By
From the * Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo
113-8421, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science
and Technology Corporation (JST), Chiyoda-ku, Tokyo 101-0062, Japan; and the § Department of
Urology, Kobe University School of Medicine, Chuo-ku, Hyogo 650-0017, Japan
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Abstract |
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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a proapoptotic
member of the TNF family of type II membrane proteins, which constitutes one component of
T cell cytotoxicity. In this study, we investigated the expression and function of TRAIL in human peripheral blood T (PBT) cells. Although freshly isolated PBT cells did not express a detectable level of TRAIL on their surface, a remarkable TRAIL expression was rapidly induced on the surface of both CD4+ and CD8+ PBT cells upon stimulation with anti-CD3 monoclonal antibody and type I interferons (IFNs). This enhancement of TRAIL expression was a
unique feature of type I IFNs (IFN- and IFN-
), and neither type II IFN (IFN-
) nor various other cytokines enhanced TRAIL expression on anti-CD3-stimulated PBT cells. Type I
IFNs have been used for clinical treatment of renal cell carcinomas (RCCs), and we found that
most RCC cell lines were susceptible to TRAIL-induced apoptosis. Type I IFNs substantially
augmented cytotoxic activity of anti-CD3-stimulated PBT cells against RCC cell lines in a
TRAIL-dependent manner. These results indicate a unique feature of type I IFNs to regulate
TRAIL-mediated T cell cytotoxicity, which may be involved in the antitumor effects of type I
IFNs against various tumors.
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Introduction |
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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)1/APO-2L is a recently identified
type II integral membrane protein belonging to the TNF
family, which induces apoptotic cell death in a variety of
tumor cells (1). Among the members of this family, TRAIL
exhibits highest homology to a well-characterized proapoptotic factor, FasL/CD95L, which has been implicated in T
cell cytotoxicity and immune regulation (4). TRAIL mRNA
was found in a variety of tissues and cells (1), but little is known about the expression of TRAIL at the protein level
or its physiological functions. Recent studies revealed that
at least four receptors, TRAIL-R1/DR4, TRAIL-R2/
DR5/TRICK2/killer, TRAIL-R3/TRID/DcR1/LIT, and
TRAIL-R4/TRUNDD/DcR2, bind to TRAIL with similar affinities (5). Both TRAIL-R1 and TRAIL-R2
contain a death domain homologous to that in Fas,
TNFR-I, and DR3/TRAMP/APO-3/WSL-1. Oligomerization of the death domain in TRAIL-R1 and TRAIL-R2
recruits caspase-8 or -10 via Fas-associated death domain
(FADD) or a FADD-like adapter molecule, and activates
the subsequent caspase cascade resulting in apoptotic cell
death (5, 10). In contrast to these proapoptotic receptors,
TRAIL-R3 completely lacks a cytoplasmic domain and exists as a glycophospholipid-anchored protein on the cell
surface. Because TRAIL-R3 can compete with the proapoptotic TRAIL-Rs for TRAIL binding, it seems to work
as a decoy receptor. It has been suggested that TRAIL induces apoptosis preferentially in transformed cells but not
in normal cells, possibly due to preferential expression of
TRAIL-R3 in the latter (6, 8, 10). TRAIL-R4 carries a
cytoplasmic domain containing a truncated death domain
that cannot transmit a death signal but can activate nuclear
factor B, which may protect the cells from TRAIL-R1-
or TRAIL-R2-induced apoptosis (9, 10). To date, the
physiological functions of these multiple TRAIL-Rs remain obscure.
