pooled human AB serum) in the presence of 20 µg/ml myelin basic protein (MBP), 5 µg/ml birch pollen (BP), or 4 µg/ml tetanus toxoid (TT) in 96-well round-bottom microtiter plates. After 7 days, 10 IU/ml recombinant human IL-2 (proleukin; Eurocetus, Frankfurt, Germany) was added to the cultures. Five to 7 days thereafter, 100 µl were taken from each original well and split into two wells on a new plate. Irradiated (3000 rad) autologous PBMC (1 x 105) were added to each well of the master plate and to the split plate in the presence or absence of Ag. Specificity was tested by a standard proliferation assay.
Proliferation. [3H]Thymidine (0.5 µCi; Amersham, Braunschweig, Germany) was added to each well of the split plate. Incorporation of radioactivity was measured after 18 h with a beta counter (Microbeta; Wallac, Turku, Finland). Specifically responding populations with stimulation indexes >3 were selected for further expansion.
Antigens. Human MBP was purified as described in established protocols (16). TT was purchased as a vaccine concentrate (Chiron Behring, Marburg, Germany), and BP was purified from a crude extract of Betula verrucosa (Allergon; Pharmacia & Upjohn, Ängelholm, Sweden).
Th differentiation.
The Th differentiation was based on the ratio of IFN- and IL-4
production. Predominant IFN- staining by intracellular flow
cytometry (17) determined a Th1-like cell line, double
staining determined a Th0 cell line, and predominant IL-4 staining
determined a Th2-like cell line. Briefly, 105
resting T cells were stimulated with 0.1 µg/ml PMA and 1 µg/ml
ionomycin in the presence of 2 µM monensin. After 6 h, cells
were permeabilized and stained by incubating with 1.5 µg/ml
FITC-conjugated rat anti-human IFN-, 0.5 µg/ml PE-conjugated
rat anti-mouse IL-4, and equivalent concentrations of
FITC-/PE-labeled rat IgG1 isotype control Abs diluted in 0.1% saponin
permeabilization solution. Analysis was performed with a FACScan flow
cytometer (BD Biosciences, Mountain View, CA) equipped with CellQuest
software (BD Biosciences), and 10,000 events were acquired.
Unspecific activation. For analysis of activated T cells, a protocol using Abs to CD3 and CD28 was used (18). Cell culture plates were coated with anti-CD3 Abs overnight at 10 µg/ml in PBS. After washing the plates, T cells were incubated together with anti-CD28 (10 µg/ml) under the respective experimental conditions.
Anergy. T cells (5 x 104/well) and irradiated matched PBMC (1.5 x 105/well) were incubated with or without Ag for 7 days using different concentrations of TRAIL. Surviving T cells were washed and seeded at 5 x 104 cells/well together with irradiated matched PBMC (1.5 x 105/well) and Ag. Proliferation was measured by [3H]thymidine uptake. Parallel to this, IL-2 secretion 24 h after the initial and second stimulation was measured using the IL-2-dependent T cell line CTLL-2.
DNA fragmentation
For quantitative analysis of DNA fragmentation, 105 cells were treated according to the protocol described by Nicoletti et al. (19). Briefly, a hypotonic fluorochrome solution (50 µg/ml propidium iodide in 0.1% sodium citrate and 0.1% Triton X-100) was added to 105 cells followed by incubation overnight at 4°C. The level of the hypodiploid DNA peak was determined as the percentage of total events by flow cytometry. Data are presented as specific DNA fragmentation (with stimulus/control).
Cytokines
IFN- and IL-4 production upon T cell activation with
PMA/ionomycin was measured by using intracellular cytokine staining as
described above. Secreted IFN- (Biomedical Laboratories, New
Brunswick, NJ) and IL-4 (R&D Systems, Minneapolis, MN) were further
quantified using sandwich ELISAs. For the latter analysis, 2 x
105 cells/well were stimulated with
anti-CD3/CD28 and cultured for 48 h in the absence or presence
of TRAIL.
Soluble TRAIL was quantified in the supernatants of Ag-activated T cells after 24, 48, and 72 h of culture and in sera of 20 healthy volunteers using a sandwich ELISA (Trinova Biochem, Gießen, Germany).
IL-2 levels were measured 48 h after Ag stimulation according to a standard bioassay protocol using the IL-2-dependent T cell line CTLL-2.
