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Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-converting
enzyme inhibitory protein (FLIP), an inhibitor of Fas-mediated
apoptosis, at 24–48 h after Ag restimulation than naive T cells. In
addition, Bcl-2 expression was equally observed between activated naive
and primed T cells after Ag restimulation. Thus, these results indicate
that naive T cells are sensitive to Fas-mediated AICD and are easily
deleted by Ag restimulation, while primed/memory T cells express higher
levels of FLIP after Ag restimulation, are resistant to Fas-mediated
AICD, and thus function as efficient effector cells for a longer
period. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Upon TCR stimulation with Ag, resting T cells are activated to proliferate and produce cytokines. When activated T cells are restimulated with Ag through TCR, those T cells undergo apoptosis termed activation-induced cell death (AICD)4 (9, 10). The susceptibility to AICD develops during the activation of T cells; resting T cells that are resistant to TCR-mediated apoptosis become sensitive to the death by TCR ligation (11, 12, 13, 14). AICD is thus thought to be an important mechanism to control clone size and to terminate immune responses (9, 10). AICD also plays important roles in the establishment of peripheral tolerance. AICD has recently been shown to be mediated predominantly by Fas/Fas ligand (FasL) interaction (15, 16, 17, 18), in which activated T cells express FasL, which interacts with Fas on their surface, resulting in activating caspases and inducing apoptosis of these cells (19). However, it is still unknown whether the susceptibility of memory T cells to AICD differs from that of naive T cells.
To elucidate this issue, we studied apoptosis of activated naive and primed T cells from OVA-specific TCR transgenic DO10 mice and Fas-deficient DO10 lpr/lpr mice after in vitro Ag restimulation. We further investigated the sensitivity to apoptosis induced by Fas-mediated signals and the expression levels of FLICE inhibitory protein (FLIP) (20, 21), an inhibitor of Fas-mediated apoptosis, and of Bcl-2 (22, 23). Our results indicate that naive T cells are sensitive to Fas-mediated AICD and are easily deleted by Ag restimulation, while primed/memory T cells express higher levels of FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus function as efficient effector cells for a longer period.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DO10 TCR transgenic mice (BALB/c background;
H-2d), which express a transgenic TCR
specific for OVA peptide 323–339 (OVA
peptide)/I-Ad complex (24), were
provided by Dr. D. Loh (Washington University, Seattle, WA) and were
maintained in our university animal facility. Fas-deficient mice
bearing the transgenic DO10 TCR and H-2d (DO10
lpr/lpr mice) were generated by crossing DO10 TCR transgenic
mice with MRL-lpr/lpr mice for more than six generations.
All mice were housed under specific pathogen-free conditions and used
at the age of 6–8 wk.
Generation of memory T cells
Mice were immunized i.p. twice with 10 µg of OVA (Sigma, St. Louis, MO) in 4 mg of aluminum hydroxide at a 2-wk interval. Two weeks after the second immunization, splenic CD4+ T cells were prepared from the mice and used as primed T cells for experiments. Splenic CD4+ T cells from unimmunized mice were used as naive T cells for experiments.
Flow cytometry
Splenocytes (1 x 106) before and
after culture were stained with fluorescence- or biotin-conjugated Abs
in PBS containing 1% FCS for 30 min at 4°C. The following FITC-,
PE-, or biotin-conjugated Abs were used: CD4 (YTS191.1), CD8
(YTS169.4), CD25 (PC61 5.3; Caltag, South San Francisco, CA), CD69
(H1.2F3), CD44 (IM7), CD62L (MEL-14), and Fas (Jo2; PharMingen, San
Diego, CA). DO10 transgenic TCR clonotype mAb KJ1-26 (24)
(a gift from Dr. D. Loh) was purified from the hybridoma supernatant by
a protein G affinity column. Cells stained with biotinylated mAb were
then incubated with streptavidin-PE or -Tricolor (Caltag). Stained
cells were resuspended in PBS containing 1% FCS and analyzed by
FACScan (Becton Dickinson, Mountain View, CA) using LYSIS II
software.