It has been shown that CTLs kill target cells by two major effector mechanisms, which are mediated by perforin or FasL (11), and that these effector molecules are required for the elimination of virus-infected cells or certain tumor cells (14). Furthermore, we and others have demonstrated that these molecules are responsible for mediating tissue damage associated with T cell-mediated diseases such as graft-versus-host disease and hepatitis by using murine models (17). In addition to these molecules, we recently revealed that TRAIL was expressed on human CD4+ T cell clones and mediated their cytotoxicity against some tumor cells, such as a human T lymphoma Jurkat and a transformed keratinocyte HaCaT (20). Thomas and Hersey also reported recently that TRAIL at least partly mediated cytotoxicity of melanoma-specific CD4+ T cell clones against some melanoma cells and Jurkat cells (3). These observations suggested that TRAIL constitutes an additional pathway of T cell cytotoxicity against certain tumor cells. However, it remains to be determined whether TRAIL can be expressed not only on particular T cell clones but also on circulating T cells and whether it can be used as a general mechanism of T cell cytotoxicity.
IFNs are the most classical cytokines, and were discovered on the basis of their antiviral activities. It is well
known that a variety of cells produce IFNs in response to
infection by various viruses, bacteria, and mycoplasmas (21,
22). IFNs can be classified into two groups, type I (IFN-,
IFN-
, and IFN-
) and type II (IFN-
). All of the type I
IFNs share the same cell surface receptor (IFNAR) composed of at least two subunits, IFNAR-1 and IFNAR-2b/c. In addition to their antiviral effects, IFNs exhibit pleiotropic biological activities, including antitumor and immunomodulatory effects (21, 22). Type I IFNs have been commonly used for clinical treatment of certain tumors, including
melanomas, gliomas, chronic myelogenous leukemias (CMLs),
and renal cell carcinomas (RCCs) (23, 24). The antitumor
effects of type I IFNs appear to be mediated by either or
both of the following two mechanisms: (a) direct cytotoxic
or cytostatic activity against tumor cells, and (b) indirect
cytotoxicity by modulating host immune responses. However, the effector molecules responsible for mediating the antitumor effects of type I IFNs remain largely unknown.
In this study, we characterized the expression and function of TRAIL on human peripheral blood T (PBT) cells, and found a unique feature of type I IFNs to upregulate TRAIL expression on anti-CD3-stimulated PBT cells. We also demonstrated that almost all RCC cell lines are susceptible to TRAIL-induced cytotoxicity, and that type I IFNs augment cytotoxic activity of anti-CD3-stimulated PBT cells against RCC cell lines in a TRAIL-dependent manner. The physiological and clinical relevance of these findings is discussed.
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Materials and Methods |
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Cells.
A human T lymphoma cell line Jurkat was obtained from Japan Cancer Research Bank and cultured in RPMI 1640 medium containing 10% FCS, 100 µg/ml streptomycin and penicillin, and 2 mM glutamine (culture medium). A mouse B lymphoma cell line 2PK-3 was obtained from American Type Culture Collection and maintained in culture medium. 2PK-3-derived transfectants, hTRAIL/2PK-3 and hFasL/2PK-3, which stably express human TRAIL and human FasL, respectively, were prepared as described previously (20) and maintained in culture medium. Human RCC-derived cell lines 769P, A498, ACHN, Caki 1, and Caki 2 were obtained from American Type Culture Collection, and KO-RCC-1 was established as described previously (25). RCC-derived cell lines KN-39, KN-41, and OWR-10 were provided by Dr. Y. Kinoshita (Kobe University, Kobe, Japan). All of these RCC-derived cell lines were maintained in culture medium.Reagents.
Human IFN-Cell Preparation and Activation.