Measurement of [Ca2+]i
Intracellular free calcium concentrations of fura 2-AM-loaded T cells were monitored with a Hitachi F4500 fluorescence spectrophotometer (Hitachi, Tokyo, Japan). T cell suspensions (10 x 106 cells/ml) were loaded with 1 µM of the acetoxymethyl ester precursor of fura 2 (Sigma-Aldrich) for 30 min at 37°C. A dual mirror chopping mechanism within the spectrophotometer permitted rapid alternating (30 Hz) excitation of fura 2 at 2 wavelengths (340 and 380 nm). Unloaded dye was removed by centrifugation, and cells were resuspended in PBS without calcium. Typical measurements involved 2–3 x 106 cells in 1 ml of cell medium in a temperature-controlled plastic cuvette at 37°C with constant stirring. Fura 2-loaded cells were incubated with 0.5 mM EGTA for 5 min to bind any external calcium. During the last minute of incubation, the measurement was started and 2 µM thapsigargin (Tg; Calbiochem, Schwalbach, Germany) was subsequently added to fully deplete intracellular Ca2+ stores. Following a 5-min incubation with Tg, 1.2 mM calcium was added to the cell suspension to monitor the extent of Ca2+ influx. Each measurement was terminated by a calibration for maximum (Rmax) and minimum (Rmin) calcium release with Triton X-100 and 3 mM MnCl2, respectively. The results obtained (intracellular calcium concentration expressed in nanomoles) were calculated using the standard equation: intracellular Ca2+ concentration ([Ca2+]i) = Kd x (R - Rmin)/(Rmax - R) as described (20), using 224 nm as the apparent Kd for Ca2+ and fura 2.
Western blot
Immunoblot studies were performed according to standard
procedures. T cell lines were harvested and washed in PBS. Cell pellets
(minimum of 3 x 106 cells) were stored at
-80°C before resuspension in lysis buffer (0.15 M NaCl, 0.01 M
Tris-HCl, 0.005 M EDTA, 1% Triton X-100, 2 µg/ml aprotinin, and 100
µg/ml PMSF) with a Hamilton syringe. After a 15-min incubation on
ice, cell lysates were centrifuged for 15 min in a microfuge at 13,000
rpm. Cellular lysates equivalent to 10 µg protein, as determined by
the bicinchoninic acid method (Pierce, Rockford, IL), were separated
using 12% PAGE and blotted onto nitrocellulose membranes using
standard procedures. Following a 2-h incubation at 37°C in a blocking
mixture (5% milk powder, 2% BSA in 0.01 Tris-HCl, and 0.1% Tween
20), membranes were incubated overnight at 4°C with specific primary
Abs: monoclonal mouse anti-p27Kip1 was used
at a concentration of 2 µg/ml, polyclonal rabbit anti-CDK4 at 1
µg/ml, and monoclonal anti--actin at 24 ng/ml. Abs were
diluted in a 1/40 dilution of the blocking buffer. Following a series
of washing steps, the membranes were incubated for 1 h with 1.25
µg/ml secondary Ab coupled to HRP (DAKO, Carpinteria, CA). Specific
bands were detected using the ECL-plus system (Amersham Pharmacia
Biotech, Uppsala, Sweden) and densitometrically quantified using TINA
Version 2.09g (Santa Cruz Biotechnology, Heidelberg, Germany).
CDK4 and p27Kip1 immunoblots were sequentially
incubated with anti--actin as control.
Statistics
Statistics were performed using SPSS 10.0 software for Windows (SPSS, Chicago, IL). A p value <0.05 was regarded as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, we reported that human (auto)antigen-specific T cells
are resistant to apoptosis mediated by functionally active TRAIL, which
does induce apoptosis in human Jurkat T lymphoma cells
(6). Because there are lines of evidence indicating that
different recombinant TRAIL versions vary in their biochemical
propertiesand cytotoxic potential (21), we first
assessed the biological activity of the TRAIL preparation used in this
study by investigating its apoptosis-inducing potency in susceptible
cells. Fig. 1
illustrates that the TRAIL
preparation used in this study is capable of inducing apoptosis in
tumor cells in a dose-dependent manner. Incubation of human T cell
lines with different concentrations of this TRAIL preparation did not
reveal any susceptibility to apoptotic cell death as determined by DNA
fragmentation. Furthermore, human unstimulated
CD3+ T cells that were separated from freshly
isolated PBMC were also fully resistant to TRAIL-induced apoptosis
(specific DNA fragmentation index: 1.035 (100 ng/ml TRAIL) and 1.026
(300 ng/ml TRAIL)). Thus, the biologically active TRAIL used throughout
the whole study is not capable of killing nontransformed human T cells
in vitro.
