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(SDF-1) induces CD4+ T cell apoptosis via the functional up-regulation of the Fas (CD95)/Fas ligand (CD95L) pathway
* Department of Morphology and Embriology, Human Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy
Institute of Normal Morphology, "G. d’Annunzio" University of Chieti, 66100 Chieti Scalo (CH), Italy
Correspondence: Silvano Capitani, M.D., Ph.D., Department of Morphology and Embriology, Human Anatomy Section, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy. E-mail: cps{at}dns.unife.it
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(SDF-1), the high-affinity ligand of
CXC-chemokine receptor 4 (CXCR4), induced a progressive increase of
apoptosis when added to the Jurkat CD4+/CXCR4+
T cell line. The SDF-1-mediated Jurkat cell apoptosis was observed
in serum-free or serum-containing cultures, peaked at SDF-1
concentrations of 10–100 ng/ml, required 3 days to take place, and was
completely blocked by the z-VAD-fmk tripeptide caspase inhibitor.
Although SDF-1 did not modify the expression of TNF- or that of
TNF-RI and TNF-RII, it increased the expression of surface Fas/APO-1
(CD95) and intracellular Fas ligand (CD95L) significantly. Moreover,
the ability of SDF-1 to induce apoptosis was inhibited by an
anti-CD95 Fab' neutralizing antibody. These findings suggest a role for
SDF-1 in the homeostatic control of CD4+ T-cell
survival/apoptosis mediated by the CD95-CD95L pathway.
Key Words: T lymphocytes • CXCR4 • TNF- • TNF-RI • TNF-RII
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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It has been shown that activated/memory T lymphocytes display a higher
density of the CC chemokine receptor CCR5 than do resting/naive T
lymphocytes. Conversely, naive T lymphocytes express higher levels of
CXCR4 than do memory T lymphocytes and, as a result, show greater
chemotaxis in response to stromal-derived factor-1 (SDF-1), the
high-affinity ligand for CXCR4 [6
, 7
].
Chemokine receptor density is altered in the presence of its
natural ligands [8
] by the addition of several cytokines
[9
] and appears to be regulated by gene expression and
continual recirculation of receptors between the cell surface and
endosomal compartments [10
11
12
13
].
Previous studies have shown that SDF-1 is produced by a variety of
tissues, including bone marrow, thymus, and spleen [14
]
and that its presence is essential for correct cerebral and bone-marrow
development [15
]. Moreover, SDF-1 can mediate a
proliferative [16
] or an apoptotic stimulus in
hematopoietic cells [17
18
19
]. In particular, ligation of
CXCR4 by SDF-1 or by HIV-1 envelope gp120 results in the induction of
apoptotic cell death of CD8+ T cells [18
].
Moreover, preliminary evidence of our group suggests that preactivated
CD4+ T cells are also susceptible to SDF-1-mediated
apoptosis [19
].
In the effort to elucidate how SDF-1 induces apoptosis in T lymphoid
cells, we have used, as a model system, the CD4+
lymphoblastoid Jurkat T cell line. For this purpose, Jurkat cells were
incubated with increasing concentrations of SDF-1 in both serum-free
and serum-containing culture conditions and the percentage of apoptosis
was quantitatively analyzed by flow cytometry after propidium iodide
(PI) staining. In parallel, the surface and intracellular expression of
members of the tumor necrosis factor (TNF)/TNF receptor (TNFR)
superfamily was investigated.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Exponentially growing Jurkat cells were seeded in fresh RPMI alone
(serum-free culture) or RPMI plus 10% FBS and treated with increasing
concentrations (0.1–1000 ng/ml) of recombinant human SDF-1
purchased from two different companies (PeproTech, London, UK, and
Pharmingen, San Diego, CA), which gave rise to similar results.
Anti-CD95 agonistic immunoglobulin M (IgM) monoclonal antibody (mAb;
clone CH11, Immunotech, Marseille Cedex, France), which triggers
apoptosis by interacting with surface CD95, was used at concentrations
of 1–100 ng/ml. Anti-CD95 Fab' IgG mAb (kindly provided by Dr. Peter
Kramer, Heidelberg, Germany), which specifically blocks the ability of
CD95L to interact with CD95, was used at a concentration of 1 µg/ml.