PBMCs were prepared from healthy volunteers by Ficoll-Hypaque (Sigma) centrifugation. PBMCs (3 × 106 cells/ml) were cultured at 37°C for 24 or 48 h on 24-well plates precoated with 10 µg/ml of anti-CD3 mAb, or in the presence of IL-2 (500 U/ml), PHA (20 µg/ml), or poly IC (20 µg/ml). For preparation of PBT cells, PBMCs were first cultured on plastic dishes for 1 h at 37°C to deplete adherent monocytes. After passage of nonadherent cells through a nylon wool column, PBT cells were isolated by E-rosetting with sheep red blood cells followed by depletion of residual NK and B cells by using anti-CD16 mAb (3G8; PharMingen), anti-CD20 mAb (2H7; PharMingen), anti-CD56 mAb (B159; PharMingen), and anti-mouse Ig immunomagnetic beads (Dynal). Purity of PBT cells was >95% CD3+ as determined by flow cytometry. In some experiments, CD4+ and CD8+ T cells were isolated from PBT cells by using anti-CD4 or anti-CD8 immunomagnetic beads (Dynal) and DetachaBead® (Dynal). The purity of each population was >98% CD3+CD4+ or >98% CD3+CD8+ as estimated by flow cytometry. Purified PBT cells (3 × 106 cells/ml) were cultured on plates uncoated or precoated with anti-CD3 mAb (10 µg/ml) in the presence or absence of IFN-Flow Cytometric Analysis.
Cells (106) were incubated with 1 µg of biotinylated RIK-2 or control mouse IgG1 (PharMingen) for 1 h at 4°C followed by PE-labeled avidin (PharMingen). After washing with PBS, the cells were analyzed on a FACScanTM (Becton Dickinson), and data were processed by using Cell QuestTM software (Becton Dickinson). In some experiments, FITC-labeled anti-human CD3 mAb (PharMingen) was included to identify T cells in PBMCs.Northern Blot Analysis.
PBT cells (3 × 106 cells/ml) were cultured on plates uncoated or precoated with anti-CD3 mAb (10 µg/ml) in the presence or absence of IFN-Cytotoxic Assay.
PBT cells (3 × 106 cells/ml) were prestimulated for 12 h on plates uncoated or precoated with anti-CD3 mAb (10 µg/ml) in the presence or absence of IFN- ![]() |
Results |
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We recently demonstrated that human CD4+
T cell clones constitutively expressed TRAIL on their surface as estimated by staining with neutralizing anti-TRAIL
mAbs, RIK-1 and RIK-2 (20). In contrast, as represented
in Fig. 1, we could not find a detectable level of surface
TRAIL on freshly isolated PBT cells. Because the expression of TNF family proteins such as TNF- and FasL can be induced on activated T cells, we examined whether surface TRAIL expression can be also upregulated on PBT cells
by various stimuli. PBMCs were stimulated with immobilized anti-CD3 mAb, PHA, IL-2, or poly IC for 24 or 48 h,
and TRAIL expression on CD3+ PBT cells was then examined by flow cytometry with RIK-2 mAb. As represented in Fig. 1, no detectable level of TRAIL was found on PBT cells when stimulated with PHA or IL-2. In contrast, marginal but significant levels of TRAIL expression
were consistently observed upon stimulation with anti-CD3
mAb or poly IC.
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Since poly IC has been known to be a potent inducer of
type I IFNs (21, 22), we next examined whether IFN-
can directly affect TRAIL expression on PBT cells. As represented in Fig. 2 A, marginal but significant levels of TRAIL
expression were observed on both CD4+ and CD8+ PBT
cells at 12 h after stimulation with either anti-CD3 mAb or
IFN-
alone. Interestingly, the combination of anti-CD3
mAb and IFN-
greatly upregulated TRAIL expression on
both CD4+ and CD8+ PBT cells. Similar results were obtained at 24 or 48 h after each stimulation (data not shown).
These results indicated that stimulation with anti-CD3
mAb alone is not sufficient for maximal induction of surface TRAIL expression on PBT cells, and that IFN-
provides a costimulatory signal that synergistically upregulates TRAIL expression.
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It has been shown that expression of some TNF family
proteins such as CD40L on activated T cells was upregulated by a CD28-mediated costimulatory signal (30). Therefore, we tested whether the CD28-mediated costimulation
might affect expression of TRAIL on anti-CD3-stimulated
PBT cells. As represented in Fig. 2 A, the addition of an
agonistic anti-CD28 mAb barely affected the expression levels of surface TRAIL on anti-CD3- or anti-CD3 plus
IFN--stimulated PBT cells, indicating that the CD28-
mediated costimulatory signal does not contribute to TRAIL
induction in PBT cells.