Induction of AICD by in vitro Ag restimulation
Splenic CD4+ T cells were prepared as described previously (25). Briefly, splenocytes were passed over nylon columns and then incubated with anti-CD8 mAb (53.6.7; PharMingen) followed by addition of magnetic beads (Advanced Magnetics, Cambridge, MA) coupled with goat anti-mouse IgG Ab (Cappel, West Chester, PA).
Splenic CD4+ T cells (2 x 106/ml) from primed or unprimed mice were stimulated with OVA peptide (0.3 µM) and APC (30 gray-irradiated normal BALB/c splenocytes; H-2d; 5 x 105/ml) in RPMI 1640 medium containing 10% FCS at 37°C for 48 h. Cells were then harvested, and viable cells were isolated with Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden). Separated live cells were resuspended at 2 x 106/ml and restimulated with 0.03, 0.3, or 3.0 µM OVA peptide plus APC (5 x 105/ml). At 24–96 h after restimulation with Ag, cells were harvested, and viable and apoptotic K J1-26+ CD4+ T cells were counted by flow cytometry.
Detection of apoptosis
Apoptotic cells among K J1-26+ CD4+ T cells were detected by the TUNEL method. Cells were stained with KJ1-26 mAb and fixed with PBS containing 4% paraformaldehyde for 30 min at 4°C. The cells were then washed with PBS, permeabilized with 0.1% sodium citrate containing 0.1% Triton X-100 for 2 min at 4°C, and washed twice with PBS. DNA strand breaks by apoptosis in the cells were labeled by the fluorescein-labeled TUNEL reaction mix for 60 min at 37°C using an in situ cell death detection kit (Boehringer Mannheim, Mannheim, Germany) according to the manufacturer’s recommendations. As a negative control, cells were incubated without TdT. Cells were then washed with PBS and analyzed by flow cytometry.
Detection of FasL and FLIP mRNA by RT-PCR
FasL and FLIP mRNA expression was detected by PCR amplification of cDNA from splenocytes using specific primers. Briefly, total RNA was prepared from splenocytes by the method of acid guanidinium thiocyanate/phenol/chloroform extraction using Isogen solution (Nippon Gene, Tokyo, Japan). The first-strand cDNA was then synthesized from 0.1–1 µg of total RNA in 20 µl of reaction buffer containing oligo(dT) primer using avian myeloblastosis virus reverse transcriptase (1st Strand cDNA Synthesis Kit, Boehringer Mannheim). The reaction mixture was incubated at 25°C for 10 min and then at 42°C for 60 min.
PCR amplification of the cDNA was performed with Taq DNA polymerase (Boehringer Mannheim) in the presence of specific primers for FasL (5'-TATTCCTGGTGCCCATGAT-3' and 5'-TCTGGTGGCTCTGGAA-3'), FLIP (5'-CTGATGGAGATTGGTGAGAGC-3' and 5'-GAGCGAAGCCTGGAGAGTATT-3'), or HPRT (5'-GTTGGATACAGGCCAGACTTTGTTG-3' and 5'-GATTCAACTTGCGCTCATCTTAGGC-3'). The denaturing step was performed at 95°C for 1.5 min, the annealing step at 60°C for 1 min, and the extension step at 72°C for 1 min for 30 cycles on a DNA thermal cycler (Perkin-Elmer, Norwalk, CT). The PCR-amplified sample was run on 1.5% agarose gel and visualized using ethidium bromide. FasL and FLIP mRNA expression was measured by a densitometry and expressed as the amount relative to that of HPRT.
Induction of apoptosis by anti-Fas mAb
Splenic CD4+ T cells from primed and unprimed mice were stimulated with OVA peptide (0.3 µM) for 48 h and restimulated with OVA peptide (0.3 µM) for 24 h as described above. Cells were harvested, and viable cells were isolated with Ficoll-Paque. Separated live cells were then stimulated with anti-Fas mAb (Jo2; 0.003–1 µg/ml; PharMingen) in RPMI 1640 medium containing 10% FCS and murine IL-2 (20 U/ml; PharMingen). After 24 h of culture, cells were fixed with cold 80% ethanol, washed, resuspended in a permeability buffer (0.1 mM EDTA and 0.1% Triton X-100 in PBS) containing RNase (25 µg/ml). Then, cells were stained with 50 µg/ml propidium iodide at 4°C in the dark overnight, and the propidium iodide fluorescence of individual nuclei was analyzed by FACScan. Cells with hypodiploid DNA were counted as apoptotic cells.