The caspase inhibitor Cbz-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk) and the peptide control Cbz-Phe-Ala-fluoromethyl ketone (z-FA-fmk), both from Enzyme Systems Products (Dublin, CA), were dissolved in dimethyl sulfoxide (DMSO), stocked in aliquots at -20°C until used.
Analysis of apoptosis
The presence of apoptosis was analyzed by flow cytometry after
PI staining of ethanol-fixed cells and morphological examination at
transmission electron microscopy (TEM).
PI staining and flow cytometry analysis were performed as previously described [20 ]. Briefly, after washing in RPMI, 3 x 105 cells were fixed in 1 ml, cold, 70% ethanol at 4°C for at least 1 h. The cells were then centrifuged, washed twice in phosphate-buffered saline (PBS), resuspended in 0.5 ml PBS, and treated with 0.1 µg RNAse (Type I-A, Sigma Chemical Co., St. Louis, MO) for 30 min at 37°C. PI (20 µg/ml; Sigma) was then added to each sample, and, after gentle mixing, samples were incubated in the dark at room temperature for 30 min. The PI fluorescence of individual nuclei was measured using a FACScan (Becton-Dickinson, San Jose, CA). The threshold was triggered on the same FL2 (PI fluorescence) signal, where a clear-cut distinction between cell debris and apoptotic cells was virtually always present. Quantitative evaluation of apoptosis was performed by the Lysis II analysis software (Becton-Dickinson), and data were expressed as percentage of apoptotic versus nonapoptotic cells, regardless of the specific cell-cycle phase.
For TEM, cells were fixed with 2.5% glutaraldehyde in 0.1 M sodium cacodylate buffer, pH 7.2, post-fixed with 1% osmium tetroxide, and embedded in araldite according to routine technique, as previously described [21 ]. Thin sections were mounted on nickel grids and examined by TEM after staining with uranyl acetate and lead citrate.
Flow cytometric analysis of surface and intracellular antigens
Surface CXCR4 expression in Jurkat cells was analyzed by a
single-step staining using the phycoerythrin (PE)-conjugated anti-CXCR4
mAb (Pharmingen). At various culture times, the surface expression of
TNF-, TNF-RI, TNF-RII, and CD95 (Fas/Apo-1) was evaluated by direct
staining with the PE-conjugated anti-TNF-, anti-CD95 (both from
Pharmingen), anti-TNF-RI, and anti-TNF-RII (R&D System, Oxon, UK) mAbs.
CD95L surface expression was analyzed by indirect staining using biotin
anti-CD95L (Pharmingen) followed by fluorescein isothiocyanate
(FITC)-conjugated streptavidin anti-mouse IgG (Immunotech). Briefly,
staining was performed on 3 x 105 cells in 200 µl
PBS contaning 1% FBS and 5 µl of each mAb and incubated on ice for
30 min. Cells were washed with PBS plus 1% FBS before performing
analysis by flow cytometry. Nonspecific fluorescence was assessed by
using isotype-matched controls.
To evaluate the expression of intracellular CD95L, Jurkat cells were fixed in PBS-2% paraformaldehyde for 20 min at room temperature, washed twice with PBS containing 1% FBS, and permeabilized in PBS-Triton X 1% for 5 min at 4°C. After two washings with PBS, the cells were resuspended in PBS plus 1% FBS and 5 µl biotin-conjugated anti-CD95L mAb and incubated on ice for 30 min. After two washings with PBS plus 1% FBS, streptavidin-FITC secondary Ab was added to cells and incubated for further 30 min on ice. The negative control consisted of an isotype-matched biotin mAb followed by identical second-layer labeling as before.
For surface and intracellular analyses, samples were assayed in duplicate, and viable cell gate was used to collect 10,000 events. Data collected from 10,000 events are presented as either percentage of positive cells or mean fluorescent intensity (MFI) values calculated by point-to-point subtraction of positive counts on the negative controls.
