(Journal of Leukocyte Biology. 2000;68:81-86.)
© 2000
by Society for Leukocyte Biology
T cell lysis of murine renal cancer: multiple signaling pathways for cell death via Fas
Thomas J. Sayers*,
Alan D. Brooks*,
Naoko Seki
,
Mark J. Smyth
,
Hideo Yagita
,
Bruce R. Blazar|| and
Anatoli M. Malyguine¶
* Intramural Research Support Program,
¶ Clinical Services Program, SAIC-Frederick,
Laboratory of Experimental Immunology, DBS, NCI-FCRDC, Frederick, Maryland;
Cellular Cytotoxicity Laboratory, The Austin Research Institute, Heidelberg, Victoria, Australia;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan; and
|| Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis
Correspondence: Dr. Thomas Sayers, SAIC-Frederick, NCI-FCRDC, Building 560, Room 31-30, Frederick, MD 21702-1201. E-mail: Sayers{at}mail.ncifcrf.gov
 |
ABSTRACT
|
|---|
Activated T cells lyse the murine renal cancer Renca. We have examined
the mechanism of tumor cell lysis with the use of T cells derived from
C57BL/6, BALB/c, B6.gld, and B6.Pfp-/- mice. C57BL/6 and
BALB/c T cells can lyse Renca cells through the use of both granule-
and Fas ligand (FasL)-mediated pathways. However, B6.gld T cells
predominantly use granule-mediated killing, whereas
B6.Pfp-/- T cells use FasL. The lysis of Renca by
Pfp-/- T cells is only partially inhibited by the caspase
inhibitor ZVAD-FMK, suggesting that caspase-independent signaling is
also important for Renca cell lysis. When the reactive oxygen scavenger
butylated hydroxyanisole was used alone or in combination with ZVAD-FMK
a substantial reduction of Renca lysis was observed. Therefore, the
caspase-independent generation of reactive oxygen intermediates in
Renca after Fas triggering contributes to the lysis of these
cells.
Key Words: Fas ligand • cell-mediated cytotoxicity • Renca cells • kidney cancer
|
INTRODUCTION
|
|---|
Studies on the immune-mediated lysis of the murine renal cancer
Renca suggest that this tumor can by lysed by both granule- and Fas
ligand (FasL)-mediated lytic mechanisms [1
]. It is
interesting that studies on effector cells from mutant or gene-targeted
mice suggested that granule-mediated killing was the major lytic
mechanism used by natural killer (NK) cells, whereas FasL-mediated
lysis played a significant role in lysis of Renca by activated T cells.
However, the relative importance of either of these lytic mechanisms to
antitumor responses in vivo remains unclear. Successful
immunotherapy of some experimental tumors in mice suggested that
cell-mediated immunity and anti-tumor response predominantly involve
granule-mediated killing, where the granule protein perforin was the
critical component [2
3
4
]. However, in some of these
therapy models, immune responses were directed against relatively
strong antigenic stimuli (like xenoantigens) provided by these tumors.
In most spontaneously arising tumors, immune recognition of weaker
antigenic determinants must occur. Indeed, most tumor antigens are
thought to be differentiation-specific antigens, cancer/testis
antigens, or single point mutations of ubiquitously expressed genes
[5
]. Due to the induction of self-tolerance in the
immune system, the self or slightly modified self peptides derived from
tumors are likely to be recognized by T cells with only an intermediate
affinity for such peptides.
Experiments using specific T cell clones have indicated that signaling
requirements for granule-mediated killing are more stringent than those
required for FasL-mediated killing. Therefore, high-affinity TCR
recognition of MHC-associated peptides will induce both granule and
FasL-mediated lytic pathways [6
7
8
]. In contrast,
signaling of the same T cells with ligands of lower affinity (like self
peptides) only triggers the FasL lytic pathway [7
,
8
]. These responses seem to correlate with the
Ca2+ influx, because rapid influx triggers granule release
[9
], whereas only a lower, more prolonged influx of
Ca2+ is necessary to signal T cells to express FasL on
their cell surface [10
]. This suggests that during some
antitumor responses FasL-mediated killing may be more important than
has previously been assumed. Renca cells overexpressing Fas grow at
much slower rates in vivo than control transfectant cells,
whereas the in vitro growth rates of these cells are
identical [10a
]. In addition, recent experiments using
FLIP transfectants of various tumors have shown that these tumors grow
more rapidly than control transfectants in wild-type mice, but at equal
rates in SCID mice [11
, 12
]. Because FLIP
only blocks lysis through death receptors, but not granule-mediated
killing, these data also indicate that FasL may be important in the
immune responses to these particular tumors in vivo. One
requirement for FasL-mediated killing of tumor cells is the presence of
the Fas receptor on the target cell surface. Furthermore, this receptor
must transmit signal(s) that will ultimately result in the death of the
cell. However, the signaling of cell death through the Fas receptor can
occur through distinct biochemical pathways that may be cell-type
specific [13
]. We have determined the sensitivity of the
Renca tumor to lysis by activated T cells, and have further
investigated signal pathways from the Fas receptor, which may be
important in determining the fate of these tumor cells.