Intracellular staining of Bcl-2
Splenocytes (1 x 106) were permeabilized in PBS containing 1% BSA and 0.04% saponin (saponin buffer) and incubated with anti-bcl-2 mAb (clone 3F11; 2 µg/ml; PharMingen) or purified hamster IgG as a negative control at 4°C for 30 min. Cells were washed twice with saponin buffer, incubated with anti-hamster IgG-FITC (PharMingen) at 4°C for 30 min, washed once with saponin buffer and once with PBS containing 1% BSA, stained with anti-CD4-PE, and analyzed on a FACScan.
Data analysis
Data are summarized as the mean ± SD. The statistical analysis of the results was performed by unpaired t test. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DO10 TCR transgenic mice (24) were immunized i.p.
twice with 10 µg of OVA in aluminum hydroxide at a 2-wk interval. Two
weeks after the second immunization, splenocytes were prepared from the
mice and used as primed T cells for experiments. To confirm that the
immunization with OVA generated memory T cells in the mice, splenic T
cells from primed and unprimed mice were stained with anti-CD44 and
anti-MEL-14 mAbs and analyzed by flow cytometry. CD44 was expressed
at higher levels on primed T cells than on naive T cells (Fig. 1
), while MEL-14 expression levels on
primed T cells were lower than that on naive T cells (Fig. 1). Further,
no significant differences were found in the cell size, the cell cycle,
or the levels of expression of CD25 and CD69 between naive and primed T
cells (data not shown). Therefore, splenic T cells from primed mice
showed the phenotype of resting memory T cells (5).
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To investigate the difference in the susceptibility to AICD in
naive and primed T cells, we examined the apoptosis of OVA-specific T
cells induced by in vitro Ag restimulation between activated naive and
primed T cells. Splenic CD4+ T cells from primed
and unprimed DO10 mice were stimulated with OVA peptide (0.3 µM) plus
APC (irradiated normal BALB/c splenocytes) at 37°C for 48 h and
restimulated with OVA peptide (0.3 and 3 µM) plus APC for 24–72 h.
At the time of Ag restimulation, OVA-specific T cells (K
J1-26+ CD4+ T cells) had
been activated by Ag, because those cells were large, expressed CD25,
and produced IL-2 (data not shown). At 24–72 h after restimulation
with Ag, apoptotic cells among K J1-26+
CD4+ T cells were detected by the TUNEL method
and analyzed by flow cytometry (Fig. 2).
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and 3). On the other hand, apoptosis was not
significantly increased in activated primed T cells at 24–72 h after
Ag restimulation (6.9 ± 1.4% at 3 µM at 72 h; Figs. 2 and 3). Because AICD has been shown to be mediated largely by the Fas/FasL
interaction (15, 16, 17, 18), we determined whether the Fas/FasL
system is involved in AICD of activated naive T cells induced by Ag
restimulation. In contrast to naive and primed T cells from DO10 mice,
apoptosis was not significantly induced in either activated naive or
primed T cells from Fas-deficient DO10 lpr/lpr mice at
72 h after Ag restimulation (n = 5 mice in each
group; Fig. 4). These results indicate
that primed T cells are more resistant to Fas-mediated AICD than naive
T cells.
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To investigate the mechanism(s) for the resistance to Fas-mediated
AICD in primed T cells, we first examined the expression of Fas and
FasL on activated naive and primed T cells after Ag restimulation. As
shown in Fig. 5, when the T cells were
activated by OVA peptide (0.3 µM) for 48 h and restimulated by
OVA peptide (3 µM) for 48 h, the levels of Fas expression were
not significantly different in activated naive and primed T cells
before or after Ag restimulation.