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, TRAIL inhibited
the Ag-induced proliferation of 22 well-characterized T cell lines, in
eight of them by >40%. This effect was also observed in freshly
isolated CD3/CD28-stimulated T cells (maximal inhibition 22.94% after
5 days of culture), but not as marked as in the long-term Ag-specific T
cell lines. The inhibitory effect was independent of the Ag specificity
and Th1/Th2 differentiation of these T cells. Furthermore, no
differences in the proliferative response of the T cell lines derived
from MS patients or healthy individuals were observed. TRAIL at
concentrations ranging from 30 to 300 ng/ml did not affect
proliferation of the T cell lines cultured with APC in the absence of
the nominal Ag (data not shown).
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, TRAIL substantially inhibited T cell
proliferation in the absence of APC, indicating that this cytokine
influences T cell function directly rather than via APC-mediated
signals.
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Antigenic stimulation of T cells triggers intracellular calcium
release and the consequent opening of calcium release-activated calcium
channels (CRAC) that in turn generate the prolonged elevation of
cytosolic calcium
([Ca2+]i) required for T
cell activation (22). A lasting rise >200 nM is required
to induce IL-2 synthesis (23). Because Tg has been shown
to activate the same CRAC as TCR stimulation by Ag (24),
we used a Tg model of calcium influx to bypass TCR signals upstream of
the endoplasmic calcium store and to directly monitor the influence of
TRAIL on CRAC. As shown in Fig. 3A, addition of external
calcium to Tg-treated cells causes a peak in intracellular calcium, and
incubation with TRAIL causes a down-regulation of this calcium entry
into the cell. This effect could be confirmed in freshly isolated T
cells (data not shown). The blockade of calcium influx was further
accompanied by an inhibition of proliferation (Fig. 3B).
Thus, interaction of TRAIL with its receptors negatively regulates
human T cell calcium channels resulting in reduced T cell
activation.
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Because failure to produce IL-2 and proliferate after reencountering Ag is a hallmark of clonal T cell anergy, we used four representative cell lines (FZ2, LS4, MA1, and GU3) to investigate whether TRAIL can anergize Ag-specific T cells. T cells were stimulated with Ag and APC in the presence of different TRAIL concentrations, allowed to rest for 7 days, and then rechallenged with Ag and APC. The capacity of the T cells to proliferate and to produce IL-2 was studied after both the initial and second stimulations.
Although we found a trend toward an inhibition of proliferation after
the rechallenge in some T cell lines, these effects were not reflected
by an inhibition of IL-2 production (Fig. 4).
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T cell proliferation upon TCR engagement is tightly controlled by
a large number of positive regulators, such as cyclins and CDK,
and negative regulators, such as CDK inhibitors (25, 26). Because DNA synthesis and
[3H]thymidine incorporation occur during the S
phase of the cell cycle, TRAIL could block cell cycle progression
during the G1 to S phase transition. CDK4 allows
transit through the G1 phase of the cell.
Therefore, we examined whether TRAIL is capable of regulating the
expression of this kinase. Furthermore, we investigated the expression
of the CDK inhibitor, p27Kip1, which has
recently been found to be responsible for the blockade of clonal
expansion of anergic T cells (27, 28). The expression
levels of CDK4 and the kinase inhibitor p27Kip1
were measured following both antigenic stimulation and
anti-CD3/CD28 stimulation in the presence or absence of TRAIL in
seven T cell lines. Fig. 5 depicts data
from a representative T cell line showing an up-regulation of CDK4 upon
T cell stimulation as expected (25, 26). Coincubation of
TRAIL with either of both stimuli, MBP and anti-CD3/CD28,
resulted in decreased levels of CDK4 expression compared with
stimulation in the absence of TRAIL. This indicates an inhibition of
cell cycle progression at the G1/S transition
level. However, p27Kip1 expression was unaltered
in the presence of TRAIL. These data further argue against the
induction of clonal anergy by TRAIL as an underlying mechanism of the
observed inhibitory properties on T cell activation.