|
MATERIALS AND METHODS
|
|---|
Mice
Specific pathogen-free BALB/c and C57BL/6 mice were obtained
from the Animal Production area, National Cancer Institute, Frederick
Cancer Research and Development Center (Frederick, MD). The
B6Smn.C3H.FasL gld (B6.gld) and perforin-deficient
(B6.Pfp-/-) C57BL/6-Pfptm1Sdz mice were
purchased from The Jackson Laboratory (Bar Harbor, ME) and bred at our
facility.
Tumor cell lines
The Renca tumor cell line and the A20 B lymphoma are of BALB/c
origin. Cells were all maintained in RPMI 1640 supplemented with 10%
fetal bovine serum (FBS), 2 mM L-glutamine, 1x
nonessential amino acids, 1 mM sodium pyruvate, 100 U/mL penicillin,
100 µg/mL streptomycin, 10 mM HEPES, and 5 x 10-5
M 2-mercaptoethanol, pH 7.4 (complete medium). The A20 lymphoma is very
sensitive to Fas-mediated lysis. The d11S hybridoma cells kindly
provided by Dr. P. Henkart (National Cancer Institute, National
Institutes of Health, Bethesda, MD) utilize FasL to mediate their
cytotoxic activity. The 2PK-3 cells, and transfectants of mouse TRAIL
(mTRAIL/2PK-3) or murine FasL (mFasL/2PK-3) have previously been
described [14
].
Reagents
Mouse recombinant interferon-
(IFN-; specific activity
4.7 x 106 U/mg) was generously provided by Genentech
(South San Francisco, CA). Mouse recombinant tumor necrosis factor 
(TNF-; 107 U/mg) was purchased from PharMingen (San
Diego, CA). Anti-mouse Fas (Jo2) monoclonal antibody, antibody to mouse
CD3, and neutralizing antibody to murine TNF- were all purchased
from PharMingen. The neutralizing antibodies to murine FasL (MFL-1) and
murine TRAIL (N2B2) were prepared as previously described
[14
]. Soluble recombinant human Fas ligand (sFasL) was
purchased from Alexis (San Diego, CA). The enzyme inhibitors
Z-Val-Ala-Asp-(OMe)-CH2F (ZVAD-FMK) and
Z-Phe-Ala-(OMe)-CH2F (ZFA-FMK) were purchased from Enzyme
Systems Products (Dublin, CA). Butylated hydoxyanisole (BHA) and
concanamycin A were purchased form Sigma Chemical (St. Louis, MO).
Cytotoxicity assays
Renca or A20 cells that had been incubated overnight in the
presence or absence of various cytokines were labeled with
111indium-labeled 8-hydroxyquinolone
(111In-oxine; Medi-Physics, Silver Spring, MD) as
previously described [1
]. Briefly 1 x
106 target cells were incubated with 10 µCi of
111In-oxine for 30 min at room temperature. Cells were then
washed twice in complete medium, and labeled cells (1 x
104) were then incubated for 18 h at 37°C in the
presence or absence of various antibodies or cells in a final volume of
200 µL. The d11S cells (FasL-positive hybridoma) or T cells were
added at various effector-to-target ratios. Different concentrations of
anti-Fas antibody (Jo2) or isotype control antibody were added alone or
in the presence of P815 cells (1 x 105) to promote
antibody cross-linking. This method of efficiently cross-linking
antibodies on target cells was kindly provided by Dr. H. Kojima
(National Institute of Arthritis and Infectious Diseases, National
Institutes of Health, Bethesda, MD). Controls were always run with P815
cells in the absence of antibodies. In the absence of cross-linking the
Jo2 antibody does not trigger lysis of Renca but acts as a blocking
antibody. sFasL was added at various concentrations. In experiments
where inhibitors were used, the caspase inhibitors ZVAD-FMK or control
ZFA-FMK (Enzyme System Products, Dublin, CA) were added to target cells
at 4x final concentrations (final concentration in assay, 50 µM) in
medium (50 µL). In a similar manner, target cells were also incubated
with 4x final concentration of BHA (final concentration 100 µM).