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). When the T cells
were activated by OVA peptide (0.3 µM) for 48 h and restimulated
by OVA peptide (3 µM) for 24–96 h, both activated naive and primed T
cells similarly expressed FasL mRNA at high levels for the first 24–48
h (Fig. 6). Because two forms of FasL have been reported (26, 27), soluble and membrane-bound FasL, we performed flow
cytometry analysis to detect membrane-bound FasL, an apoptosis-inducing
form, on activated T cells at 24 and 48 h after Ag restimulation.
We found that the levels of FasL expression were similar in activated
naive and primed T cells after Ag restimulation (data not shown). These
results indicate that Fas and FasL were expressed similarly on both
activated naive and primed T cells after Ag restimulation and that the
difference in the susceptibility to Fas-mediated AICD between naive and
primed T cells was not due to Fas or FasL expression levels on those T
cells.
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Because TCR-mediated signaling equally activated both naive and primed T cells to induce Fas and FasL expressions, we next examined the susceptibility to Fas-induced apoptosis between activated naive and primed T cells using anti-Fas Ab. Apoptosis of activated naive and primed T cells was induced by the stimulation with anti-Fas mAb (Jo2; 0.003–1 µg/ml) for 24 h.
As shown in Fig. 7, activated primed T
cells were 
10-fold more resistant to anti-Fas mAb-induced
apoptosis than activated naive T cells. Apoptosis of activated naive T
cells was induced by anti-Fas mAb at a minimal dose of 0.003
µg/ml and was increased by higher doses of anti-Fas mAb in a
concentration-dependent manner (Fig. 7). In contrast, apoptosis of
activated primed T cells was induced by 0.01 µg/ml of anti-Fas
mAb and was increased by higher concentrations of anti-Fas mAb
(0.03–1 µg/ml; Fig. 7), but the apoptosis of activated primed T
cells induced by anti-Fas mAb was significantly lower than that of
activated naive T cells at any concentrations examined (0.003–1
µg/ml; n = 6 mice at each concentration;
p < 0.005–0.01).
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To determine whether the activation of antiapoptotic molecules is
different between activated naive and primed T cells, we examined the
expression of the antiapoptotic molecule Bcl-2 (22, 23)
assayed by intracellular staining and FLIP (20, 21)
detected by RT-PCR using specific primers. Bcl-2 was equally expressed
in activated naive and primed T cells and was further increased at
48 h after the restimulation with OVA peptide (3 µM) in both
naive and primed T cells, but the levels of Bcl-2 expression were not
significantly different in activated naive and primed T cells before or
after Ag restimulation (Fig. 8).
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). FLIP mRNA was not significantly
expressed in either resting naive or primed T cells (Fig. 9). When the
T cells were activated by OVA peptide (0.3 µM) for 48 h (at
0 h after Ag restimulation), FLIP mRNA was expressed at highest
levels equally in the activated naive and primed T cells (Fig. 9).
However, after Ag restimulation, FLIP expression was rapidly decreased
in activated naive T cells, while FLIP expression remained at
significantly higher levels in activated primed T cells at 24–48 h
after Ag restimulation (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
We further showed that the resistance to AICD in primed T cells was due
to the decreased sensitivity to apoptosis induced by Fas-mediated
signals (Fig. 7), but TCR-mediated signaling equally activated both
naive and primed T cells to induce Fas and FasL expressions (Fig. 5 and 6). Furthermore, we demonstrated that primed T cells expressed higher
levels of FLIP, an inhibitor of Fas-mediated apoptosis (20, 21), at 24–48 h after Ag restimulation than naive T cells (Fig. 9). Thus, these results indicate that naive T cells are sensitive to
Fas-mediated AICD and are easily deleted by Ag restimulation, while
primed/memory T cells express higher levels of FLIP after Ag
restimulation, are resistant to Fas-mediated AICD, and thus function as
efficient effector cells for a longer period. To our knowledge, no
studies have clearly revealed the difference in the susceptibility to
AICD between naive and memory T cells.