We also examined the kinetics of TRAIL expression after stimulation with anti-CD3 plus IFN-. As represented
in Fig. 2 B, TRAIL expression appeared on both CD4+ and
CD8+ PBT cells at 2 h after stimulation, and reached a peak
at 6 h. Similar levels of surface TRAIL expression were retained on CD4+ and CD8+ PBT cells at 48 h (not shown).
We next examined various cytokines for their
ability to regulate TRAIL expression on unstimulated or
anti-CD3-stimulated PBT cells. IFN-, another type I IFN
that shares the same receptor (IFNAR) with IFN-
(21,
22), exhibited a similar effect as IFN-
, which alone induced a marginal TRAIL expression on PBT cells and
greatly upregulated TRAIL expression on anti-CD3-stimulated PBT cells (Fig. 3). Similar levels of TRAIL expression on anti-CD3-stimulated PBT cells were observed upon
costimulation with a lower dose of IFN-
and IFN-
(50 U/ml; not shown). In contrast, the type II IFN (IFN-
),
which stimulates a distinct receptor (IFNGR), exhibited no
effect on TRAIL expression on unstimulated or anti-CD3-
stimulated PBT cells at 12 h (Fig. 3) or 24 or 48 h (not shown)
even at a high dose of 500 U/ml. We also examined IL-2,
IL-15, IL-12, and IL-18, which have been reported to upregulate FasL expression on T and NK cells (4, 31), but
observed no effect on TRAIL expression (Fig. 3). Similarly,
no effect was observed with the other cytokines tested, including TNF-
, IL-1
, IL-1
, IL-4, IL-6, IL-7, and IL-16
(data not shown). These results indicated that the ability to
induce TRAIL expression on PBT cells is a unique feature of
type I IFNs.
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It has been reported
that TRAIL mRNA was detectable in a variety of tissues
and cells (1). Furthermore, a recent study demonstrated
TRAIL mRNA expression in human PBT cells after activation with anti-CD3 mAb or PMA plus ionomycin (34).
Therefore, we examined whether stimulation with anti-CD3 mAb and/or IFN- upregulates TRAIL expression
in PBT cells at the transcriptional level. As represented in
Fig. 4, PBT cells cultured with medium alone expressed only a marginal level of the 1.6-kb TRAIL transcript. Although stimulation with either IFN-
or anti-CD3 mAb
alone significantly increased TRAIL mRNA expression, a
remarkable increase was observed after stimulation with the
combination of anti-CD3 mAb and IFN-
. It was also
noted that IFN-
was more effective than anti-CD3 mAb
in inducing TRAIL mRNA expression when used alone.
Similar results were obtained when PBT cells were stimulated with IFN-
(not shown). These results indicated that
type I IFNs regulate TRAIL expression in unstimulated or
anti-CD3-stimulated PBT cells at the transcriptional level.
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Type I IFNs have been used for clinical treatment of various tumors, including melanomas, gliomas, CMLs, and RCCs (23, 24). The unique feature of type I IFNs to upregulate TRAIL expression on PBT cells prompted us to examine whether IFN-induced TRAIL on PBT cells might be directly involved in enhanced cytotoxicity against tumor cells. In this respect, we first examined the susceptibility of human RCC cell lines to cytotoxicity by human TRAIL transfectants. We also examined their susceptibility to human FasL, which constitutes another pathway of T cell cytotoxicity. As represented in Fig. 5, eight out of nine RCC cell lines tested were sensitive to TRAIL-induced cytotoxicity. Some RCC cell lines (A498 and KN-41) exhibited as high sensitivity as Jurkat, which has been commonly used as a highly sensitive target for TRAIL (1). On the other hand, the FasL transfectants lysed five out of nine RCC cell lines, all of which were also lysed by the TRAIL transfectants. Some RCC cell lines (Caki 1, KN-39, and KN-41) were sensitive to TRAIL but not to FasL.