Targets plus inhibitors were then immediately added to U-bottomed
microtiter plates and left for 3 h to allow target cells to
adhere. Effector cells were then added at various ratios. For
concanamycin treatment of effector cells, the effectors were
preincubated with concanamycin A (100 nM) for 2 h before addition
of the target cells. After overnight incubation at 37°C, supernatants
were harvested and counted on a gamma counter. Specific killing (%
cytotoxicity) was calculated as [(experimental release -
spontaneous release)/(maximal release - spontaneous release)] x
100. All groups were run in triplicate, and standard deviations were
calculated for all groups. Student’s t test was used to
determine the significance of cytotoxicity differences between groups.
Activation of T cells
Activated murine T cells were prepared as previously described
[1
]. Briefly, resting mouse lymph node cells were
cultured in 5 µg/mL concanamycin A for 72 h, incubated
with 10 mg/mL -methylmannoside (Sigma) for 30 min at 37°C, washed,
and incubated with 100 U/mL of interleukin-2 (IL-2) for a further
48–72 h. These cells were used as activated T cells in cytotoxicity
assays and were >93% CD3+ <2% CD3-,
DX5+ from all strains of mice used. Activated T cells were
used as effectors in the presence of an antibody to mouse CD3
(PharMingen) at 1 µg/mL to promote cross-linking of the T cell
receptor. Appropriate control antibody was added at the same
concentration.
|
RESULTS
|
|---|
Fas antibodies block T cell killing
In the presence of activated T cells stimulated through anti-CD3,
Renca target cells are efficiently lysed in an 18-h indium-release
assay. To evaluate the contribution of granule and FasL-mediated lytic
mechanisms wild-type, gld, and Pfp-/- T effector cells were
used in cytotoxicity assays. Also, the effect of an antibody against
murine Fas (Jo2 antibody) was determined. This antibody to murine Fas
can act as a blocking antibody in the absence of cross-linking (data
not shown). Blocking using the Fas antibody Jo2 (10 µg/mL)
significantly reduced (P < 0.005) killing by wild-type
C57BL/6, BALB/c T cells, as well as by Pfp-/- T cells and
the hybridoma dllS (Fig. 1
). It is interesting that no blocking of killing by gld T cells was seen
in the presence of this antibody. This suggests, as might be expected,
that FasL-mediated killing is much reduced in cells from gld mice.
However, gld T cells do show potent lytic activity against Renca,
particularly after 5–6 days stimulation in vitro. The basis
of this lytic activity was further investigated.
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Figure 1. Activated T cell lysis of Renca target cells. Renca cells were labeled
with 111In-oxine and effector T cells from C57BL/6, BALB/c,
B6.gld, and Pfp-/- mice or the hybridoma cells d11S were
added at an effector-to-target ratio of 20:1 in the presence of Ab to
CD3 at 1 µg/mL, and in the presence (open bars) or absence (filled
bars) of a blocking antibody to Fas at 10 µg/mL. After 18 h cell
supernatants were harvested and counted.
|
|
Granule-mediated Renca lysis
To assess the contribution of granule-mediated killing of Renca by
T cells, cytotoxic assays were carried out in the presence of the
perforin inhibitor concanamycin A. Concanamycin A had particularly
pronounced effects on inhibiting lysis by gld T cells (Fig. 2
). Substantial inhibition (25–50%) was also seen on lysis mediated by
C57BL/6 and BALB/c T cells (P < 0.005). By contrast,
there was no effect on Renca killing by Pfp-/- T cells or
the dllS hybridoma. This suggests that the effects of this inhibitor
are probably specific for granule-mediated killing. Granule-mediated
lysis can usually occur with a more rapid kinetics of lysis than
FasL-mediated killing. However, using Renca targets, very little lysis
of targets was seen in 4- to 6-h assays. Even if granule-mediated
killing was the predominant mechanism of lysis as is the case with gld
T cells (data not shown).
Effect of caspase inhibitors on lysis of Renca
The triggering of apoptosis via receptors for FasL, TNF, and TRAIL
usually involves signaling through initiator caspases
[15
, 16
]. Therefore, in the majority of
cells, caspase inhibition will block death receptor-mediated lysis. We
used the general caspase inhibitor ZVAD-FMK to block caspases in target
cells, and compared using Renca to that of the FasL-sensitive cell line
A2O (Fig. 3
). No effect of ZVAD-FMK was seen for gld T cell killing of either Renca
or A2O. Because granule-mediated lysis is not usually blocked by
caspase inhibitors, this further reinforces the assumption that killing
by gld T cells is mostly granule-mediated. It was surprising that,
although ZVAD-FMK could completely block killing of A2O cells by either
Pfp-/- T cells or dllS hybridoma cells (P < 0.005), Renca cells were still significantly lysed in the presence
of ZVAD-FMK. Therefore, in the presence of ZVAD-FMK some reduction of
killing of Renca by Pfp-/- T cells was usually observed
(ranging from 10 to 40% reduction). Nonetheless, a substantial amount
of lysis still occurred even in the presence of high concentrations of
this inhibitor. Killing of Renca by dllS cells was usually more
sensitive to inhibition by ZVAD-FMK than killing by Pfp-/-
T cells. This suggested that at least part of the killing of Renca
cells by Pfp-/- T cells was caspase-independent, whereas
killing of A2O was completely caspase dependent.