There have been several mechanisms reported by which activated T cells
undergo apoptosis (28). When activated T cells are
restimulated with Ag through TCR, those T cells undergo apoptosis
predominantly by Fas/FasL interaction, in which activated T cells
express FasL, which interacts with Fas on their surface resulting in
apoptosis of these cells (15, 16, 17, 18). TNF- produced by
activated T cells also induces apoptosis of the activated T cells
through the activation of caspase cascades in a way similar to that of
Fas/FasL interaction (29). Furthermore, withdrawal of
growth factors such as IL-2 also causes the death of activated T cells
(30). The apoptosis of activated T cells induced by in
vitro Ag restimulation in our system was mediated by the Fas/FasL
system, but not by other mechanisms, because apoptosis of activated
naive or primed T cells was not induced by Ag restimulation in
Fas-deficient DO10 lpr/lpr mice (Fig. 4), but was readily
induced in DO10+/+ mice. In addition, we found
that the addition of exogenous IL-2 into the culture had no effect on
apoptosis produced by Ag restimulation (unpublished observations).
The sensitivity of cells to Fas-mediated apoptosis is controlled by multiple intracellular antiapoptotic molecules that counteract apoptotic signals (21). FLIP, a homologue of caspase-8 (FLICE) that has death effector domain (DED), but not proteolytic, activity, binds to Fas-associated death domain (FADD) and caspase-8/-10 via DED-DED interaction and blocks FADD/caspase-8 interaction and the resultant apoptosis (20, 21). Therefore, our observations that primed T cells show the sustained expression of FLIP after Ag restimulation in correlation with the decreased sensitivity to Fas-mediated apoptosis strongly suggest that the higher levels of FLIP expression render activated primed T cells resistant to Fas-mediated AICD.
The levels of FLIP expression are also kinetically linked with
Fas-mediated AICD in naive T cells. FasL expression was strongly
induced in activated naive T cells at 24–48 h after Ag restimulation
(Fig. 6). FLIP expression was transiently induced at 0 h and
drastically decreased after 24 h of Ag restimulation in activated
naive T cells (Fig. 9). Subsequently, Fas-mediated AICD was induced in
activated naive T cells at 48–72 h after Ag restimulation (Fig. 3).
Our findings are consistent with a previous report by Irmler et al.
(20) showing that FLIP is expressed during the early stage
of T cell activation (on day 1 after stimulation) in Con A-activated
naive T cells, but disappears when T cells become susceptible to
FasL-mediated apoptosis (on day 3).
Bcl-2 has been shown to prevent cells from apoptosis by radiation,
withdrawal of growth factors (30), and Fas
(31). However, Bcl-2 expression was equally observed
between activated naive and primed T cells after Ag restimulation (Fig. 8), indicating that Bcl-2 expression is not responsible for the
difference in susceptibility to AICD between activated naive and memory
T cells. This finding is consistent with a previous report that
overexpression of Bcl-2 did not protect T cells from Fas-mediated
apoptosis but resisted the x-ray irradiation-induced apoptosis
(32).
In addition to FLIP and Bcl-2, other antiapoptotic molecules have been reported. Bcl-x, a member of the Bcl-2 family (33), has been shown to be up-regulated in activated T cells (34). The inhibitor of the apoptosis protein (IAP) family, cellular IAP-1 and IAP-2 (35), X-linked IAP (36) and survivin (37), has also recently been identified to inhibit caspase-3, an essential molecule for Fas-mediated apoptosis (38). Survivin has also been shown to be induced in activated T cells (39). Therefore, further studies are needed to examine whether Bcl-x and IAPs might be involved in the resistance of primed T cells to Fas-mediated AICD.
AICD has been considered to play two roles in vivo: clonal downsizing after Ag elimination and clonal deletion of autoreactive T cells in the periphery (9, 10, 40). Overexpanded T cells are removed by AICD to terminate immune responses effectively. AICD is also an important mechanism of self tolerance. Our findings of the resistance of memory T cells to Fas-mediated AICD imply that memory T cells could escape AICD in the presence of antigenic stimuli such as micro-organisms and could proliferate and differentiate to effector cells and thus efficiently eliminate those micro-organisms. Conversely, in autoimmune diseases, autoreactive memory T cells could be hardly deleted by AICD, and the persistence of activated autoreactive T cells could cause the progression of the disease. Thus, modulation of antiapoptotic molecules such as FLIP, which can render memory T cells susceptible to Fas-mediated AICD, would be a new strategy for treatment of autoimmune diseases.