Statistics
Results are expressed as means ± SD of three
or more experiments performed in duplicate. Statistical analysis was
performed using the two-tailed Student’s t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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induces a progressive increase of apoptosis in
CD4+ lymphoblastoid Jurkat T cells (0.1–1000 ng/ml) on the
survival of CD4+ lymphoblastoid Jurkat T cells, which
co-express high surface levels of CXCR4 (Fig. 1A
). Apoptosis was analyzed by flow cytometry after PI staining of
fixed cells to quantify the DNA/chromatin changes occurring during
apoptosis [22
]. In serum-free cultures, the percentage
of apoptosis increased progressively in untreated cells. In the
presence of all the SDF-1 concentrations tested, no significant
variations in cell survival were observed up 72 h. Conversely, a
significant (p<0.05) increase of apoptosis was noticed in
cells treated with concentrations of SDF-1 ranging from 10 to 1000
ng/ml from 96 h onward (Fig. 1B) . This delayed kinetics of
SDF-1-mediated apoptosis was in sharp contrast with that observed in
cultures treated with anti-CD95-agonistic IgM (10 ng/ml), which induced
>40% apoptosis in Jurkat cells already after 24 h of treatment
(Fig. 1B)
.
|
to induce Jurkat cell apoptosis,
next experiments were performed by adding SDF-1 in cultures
supplemented with 10% FBS (Fig. 1C)
. Under these culture conditions,
the percentage of apoptosis in untreated cells was constantly below
10%, and SDF-1 induced a progressive and significant
(p<0.05) increase of apoptosis starting from 72 h of
treatment onward. Therefore, once established that FBS does not affect
the SDF-1-induced apopotosis, all subsequent experiments were
performed in serum-containing medium to eliminate the interference of
apoptosis induced by serum withdrawal.
One common problem that arises from flow cytometric analysis of
apoptosis is the distinction between late-stage apoptotic and necrotic
cells. Therefore, both cells treated with SDF-1 and cells left
untreated were also analyzed by TEM (Fig. 1D)
. When cultured with
SDF-1 (100 ng/ml) for 96 h, several Jurkat cells showed
features charateristic of apoptosis, such as chromatin margination in
tight apposition to the nuclear envelope, forming cup-shaped masses. In
agreement with previous findings [22
], SDF-1-treated
apoptotic Jurkat cells also displayed alterations of the nuclear
envelope, whereas the integrity of the plasma membrane and organelles
was preserved. On the contrary, the number of cells showing necrotic
features, characterized by a vacuolized cytoplasm and discontinuation
of the plasma membrane in the absence of chromatin condensation, was
much lower than that of apoptotic cells (unpublished results). These
findings clearly indicate that the SDF-1-induced cell death could
not be ascribed to an aspecific toxic effect.
SDF-1-mediated Jurkat cell apoptosis is blocked by the caspase
inhibitor z-VAD-fmk
In the next group of experiments, we sought to investigate whether
the Jurkat cell apoptosis observed in cultures supplemented with
SDF-1 was susceptible to the pharmacological activity of caspase
inhibitors [23
]. Cell preincubated and cultured with 20
µM of the broad-range caspase inhibitor z-VAD-fmk [24
]
completely inhibited the SDF-1-induced apoptosis of Jurkat cells
(Fig. 2
, top panel). Conversely, the control peptide z-FA-fmk (20 µM)
had no effect on SDF-1-induced apoptosis (Fig. 2
, top panel). As
expected, the z-VAD-fmk peptide inhibitor efficiently suppressed
apoptosis induced by 10 ng/ml of anti-CD95 IgM agonist mAb (Fig. 2
,
bottom panel), which is known to activate the caspase cascade rapidly
[25
].
|
treatment does not affect the surface expression of
TNF- and TNFRs in Jurkat cells required a relatively
long time period to take place (>3 days compared with the 12–24 h
required for anti-CD95-agonistic IgM-mediated apoptosis) and that it
was abrogated by the caspase inhibitor z-VAD-fmk, suggested that other
molecules were likely involved in the SDF-1-mediated
CD4+ T cell apoptosis. Therefore, in the effort to clarify
the mechanisms by which SDF-1 induces apoptosis, we next
investigated the surface expression of molecules that are known to play
a key role in the control of lymphoid cell survival/growth, such as
TNF-, TNF-RI, and TNF-RII in Jurkat cells, treated or not with
SDF-1 for up to 96 h (Fig. 3
).