Lysis of Renca by TNF-family members
There are reports that TNF- can kill certain tumor targets via
a necrotic pathway that is caspase independent [17
,
18
]. Therefore we assessed the ability of other
TNF-family proteins to lyse Renca. However, Renca cells are extremely
resistant to exogenous TNF even at very high concentrations of up to
10,000 U/mL. Furthermore, neutralizing antibodies to TNF- did not
reduce killing by activated T cells (data not shown). This makes it
unlikely that TNF- produced by Pfp-/- T cells is of
major importance in Renca lysis. Recently much interest has focused on
lytic effects mediated by the TNF-family member TRAIL. In initial
experiments using recombinant human TRAIL from two independent sources,
no lytic effects on Renca were seen (data not shown). However,
transfected 2PK-3 cells expressing murine TRAIL protein (mTRAIL/2PK-3)
efficiently lysed Renca cells (Fig. 4
). In addition, TRAIL killing was not modulated by cytokine treatment of
the Renca targets. In contrast, the transfectants expressing murine
FasL (mFasL/2PK-3) only lysed cytokine-treated Renca. Fas expression is
dramatically increased in Renca by prior treatment with IFN- and
TNF-, which results in increased sensitivity to Fas-mediated lysis.
In contrast, endogenous levels of expression of TRAIL receptors by
Renca must be sufficient to trigger cell death. To further dissect the
relative roles of FasL and TRAIL in lysis of Renca by T cells,
appropriate neutralizing antibodies were added to cytotoxicity assays.
Somewhat surprisingly, neutralizing antibodies to FasL completely
blocked killing of Renca by Pfp-/- T cells
(P < 0.005), whereas neutralizing antibodies to TRAIL
were without significant effect (Fig. 5
). Therefore, under the conditions we employed, TRAIL played no role in T
cell-mediated killing. Also, FasL seems to account for all the killing
by Pfp-/- T cells unless the neutralizing antibody to FasL
cross-reacts with another unidentified molecule important in lysis of
Renca cells.
Alternative caspase-independent pathways in Renca lysis?
Inhibitor studies with ZVAD-FMK showed that lysis of Renca by
Pfp-/- T cells was only partially dependent on caspases.
Therefore, we hypothesized that Pfp-/- T cells could also
trigger Renca lysis by using a signaling pathway that was
caspase-independent. It has previously been reported that TNF lysis of
L929 cells can proceed via a caspase-independent necrotic pathway
mediated by the generation of reactive oxygen intermediates
[18
]. This necrotic pathway could be blocked by the
oxygen radical scavengers like BHA, so we determined the effects of BHA
as Renca killing. As seen in Figure 6
, which is a combination of data from two independent experiments, Renca
killing by Pfp-/- T cells was blocked by BHA alone at both
effector-to-target ratios, whereas ZVAD-FMK had no effect on lysis.
Also, the combination of ZVAD-FMK and BHA was not significantly more
effective than BHA alone. Inhibition by BHA alone was highly
significant (P < 0.005) at the lowest
effector-to-target ratio. This suggests that reactive oxygen
intermediates generated in Renca cells after Fas signaling contribute
to the lysis of these tumor cells.
|
DISCUSSION
|
|---|
In recent years much progress has been made in elucidating the
molecular events that occur after engagement of the Fas receptor
[19
]. It is thought that trimerization or
oligomerization of Fas occurs. This process results in the formation of
the death-induced signaling complex or DISC [20
] via
recruitment of molecules like the adapter protein FADD and FLICE or
caspase 8 [15
, 16
, 21
,
22
]. Caspase 8 is then activated by autocatalysis to
trigger further downstream events that result in target cell apoptosis.
