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*
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Université René Descartes, Paris V, Hôpital Necker, Paris, France;
Institut National de la Santé et de la Recherche Médicale, Unité 25, and Association Claude Bernard, Hôpital Necker, Paris, France; and
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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production, NKT lymphocytes
stimulated with IL-12 plus IL-18 in vitro underwent activation in terms
of CD69 expression, blast transformation, and proliferation. Yet they
were unable to survive in culture because, once activated, they were
rapidly eliminated by apoptosis, even in the presence of their survival
factor IL-7. This process was preceded by up-regulation of Fas (CD95)
and Fas ligand expression in response to IL-12 plus IL-18 and was
blocked by zVAD, a large spectrum caspase inhibitor, as well as by
anti-Fas ligand mAb, suggesting the involvement of the Fas pathway.
In accordance with this idea, NKT cells from Fas-deficient
C57BL/6-lpr/lpr mice did not die in these conditions,
although they shared the same features of cell activation as their
wild-type counterpart. Activation-induced cell death occurred also
after TCR engagement in vivo, since NKT cells became apoptotic after
injection of their cognate ligand, 
-galactosylceramide, in
wild-type, but not in Fas-deficient, mice. Taken together, our data
provide the first evidence for a new Fas-dependent mechanism allowing
the elimination of TCR-dependent or -independent activated NKT cells,
which are potentially dangerous to the organism. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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14-J281 gene segments preferentially associated with a highly
skewed Vß repertory, represented mainly by Vß8.2 (1, 2). They express memory/activation cell markers, such as CD44
and CD69, and are positively selected by the nonpolymorphic MHC class
I-like molecule CD1d (1, 2, 3, 4). It has also been established
that they specifically recognize -galactosylceramide
(-GalCer)3 or parasite glycosylphosphatidyl inositols
presented by CD1d molecules (3, 4, 5).
An interesting feature of NKT cells consists of their ability to
express both Th1 and Th2 cytokine profiles according to their mode of
activation and the cytokines present in their microenvironment
(6, 7, 8, 9, 10). Indeed, upon TCR cross-linking, they constitute
mainly a source of IL-4 (6, 7), whereas a TCR-independent
stimulation with IL-12 plus IL-18 promotes IFN- production and
cytotoxicity (10), thus enabling them to participate in
either type of immune response. Activated NKT cells kill their targets
by perforin- or Fas-dependent mechanisms and have been reported to
prevent tumor metastasis (10, 11, 12). Our own studies and
those of others have provided evidence for a tight association between
the development of autoimmune diseases, such as lupus erythematosus or
diabetes, and the loss or dysfunction of NKT cells (13, 14). Activated NKT cells may also become dangerous to the
organism, as suggested by their implication in liver injury after
Salmonella infection and in Con A-induced hepatitis
(15, 16). It is therefore conceivable that their life span
is strictly controlled, leading to their elimination as soon as they
have fulfilled their regulatory functions. In the present study we
investigated the fate of NKT cells after their stimulation with IL-12
plus IL-18 or their specific ligand -GalCer. We found that both
TCR-dependent and -independent stimuli promoted activation and cell
death, whose mechanisms we further analyzed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Wild-type, Fas-deficient C57BL/6-lpr/lpr and
Fas ligand (FasL)-deficient C57BL/6-gld/gld mice were bred
in our own facilities and used at the age of 6–8 wk, before the onset
of lymphadenopathy in the mutant strain (17). In some
experiments 7-mo-old mice were used. RPMI 1640 (Life Technologies,
Grand Island, NY) supplemented with 10% heat-inactivated FCS (TechGen,
Les Ulis, France), 100 IU/ml penicillin, 100 µg/ml streptomycin, 10
mM HEPES buffer (all from Life Technologies), and 5 x
10-5 M 2-ME was used as the culture medium.