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We then examined the cytotoxic activity of anti-CD3-
and/or IFN--stimulated PBT cells against RCC cell lines
that were sensitive to both TRAIL and FasL (ACHN and
A498) or sensitive to TRAIL but resistant to FasL (KN-39
and KN-41). A neutralizing anti-TRAIL mAb (RIK-2
[20]) and a neutralizing anti-FasL mAb (NOK-2 [27]) were
used to assess the contribution of TRAIL and FasL to the cytotoxicity. CMA pretreatment, which inactivates perforin (26), was used to assess the contribution of perforin.
As shown in Fig. 6, anti-CD3-stimulated PBT cells exhibited substantial cytotoxic activities against both types of
RCC target cells, which were partially inhibited by RIK-2
but not by NOK-2; the residual cytotoxicity was mostly
abrogated by CMA treatment, indicating that these cytotoxic activities were mediated by TRAIL and perforin. Although IFN-
stimulation alone did not significantly induce cytotoxicity, costimulation with IFN-
greatly enhanced
the cytotoxic activities of anti-CD3-stimulated PBT cells;
this enhancement was abrogated by RIK-2 but not by NOK-2, indicating that the IFN-
-enhanced cytotoxicity
was predominantly mediated by TRAIL but not by FasL. It
was also noted that the TRAIL-independent residual cytotoxic activities, which were abrogated by CMA treatment,
were almost comparable between the anti-CD3-stimulated T cells and the anti-CD3 plus IFN-
-stimulated T cells,
indicating that IFN-
did not enhance perforin-mediated
cytotoxicity. These results indicate that IFN-
can augment the cytotoxic activity of TCR/CD3-stimulated PBT
cells against RCC cells by specifically enhancing TRAIL-mediated cytotoxicity.
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Discussion |
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We recently demonstrated that human CD4+ T cell clones constitutively expressed TRAIL, which was fully responsible for spontaneous cytotoxicity against certain tumor cells, such as Jurkat cells (20). Others have also recently shown that the cytotoxic activity of human CD4+ T cell clones against melanoma cells was at least partly mediated by TRAIL (3). In this study, we characterized the expression and function of TRAIL on human PBT cells and found that both CD4+ and CD8+ PBT cells express TRAIL upon TCR/CD3 stimulation, especially in the presence of type I IFNs. This indicated that TRAIL-mediated cytotoxicity is not confined to particular T cell clones but can be generally involved in TCR/CD3-mediated, antigen-specific cytotoxicity exerted by human T cells, especially when they are exposed to exogenously administrated or endogenously produced type I IFNs.
A previous study by others demonstrated the upregulation
of TRAIL mRNA in human PBT cells after activation with
anti-CD3 mAb or PMA plus ionomycin (34). In the present
study, we demonstrated that anti-CD3 stimulation induced
surface TRAIL expression on human PBT cells but only
marginally. We found that IFN- greatly enhanced TRAIL
expression on anti-CD3-stimulated PBT cells, whereas IFN-
solely induced TRAIL expression on PBT cells and
only marginally. This enhancement of TRAIL expression
was a unique feature of type I IFNs (IFN-
and IFN-
)
among the various cytokines so far tested. Other cytokines
that have been shown to upregulate FasL expression in T
and NK cells (IL-2, IL-12, IL-15, and IL-18 [4, 31-33]) or those enhancing T cell cytotoxicity (IL-2, IL-4, IL-6, IL-7,
IL-12, IL-15, and IL-18) did not affect TRAIL expression
on unstimulated or anti-CD3-stimulated PBT cells. Northern blot analysis showed that the synergistic effect of anti-CD3 and IFN-
was exerted at the transcriptional level. A
higher transcriptional induction by IFN-
alone than that
by anti-CD3 alone suggests the possibility that TRAIL
gene expression is primarily regulated by IFN-
and that
anti-CD3 stimulation may act synergistically by upregulating type I IFN receptors (IFNARs) on PBT cells. Binding
of type I IFN to IFNAR leads to activation of the receptor-associated tyrosine kinases, Tyk-2 and Jak-1, which
phosphorylate signal transducer and activator of transcription (STAT)-1 and STAT-2. Phosphorylated STAT-1 and
STAT-2 form a transcriptionally active heterotrimer complex (ISGF3) together with ISGF3
/p48, which binds to a
cis-acting enhancer sequence termed IFN-stimulated response element (ISRE [35]). Over 30 proteins have been
known to be the products of type I IFN-inducible genes
whose transcription can be upregulated by ISRE in the
flanking region (21, 22). Further studies are needed to
characterize the regulatory region of the TRAIL gene and
to elucidate the regulatory mechanisms for TRAIL expression at the transcriptional level.