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TRAIL was recently reported to be secreted by activated Jurkat and
human peripheral blood T cells (29). We quantified the
amount of TRAIL in the supernatants of four T cell lines (e.g., MB8,
GU3, MA1, and FZ2) after Ag stimulation. As shown in Fig. 6, we found a substantial increase of
soluble TRAIL already 24 h after stimulation. TRAIL was not
detected when Ag was not applied. This level of endogenously produced
TRAIL after activation might reflect the in vivo situation, because the
mean serum level of 20 healthy volunteers was within the same range
(1351.79 ± 203.73 pg/ml; mean ± SEM). However, in
subsequently performed blocking experiments using the soluble
rhTRAIL-R2:Fc fusion protein in concentrations ranging from 0.01 to 10
µg/ml, the net effect of proliferation upon Ag stimulation could not
be enhanced in any of the T cell lines (data not shown). Thus,
autocrine release of soluble TRAIL by human T cells does not affect
their Ag-induced proliferation.
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and IL-4 production
To investigate whether TRAIL is capable of inhibiting cytokine
secretion upon TCR stimulation, we quantified IFN- and IL-4 levels
in the supernatants of six Th1/Th0 and five Th2/Th0 T cell lines,
respectively. As shown in Fig. 7, treatment with TRAIL led to a significant down-regulation of both
cytokines as compared with anti-CD3/CD28 stimulation in the absence
of the death ligand. The IFN- response was also inhibited in freshly
isolated CD3/CD28-stimulated T cells (data not shown). Thus, reduced
production of typical Th1 and Th2 cytokines might indicate an
inhibition of T cell effector functions due to diminished activation
rather than a specific cytokine regulation by TRAIL.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/IL-4 production of human T cell lines
independent of their differentiation phenotype. The reduction of T cell
proliferation was not dependent on the Ag specificity. Both foreign
(TT/BP-specific) and autoreactive (MBP-specific) T cell lines and T
cells derived from patients with multiple sclerosis as well as healthy
individuals were inhibited. Recent studies on murine models of
autoimmune diseases suggested that, unlike TNF, TRAIL might be a member
of an inhibitor protein subfamily due to negative regulation of the T
cell cycle progression (13, 14). However, the mechanisms
of the observed TRAIL effects were not clarified. Because TRAIL had
primarily aroused tremendous interest due to its ostensible selectivity
of killing tumor cells as observed in rodents (10) and was
later reported to induce apoptosis in human hepatocytes and brain cells
(11, 12), different effector functions among different
species have to be assumed. In the human immune system, we have now
also found TRAIL-mediated inhibition of T cell proliferation, albeit to
varying degrees (Table I
). Whereas marked dose-dependent inhibition was
apparent in one-third of the T cell lines, the other T cell lines
exhibited only slight effects. Our finding of increasing TRAIL concentrations in the T cell supernatants upon Ag stimulation is compatible with the idea that the ligand also exerts its effects in a soluble form. This is further supported by data from Martinez-Lorenzo et al. (29), who reported that the cytotoxicity induced by supernatants of PHA-stimulated human PBMC on Jurkat cells could partially be blocked by a neutralizing anti-TRAIL mAb. However, blocking endogenously produced TRAIL by Ag-specific T cells through application of a soluble TRAIL receptor did not result in an enhanced proliferation. Because the inhibitory effect on T cell proliferation by exogenously applied TRAIL was shown to be dose dependent, we conclude that lower TRAIL concentrations in supernatants of activated T cells, which are comparable to serum levels of healthy volunteers, are apparently ineffective in modulating T cell growth. However, this does not inevitably exclude a possible impact of soluble TRAIL on T cell activation and growth at inflammatory sites in vivo.
Concerning the mechanism of the apoptosis-independent properties of the
death ligand TRAIL, we found an independence of APC because the
inhibitory effect was also apparent in CD3/CD28-stimulated T cells
(Fig. 2). Thus, TRAIL directly influences T cell function.