Murine IL-2, IL-4, IL-12, IL-18, and IFN- were purchased from R&D
Systems (Abingdon, U.K.). Human rIL-7 (sp. act., 8.8 x
106 U/mg) was provided by Sanofi (Labege,
France). Anti-IL-4 mAbs (11B11 and BVD6-24G2.3), anti-IFN- mAbs
(AN18 and R46A2), and anti-CD3 mAb (145-2C11) were purified in our
laboratory. The BVD6-24G2.3 clone was obtained from DNAX (Palo Alto,
CA). mAbs against CD8 (53.67), CD24 (J11d), B220 (RA3-6B2), and Mac1
(M1/70) used for cell depletion were purified in our laboratory. CD4-PE
(YTS 191.1), PE- or FITC-conjugated CD8 (YTS 169.4), CD3-FITC (500-A2),
TCRß-FITC (H57-597), and streptavidin-PE (SAV-PE) were purchased
from Caltag (Le Perray en Yvelines, France). Biotinylated
anti-NK1.1 (PK136) or anti-CD69 (H1.2F3), anti-CD122-FITC
(TM-ß1), anti-TCRß-APC (H57-597), annexin V-FITC or -PE,
anti-Fas-PE (Jo2), SAV-Cy-Chrome, and blocking NA/LE anti-FasL
(clone Kay-10) were obtained from PharMingen (San Diego, CA), and
anti-rat Ig-coated magnetic beads were purchased from Dynal
(Compiegne, France). The irreversible, large spectrum caspase inhibitor
benzyl-oxy-carbonyl-Val-Ala-Asp (zVAD)-fmk, was purchased from Bachem
(Voisins-le-Bretonneux, France).
In vivo treatment, purification of NKT lymphocytes, stimulation, and apoptosis assay
Wild-type and C57BL/6-lpr/lpr mice
received a single i.v. injection of 2 µg of -GalCer (Kirin Brewery
Co., Gunma, Japan) (18) dissolved in PBS containing
0.025% polysolvate 20 or vehicle alone and were sacrificed 2 or
18 h later. Freshly isolated splenocytes were enriched for
CD4+ and
CD4-CD8- T cells by
immunomagnetic depletion of CD8+,
Mac1+ and B220+ cells.
Enriched CD8-CD24- NKT
thymocytes were obtained as previously described (14). At
least 90% of TCRß+ splenocytes or
thymocytes were obtained after depletion. For in vitro experiments, the
enriched lymphocyte population was further labeled with
anti-TCRß and anti-NK1.1 mAbs, and
TCRß+NK1.1+ NKT
lymphocytes were sorted on a FACS Vantage cell sorter (Becton
Dickinson, Mountain View, CA). Purity was >99% upon reanalysis.
Sorted lymphocytes were then stimulated at a concentration of 5 x 105/ml with IL-12 (10 ng/ml) plus IL-18 (100 ng/ml) in the presence or the absence of IL-7 (40 ng/ml). In some experiments, zVAD-fmk or blocking anti-FasL mAb was added at a concentration of 50 µM or 10 µg/ml, respectively. After 1, 2, and 3 days of incubation, cells were washed in PBS and stained with annexin V-FITC and propidium iodide (PI) according to the manufacturer’s instructions.
In another series of experiments, NKT lymphocytes were incubated with 1
µM 5-(and 6-)-carboxyfluorescein diacetate, succinimidyl ester (CFSE;
Molecular Probes, Leiden, The Netherlands) at 37°C for 5 min. Labeled
cells were washed and then stimulated with IL-12 (10 ng/ml) plus IL-18
(100 ng/ml). After different periods of incubation, they were washed in
PBS, stained with annexin V and PI, and analyzed for apoptotic cells.
Supernatants were harvested in all experiments and stored at -80°C
until IL-4 and IFN- assays as previously described (7, 10).
Flow cytometric analysis
Cells were stained in PBS containing 2% FCS and 0.01 M sodium azide and were incubated for 30 min with appropriate dilutions of various mAbs coupled to biotin, PE, APC, or fluorescein. For biotinylated mAbs, SAV-PE or SAV-Cy-Chrome was used as a second-step reagent. At least 104 live lymphoid cells were acquired in each run and analyzed on a FACScalibur (Becton Dickinson) cytometer using CellQuest software.