|
, which is synthesized as a type II transmembrane protein, binds
to two membrane receptors of 55–60 kDa (TNF-RI) and 75–80 kDa
(TNF-RII) [26
]. TNF-RI is expressed constitutively in
nearly all tissues and represents the main mediator of cellular TNF
responses, including TNF-mediated cytotoxicity. TNF-RII is more
restricted in expression (e.g., to lymphoid tissue), is tightly
regulated in its expression, modulates T cell activation, and can also
signal cell death [27
28
29
30
].
As shown in Figure 3
, Jurkat cells dimly expressed TNF-RI, which was
functional, as Jurkat cells underwent apoptosis as soon as 12 h of
treatment with 10 ng/ml TNF- (unpublished results). The expression
of TNF-RI was not modulated significantly by SDF-1 treatment. On the
contrary, TNF-RII was not expressed by Jurkat cells, and its expression
was unaffected by SDF-1. Only 20% of untreated cells expressed
TNF- dimly, and the addition of SDF-1 did not change its
expression significantly.
SDF-1 up-regulates the expression of surface CD95 and of
intracellular CD95L in Jurkat cells
We next investigated whether SDF-1 was capable of modulating
the expression of CD95 and/or CD95L, two additional members of the
TNF/TNFR superfamily [31
], which play a pivotal role in
the control of lymphoid T cell survival/apoptosis. In fact, it has been
shown that cross-linking CD95 with anti-CD95 agonistic IgM mAb or
binding CD95 with CD95L triggers apoptosis [32
33
34
].
Moreover, the activation of T cells causes co-expression of CD95 and
CD95L on the cell surface, and the interaction of these two
death-inducing proteins triggers autocrine apoptosis
[35
36
].
As expected, on the basis of the high susceptibility of Jurkat cells to
anti-CD95-agonistic IgM (Fig. 1B
and 1C)
, Jurkat cells showed a bright
expression of CD95 (Fig. 4A
). Of note, the addition of 100 ng/ml SDF-1 induced a
significant (p<0.05) increase of CD95 expression, as
indicated by analysis of the MFI (Fig. 4A)
from 48 h of treatment
onward (Fig. 4B)
. Conversely, CD95L was not expressed on the surface of
Jurkat cells, and it was not induced by SDF-1 (unpublished results).
Because CD95L can be shed from the cell surface rapidly and released in
the culture medium [37
], we have also investigated the
expression of intracellular CD95L in cells treated or not with
SDF-1. As shown in Figure 5
, SDF-1 induced a progressive increase of intracellular CD95L,
which peaked (p<0.05) at 72 h of culture, declining
thereafter.
|
|
-induced
apoptosis of Jurkat cells, we investigated the
effect of the Ab-mediated blockade of CD95/CD95L interaction on
SDF-1-induced apoptosis. In these experiments, cells were pretreated
or not with 1 µg/ml of anti-CD95 neutralizing, Fab' IgG, which
selectively blocks CD95/CD95L interaction [38
] before
adding 100 ng/ml SDF-1. Anti-CD95- of blocking IgG was
re-added in culture every 24 h. In the presence of
anti-CD95-blocking IgG, the levels of SDF-1-mediated apoptosis were
significantly (p<0.05) reduced at all time-points examined,
strongly indicating that the CD95/CD95L pathway was involved in the
SDF-1-induced apoptosis of Jurkat cells. The specificity of the
anti-CD95 blocking IgG was demonstrated by the inability of control IgG
to affect SDF-1–induced apoptosis (Fig. 6A
). As expected, anti-CD95-blocking IgG abrogated anti-CD95 IgM,
agonistic-induced apoptosis completely (Fig. 6B) .
|
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and
SDF-1ß, have been identified, which are encoded by a single gene and
arise by alternative splicing [39
]. SDF-1 is
expressed widely and became a potent chemotactic factor for pro-B
cells, monocytes, T-lymphocytes, and CD34+ human progenitor
cells [6
]. Because CXCR4 plays a prominent role as a
co-receptor for the highly cytopathic, T cell line-adapted isolates of
HIV-1 [5
], a number of studies have investigated its
surface expression and modulation and shown that CXCR4 can be rapidly
up- or down-regulated depending on the conditions used to stimulate
resting T cells [40
41
42
43
].