T cell proliferation is tightly regulated by positive factors such as
cyclins and CDK, and negative regulators such as CDK inhibitors. Cells
entering the G1 phase after TCR engagement are
characterized by an up-regulation of cyclin D and CDK4/6 (30, 31). We found the TRAIL-induced hypoproliferation to be
accompanied by a down-regulation of CDK4 (Fig. 5), indicating an
inhibition of cell cycle progression at the G1/S
transition. Apart from their known function in cell cycle progression,
cell cycle regulators have also been shown to control mechanisms
implicated in T cell tolerance, such as anergy (32). The
decision between activation and anergy upon TCR occupancy is generally
considered to be dependent on the balance between positive and negative
signals in T cells, with costimulatory pathways tipping this balance
from anergy to activation (33). Investigating the
relationship between cell cycle progression and tolerance, Gilbert and
Weigle (34) demonstrated that the G1
blocker n-butyrate, but not drugs that block cell cycle
progression in G0 or S/G2
phases, is capable of inducing anergy as determined by the loss of T
cell proliferation and IL-2 secretion upon subsequent Ag rechallenge.
Consistent with this paradigm, the cycling inhibitor
p27Kip1, which contributes to the association
and activation of cyclin D with their complementary CDK, was recently
demonstrated to be important for the induction and maintenance of T
cell anergy (27, 28). We did not find any evidence that
TRAIL collaborates in peripheral T cell tolerance as determined by
p27Kip1 expression as well as proliferation and
IL-2 production upon secondary Ag challenge (Fig. 4). Therefore, other
mechanisms must be responsible for the observed inhibition of T cell
proliferation.
Because calcium influx is crucial to lymphocyte activation, including
cytokine generation and cell proliferation (35), and the
inhibition of calcium-dependent signaling pathways was shown to
completely suppress T cell activation (36), we
investigated whether the inhibitory effect of TRAIL was related to
alterations in calcium signaling. Following TRAIL stimulation, we
observed an inhibition of store-operated calcium entry in human T
cells. Of note, inhibition of the CRACs has been described for other
TNF superfamily members. For example, applying a model of
Tg-evoked calcium entry, Törnquist et al.
(37) found that TNF- inhibits store-operated calcium
influx in a rat thyroid cell line. Moreover, Lepple-Wienhues et al.
(38) reported that CD95 stimulation inhibited activation
of calcium channels and subsequent IL-2 synthesis in
apoptosis-resistant Jurkat T cells. The latter observation indicates
that the CD95 system might play a role in anergy induction before or in
the absence of apoptosis. However, TRAIL reduced calcium influx to a
level just within the lower concentration limit required for subsequent
IL-2 production and proliferation (23), and thus showed no
anergy-inducing properties in the T cell lines. Having defined a novel
mechanism of action for TRAIL, which has been previously reported for
TNF and CD95 stimulation, these observations indicate that the
suppression of calcium-dependent lymphocyte activation signals might
represent a primary mechanism responsible for the immunomodulatory
properties of TNF/nerve growth factor superfamily members.
These molecules are known to be critically involved in the regulation of immune responses and are currently being targeted for therapeutic modulation in a multitude of recalcitrant autoimmune and malignant diseases. Our data indicate that TRAIL can act as a negative regulator of human T cell activation via mechanisms different from the induction of anergy or T cell clonal deletion by apoptosis.
In combination with the well-documented cytotoxic activities of TRAIL (11, 12), our data strongly suggest a two-edged role for TRAIL in human T cell effector functions, promoting both destructive and anti-inflammatory properties. Given that recent reports demonstrated that different recombinant TRAIL preparations differ widely in their capacity to induce apoptosis (21), attempts to exploit the anti-inflammatory features of TRAIL might be promising in future therapeutic strategies targeting autoimmune inflammation.
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Acknowledgments |
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Footnotes |
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2 J.D.L. and S.W. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Frauke Zipp, Division of Neuroimmunology, Department of Neurology, Charité University Hospital, Neuroscience Research Center, 10098 Berlin, Germany. E-mail address: frauke.zipp{at}charite.de
4 Abbreviations used in this paper: TRAIL, TNF-related apoptosis-inducing ligand; MBP, myelin basic protein; BP, birch pollen; TT, tetanus toxoid; Tg, thapsigargin; CDK, cyclin-dependent kinase; CRAC, calcium release-activated calcium channel.
Received for publication July 16, 2001. Accepted for publication March 6, 2002.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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K. Sato, T. Nakaoka, N. Yamashita, H. Yagita, H. Kawasaki, C. Morimoto, M. Baba, and T. Matsuyama TRAIL-Transduced Dendritic Cells Protect Mice from Acute Graft-versus-Host Disease and Leukemia Relapse J. Immunol., April 1, 2005; 174(7): 4025 - 4033. [Abstract] [Full Text] [PDF]
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