In conclusion, we have shown that naive T cells are sensitive to Fas-mediated AICD and are easily deleted by Ag restimulation, while primed/memory T cells express higher levels of FLIP after Ag restimulation, are resistant to Fas-mediated AICD, and thus function as efficient effector cells for a longer period. It is suggested that this characteristic of Ag-activated memory T cells would be beneficial to protect the infections of micro-organisms, whereas the same character of autoreactive T cells would be harmful to cause autoimmune diseases.
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Acknowledgments |
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Footnotes |
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2 M.I. and K.K. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Kazuhiro Kurasawa, Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan. E-mail address:
4 Abbreviations used in this paper: AICD, activation-induced cell death; FasL, Fas ligand; FLICE, Fas-associated death domain-like IL-1-converting enzyme; FLIP, FLICE inhibitory protein; IAP, inhibitor of apoptosis protein; OVA peptide, OVA peptide 323–339; HPRT, hypoxanthine phosphoribosyltransferase.
Received for publication February 5, 1999. Accepted for publication May 24, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 P. Gorak-Stolinska, J.-P. Truman, D. M. Kemeny, and A. Noble Activation-induced cell death of human T-cell subsets is mediated by Fas and granzyme B but is independent of TNF-{alpha} J. Leukoc. Biol., November 1, 2001; 70(5): 756 - 766. [Abstract] [Full Text] [PDF]
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M. Srinivasan, R. M. Wardrop, I. E. Gienapp, S. S. Stuckman, C. C. Whitacre, and P. T. P. Kaumaya A Retro-Inverso Peptide Mimic of CD28 Encompassing the MYPPPY Motif Adopts a Polyproline Type II Helix and Inhibits Encephalitogenic T Cells In Vitro J. Immunol., July 1, 2001; 167(1): 578 - 585. [Abstract] [Full Text] [PDF]
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V. Poulaki, N. Mitsiades, M. E. Romero, and M. Tsokos Fas-mediated Apoptosis in Neuroblastoma Requires Mitochondrial Activation and Is Inhibited by FLICE Inhibitor Protein and bcl-2 Cancer Res., June 1, 2001; 61(12): 4864 - 4872. [Abstract] [Full Text] [PDF]
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J. Zhang, T. Bardos, K. Mikecz, A. Finnegan, and T. T. Glant Impaired Fas Signaling Pathway Is Involved in Defective T Cell Apoptosis in Autoimmune Murine Arthritis J. Immunol., April 15, 2001; 166(8): 4981 - 4986. [Abstract] [Full Text] [PDF]
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H. Yoshikawa, Y. Nakajima, and K. Tasaka Enhanced Expression of Fas-Associated Death Domain-Like IL-1-Converting Enzyme (FLICE)-Inhibitory Protein Induces Resistance to Fas-Mediated Apoptosis in Activated Mast Cells J. Immunol., December 1, 2000; 165(11): 6262 - 6269. [Abstract] [Full Text] [PDF]
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S. Kirchhoff, W. W. Muller, A. Krueger, I. Schmitz, and P. H. Krammer TCR-Mediated Up-Regulation of c-FLIPshort Correlates with Resistance Toward CD95-Mediated Apoptosis by Blocking Death-Inducing Signaling Complex Activity J. Immunol., December 1, 2000; 165(11): 6293 - 6300. [Abstract] [Full Text] [PDF]
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I. Suzuki and P. J. Fink The dual functions of Fas ligand in the regulation of peripheral CD8+ and CD4+ T cells PNAS, February 15, 2000; 97(4): 1707 - 1712. [Abstract] [Full Text] [PDF]
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Y.-W. He and M. J. Bevan High Level Expression of Cd43 Inhibits T Cell Receptor/CD3-Mediated Apoptosis J. Exp. Med., December 20, 1999; 190(12): 1903 - 1908. [Abstract] [Full Text] [PDF]
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