In this study, we have demonstrated that SDF-1 induces a slow and
progressive increase of apoptosis in the CD4+
lymphoblastoid Jurkat T cell line. The ability of SDF-1 to trigger
apoptosis showed remarkable features: it started to be evident after
72–96 h from the beginning of SDF-1 treatment, it was unaffected by
the presence of serum, and it took place in the presence of
concentrations of SDF-1 as low as 10 ng/ml. The prolonged lag period
required to observe apoptosis clearly indicates that the molecular
mechanism through which SDF-1 induced apoptosis was distinct from
the rapid induction of apoptosis observed in the presence of anti-CD95
agonistic IgM, which causes a massive increase of apoptosis in its
target cells within 6–24 h. It is also particularly remarkable that
the caspase-peptide inhibitor z-VAD-fmk abrogated apoptosis induced by
anti-CD95-agonistic IgM and SDF-1 completely. Thus, although delayed
in time, it is clear that the final events mediating SDF-1-induced
apoptosis also required caspase activation.
The relatively long time period required to observe SDF-1-mediated
apoptosis reflected the need of the modulation of the expression of
genes involved in the control of cell death. In this respect, a
previous study has shown that SDF-1 up-regulates the surface
expression of TNF- in CD16+ monocytes/macrophages and of
the TNF-R in CD8+ T cells [18
]. Subsequent
contact between the SDF-1-exposed monocyte/macrophage and
CD8+ T cells triggers T cell death. These authors also
showed that SDF-1-induced, monocyte-mediated apoptosis was confined
to CD8+ T cells and did not involve CD4+ T
cells. Conversely, we have demonstrated that neither surface TNF-
nor TNF-RI and TNF-RII were involved in SDF-1-mediated apoptosis of
CD4+ T cells. Several additional differences can be
envisioned between our data and the study of Herbein et al.
[18
]. First, these authors showed the absolute
requirement of monocyte to observe apoptosis in CD8+ T
cells. Moreover, CD8+ T cell apoptosis was observed in the
presence of very high (1 µg/ml) concentrations of SDF-1 and took
place within 24 h of culture. On the contrary, we have shown that
relatively low (10 ng/ml) concentrations of SDF-1 induced
CD4+ T cell apoptosis in the absence of monocytes and only
after a prolonged (72–96 h) exposure in culture.
We could also demonstrate that SDF-1 induced Jurkat cell death
through the functional up-regulation of the CD95/CD95L system. In fact,
SDF-1-treated cultures showed a progressive increase of the surface
expression of CD95 antigen as well as of intracellular CD95L. Moreover,
the blockade of CD95/CD95L interactions by anti-CD95-blocking, Fab' IgG
reduced SDF-1-mediated apoptosis significantly. Although we have not
addressed the intracellular signal transduction pathway involved in the
SDF-1-mediated up-regulation of CD95 and CD95L, it has been shown
previously that SDF-1 recruits phosphatidyl-inositol 3 kinase
[44
, 45
], which, in turns, activates
nuclear factor-
B (NF-B) transcription factor
[46
47
48
]. A prolonged activation of NF-B is required
for CD95L transcription [49
].
Because of the pivotal role of CD95 and CD95L in the homeostatic
regulation of normal immune responses [36
,
50
], our present findings, together with previous data
obtained in primary, activated CD4+ T cells
[19
], indicate that, besides its primary role in
regulating the homing and trafficking of leucocytes [51
,
52
], SDF-1 is also involved in the physiological
regulation of CD4+ T cell survival/death.
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ACKNOWLEDGEMENTS |
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Received August 3, 2000; accepted September 25, 2000.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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induced apoptosis in activated primary CD4+ T cells AIDS 14,748-750[Medline]
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