Type I IFNs have been commonly used for clinical treatments of certain tumors, including melanomas, gliomas,
CMLs, and RCCs (23, 24). However, the majority of these
tumors are resistant to type I IFN-induced growth arrest or
apoptosis in vitro. Previous studies in the mouse system
have shown that the antitumor effect of type I IFNs in vivo
was mediated by host T cells (36, 37). Furthermore, the
combination of type I IFNs and adoptive transfer of tumor-specific T cells was effective for rejection of certain tumors
(38, 39). Although it is well known that type I IFNs exert
pleiotropic immunomodulatory effects including upregulation of MHC class I expression and enhancement of CTL
cytotoxicity (21, 22), the effector molecules responsible for
mediating the antitumor effects of type I IFNs have not
been well characterized. In this study, we revealed that type I
IFNs upregulate TRAIL expression on TCR/CD3-stimulated T cells and augment their cytotoxicity against TRAIL-sensitive tumor cells. We found that almost all of the RCC cell lines tested were TRAIL sensitive, and that IFN- substantially enhanced the cytotoxic activity of TCR/CD3-stimulated PBT cells against these target cells in a TRAIL-dependent manner. Moreover, a recent study by Thomas
and Hersey demonstrated that most of the melanoma cell
lines they tested were also sensitive to TRAIL-induced apoptosis (3). Therefore, it is possible that the enhancement by IFN-
of TRAIL-mediated cytotoxicity by TCR/
CD3-stimulated T cells at least partly accounts for the antitumor effects of type I IFNs against RCCs and melanomas.
It is known that melanomas and RCCs are highly antigenic, and tumor-infiltrating T lymphocytes (TILs) are frequently observed in patients with RCCs or melanomas (40,
41). In such a situation, the administration of type I IFNs
would upregulate TRAIL expression on TCR/CD3-stimulated TILs that are reactive to some tumor antigen and
thus augment their cytotoxicity against TRAIL-sensitive
tumor cells. Type I IFNs would also upregulate MHC class I
expression on tumor cells and thus enhance TCR/CD3-
mediated upregulation of TRAIL expression on tumor-reactive T cells. In addition, it has been shown that the combination of type I IFNs and certain chemotherapeutic drugs exerts synergistic antitumor effects (23, 24). In this respect, it is noteworthy that the expression of a proapoptotic
TRAIL receptor, TRAIL-R2/DR5/killer, can be upregulated in some tumor cells by chemotherapeutic drugs in a
p53-dependent manner (7). Therefore, it is possible that
the synergistic antitumor effects of type I IFNs and some
chemotherapeutic drugs may be at least partly mediated by
TRAIL induction by the former and TRAIL-R2 induction by the latter.
It is known that T cell cytotoxicity is mediated by perforin and FasL (11). Our present study demonstrated
that TRAIL constitutes an additional predominant pathway
of T cell cytotoxicity potentially against various tumor
cells. However, the expression of these effector molecules
in PBT cells is differently regulated. We showed previously
that the expression of perforin in PBT cells is confined to a
minor population of CD8+ T cells that express CD11b and
represent memory effector CTLs (29). We also demonstrated
previously that FasL is not expressed on PBT cells but can be
transiently expressed on CD45RO+ memory CD4+ and
CD8+ T cells upon stimulation with PMA plus ionomycin
or anti-CD3 mAb (42). However, the cell surface expression
of FasL on activated T cells is rapidly downregulated by
shedding mediated by some proteases (27). Also in the
present study, we examined FasL expression in anti-CD3-
and/or IFN--stimulated PBT cells (data not shown). Rehybridization of the Northern blot shown in Fig. 4 with a
human FasL cDNA probe showed that FasL mRNA expression was induced by anti-CD3 but not by IFN-
,
and no enhancement of anti-CD3-induced FasL mRNA
expression was observed upon costimulation with IFN-
.