However, in human cell lines at least two distinct molecular pathways
are triggered after caspase 8 activation [23
], and the
relative importance of each pathway is cell-type-specific. Therefore in
Type I cells there is formation of high levels of the DISC, which
results in substantial activation of caspase 8. Activated caspase 8 can
then directly trigger the caspase cascade of enzymes resulting in
apoptosis. This Type I killing is largely independent of mitochondria
and is not affected by the presence of the anti-apoptotic protein
bcl-2. In contrast, in Type II cells there is a lower level of DISC
formation and caspase 8 activation. Rather than directly activating the
caspase cascade, caspase 8 cleaves the cytosolic protein bid
[24
, 25
]. Cleaved bid is thought to
interact with mitochondria inducing the release of cytochrome and
activation of caspase 9. Because caspase 8 signaling is critical to
both pathways, cell death mediated through Fas is blocked by caspase
inhibitors [23
]. However, death signaling via TNF
receptor family members is not caspase-dependent in all cells.
Therefore, the TNF-mediated lysis of L929 cells is independent of
caspase signaling and proceeds with a necrotic phenotype in the
presence of caspase inhibitors [18
]. Furthermore,
activated oxygen intermediates play an important role in this death
pathway and cells undergoing death in this manner have been termed Type
III cells [26
]. The data we obtained with lysis of Renca
by Pfp-/- T cells is also consistent with a contribution of
a Type III mechanism in the death of these cells. A caspase-independent
pathway involved in Fas signaling would be consistent with recent
observations from other groups using different target cells. Vercammen
et al. demonstrated that L929 cells transfected with human Fas could be
triggered to die by agonist antibodies to human Fas in the presence of
caspase inhibitors like ZVAD [26
]. Indeed, in these L929
cells, caspase inhibitors promoted rather than inhibited death. This
pathway also seemed to involve reactive oxygen intermediates because
lysis of these L929 cells was only significantly inhibited by
combinations of ZVAD-FMK and BHA. Kawahara et al., using a
Jurkat-derived cell (JB-6), reported that the induction of dimerization
of transfected FADD resulted in a necrotic form of cell death that was
not blocked by caspase inhibitors [27
]. This suggested
that FADD could be involved in cell death signaling through a
caspase-independent pathway. It is interesting that inhibitory effects
of bcl-2 on cell death were not noted in either of these reports. Our
studies show that a caspase-independent signaling pathway can occur in
non-transfected cells. It seems likely that the lysis of Renca cells by
activated T cells can be triggered by both caspase-dependent and
caspase-independent signaling pathways, and the cells in which both
pathways are operating may therefore be more sensitive to T
cell-mediated lysis.
There are, however, some inhibitory effects of ZVAD-FMK on killing of
Renca by Pfp-/- T cells, although inhibition is somewhat
variable and never complete. One of the most likely explanations for
this observation is that the Renca cell line is heterogeneous.
Therefore a Type III mechanism could contribute in amplifying death
pathways in some Renca cells but not others. Indeed we have isolated
individual clones from the Renca cell line where lysis by
Pfp-/- T cells is totally blocked by ZVAD-FMK, so killing
is completely caspase dependent (data not shown). Therefore, a minority
of clones in the Renca population are only lysed by caspase-dependent
pathways. The proportion of these clones in the general Renca
population would therefore determine the effectiveness of inhibition by
ZVAD-FMK. In conclusion, after the engagement of Fas on Renca by FasL
on activated T cells, multiple signaling pathways can occur. In Renca
cells caspase-independent signaling is also important in determining
survival or death of these cells. In contrast, signaling in A20 cells
is completely caspase-dependent. A number of issues still need to be
resolved. The components involved in the caspase-independent signaling
pathway are as yet unidentified. Furthermore a role for the
mitochondria in this pathway is likely, but unproven. In addition, the
threshold for activation of these various pathways on the interaction
of Fas with more physiological levels of FasL is unknown. We are
currently further investigating these important questions.
|
ACKNOWLEDGEMENTS
|
|---|
This project was funded in whole or in part with Federal
funds from the National Cancer Institute, National Institutes of
Health, under contract number N01-C0-56000. The authors are grateful to
Dr. J. Ortaldo and Dr. R. Wiltrout for their suggestions and
critical reading of the manuscript. The technical assistance of John
Wine, Eric Derby, and Vasavi Reddy is much appreciated. We thank Susan
Charbonneau and Joyce Vincent for help in the preparation of the
manuscript.
By acceptance of this article, the publisher or recipient acknowledges
the right of the U.S. Government to retain a nonexclusive, royalty-free
license in and to any copyright covering the article.
Animal care was provided in accordance with the procedures outlined in
A Guide for the Care and Use of Laboratory Animals (NIH
Publication No. 86-23, 1985).
Received December 20, 1999;
revised February 24, 2000;
accepted February 25, 2000.
|
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ABSTRACT
INTRODUCTION