However, we could not find a detectable level of cell surface FasL expression on the anti-CD3-stimulated PBT
cells, possibly due to the rapid shedding. Consequently, we
could not find a substantial contribution of FasL to the cytotoxic activities of anti-CD3- and/or IFN-
-stimulated
PBT cells even against the FasL-sensitive target cells (A498
and ACHN; Fig. 6). In contrast to this transient nature of
FasL expression, TRAIL can be stably expressed on most
CD4+ and CD8+ T cells, especially when costimulated
with anti-CD3 and IFN-
(Fig. 2 B). This suggests that
TRAIL can mediate more long-lasting T cell cytotoxicity
than FasL, which would be beneficial for exerting an antitumor effect. In the case of FasL, the rapid downregulation by shedding has been suggested to be beneficial for avoiding normal tissue damage, such as in hepatitis (43, 44). In
contrast, it has been shown that TRAIL exerts no apparent
toxicity in vivo (44). Therefore, the specific upregulation
of TRAIL by type I IFNs can be expected to augment T
cell cytotoxicity against tumor cells without harmful effects
on normal tissues.
Although this study demonstrated a potential role of
TRAIL in mediating T cell cytotoxicity against tumor
cells, physiological and pathological roles of TRAIL-mediated T cell cytotoxicity remain largely unknown. It is well
known that type I IFNs can be inducible by infection of
various viruses, bacteria, and mycoplasmas (21, 22). In this
respect, TRAIL-mediated T cell cytotoxicity may play an
important role in clearance of virus- or intracellular organism-infected cells, which has been shown to be dependent on type I IFNs but not on perforin or FasL (14, 45). It is also interesting to note that TRAIL might be involved in
the pathogenesis of AIDS. Recently, Jeremias et al. reported that PBT cells from HIV-infected patients but not
those from healthy individuals were susceptible to TRAIL-induced apoptosis (34). Since elevated serum levels of IFN-
were found during HIV infection (46), it is possible that
type I IFN-induced, TRAIL-dependent T cell cytotoxicity
might be involved in clearance of HIV-infected cells or in
the pathogenesis of AIDS and HIV-associated diseases. This notion is further supported by a recent report showing a
contribution of TRAIL to anti-CD3-induced apoptosis of
PBT cells from HIV-infected patients (47). Further studies
are now underway to address these issues.
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Footnotes |
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Address correspondence to Hideo Yagita, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Phone: 81-3-3818-9284; Fax: 81-3-3813-0421; E-mail: hyagita{at}med.juntendo.ac.jp
Received for publication 2 February 1999.
We thank Drs. H. Tsutsui, H. Okamura, and K. Nakanishi for IL-18, and Dr. Y. Kinoshita for cells. We also thank Drs. S. Morimoto, H. Nakano, and T. Kobata for technical assistance.
This work was supported by grants from the Science and Technology Agency; the Ministry of Education, Science and Culture; the Ministry of Health, Japan; and the Kanae Foundation. N. Kayagaki is a Research Fellow of the Japan Society for the Promotion of Science.
Abbreviations used in this paper CMA, concanamycin A; CML, chronic myelogenous leukemia; PBT, peripheral blood T; poly IC, polyinosinic acid:polycytidylic acid; RCC, renal cell carcinoma; STAT, signal transducer and activator of transcription; TIL, tumor-infiltrating T lymphocyte; TRAIL, TNF-related apoptosis-inducing ligand.
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