Detection of FasL mRNA by RT-PCR
Crude RNA was extracted from sorted
TCRß+NK1.1+ NKT
lymphocytes after 18 h of stimulation with IL-18 and IL-12 using
TRIzol reagent (Life Technologies, Cergy-Pontoise, France), according
to the manufacturer’s instructions. The semiquantitative RT-PCR
technique used was based on the comparison between FasL mRNA levels and
those of the transcripts encoding the ubiquitous housekeeping gene
ß2-microglobulin as described previously
(7). The following primers (synthesized by Bioprobe,
Montreuil, France) were used: FasL 5', CTA CCA CCF CCA TCA CAA CC; FasL
3', CAA CCT CTT CTC CTC CAT TA;
ß2-microglobulin 5', TGA CCG GCT TGT ATG CTA
TC; and ß2-microglobulin 3', CAG TGT GAG CCA
GGA TAT AG.
Statistics
Data were expressed as the mean ± SD, and differences between means were evaluated using Student’s t test.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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We have recently demonstrated that in the absence of TCR
engagement, NKT cells produce IFN- and become cytotoxic upon
stimulation with IL-12 plus IL-18, while either factor alone has no
significant effect (10). In the present study we addressed
the question of whether the acquisition of these functional capacities
was accompanied by other features of cellular activation. As shown in
Fig. 1
A, we found that a 24-h
incubation of FACS-sorted, NKT cells with IL-12 plus IL-18 resulted in
a significant up-regulation of the activation marker CD69. This effect
coincided with another manifestation of cell activation, namely an
increase in the proportion of blast cells, as judged by light scatter
characteristics (Fig. 1B). NKT cell activation was
accompanied by increased proliferation assessed by the fluorescent dye
CFSE, which is a means of quantifying cell divisions by flow cytometry
(19). Fig. 2A
shows that 36% of the NKT population had divided after 3 days of
culture in IL-12 plus IL-18. Yet, the number of cells effectively
recovered at this time point was surprisingly low, amounting merely to
about 20% of the cells initially plated. This result could only be
explained by the disappearance of NKT cells once they had been
activated by IL-12 plus IL-18.
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To test our hypothesis, we analyzed the viability of proliferating
NKT lymphocytes gated from the population that had completed division.
Using the apoptosis assay, based on the binding of annexin V that
occurs early in programmed cell death after the externalization of
phosphatidylserine, (20), we found that nearly 40% of
divided NKT cells were about to die (Fig. 2
A).
In accordance with these findings, an important percentage of dead NKT
lymphocytes was detected after 3 days of stimulation with IL-12 plus
IL-18, similar to that for cells cultured in medium alone (Fig. 2B). In contrast, only about 10% of cells died in the
presence of IL-7 (Fig. 2B). This survival effect might be
mediated at least in part through up-regulation of the
anti-apoptotic molecule Bcl-2 (21, 22). Yet, even
though IL-7 saved NKT cells from spontaneous cell death, it did not
prevent apoptosis induced by IL-18 plus IL-12 (Fig. 2B).
This was also true when IL-2 or IL-4 was used instead of IL-7, since
neither factor could restore NKT cell survival (data not shown).
Implication of Fas/FasL interactions in NKT cell apoptosis induced by IL-12 plus IL-18
We have previously demonstrated that the cytotoxic functions
acquired by NKT cells stimulated by IL-18 plus IL-12 involve the Fas
pathway (10). It could therefore be argued that this
mechanism was also responsible for the death of the effector cells
themselves. Consistent with this view, we observed that IL-12 plus
IL-18 induced FasL transcription (Fig. 3A) and up-regulated
the surface expression of Fas (Fig. 3B), which is
spontaneously displayed by NKT cells.
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shows that the inhibition of the
caspase cascade did indeed strikingly reduce cell death. To test
whether NKT cell apoptosis was Fas dependent, we stimulated NKT cells
with IL-12 plus IL-18 in the presence of blocking anti-FasL mAb.
Fig. 4 clearly shows that anti-FasL mAb inhibited NKT cell
apoptosis. Taken together, our findings support the implication of the
Fas death pathway in the apoptosis of activated NKT cells.
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). Similar results were obtained
with FasL-deficient C57BL/6-gld/gld mice (data not shown),
proving the involvement of both Fas and FasL in this activation-induced
cell death. Increased survival of Fas-deficient NKT cells could not be
explained by a poor responsiveness to IL-12 plus IL-18, since they were
similarly activated in terms of IFN- production (up to 700
ng/2.5 x 105 NKT cells), up-regulation of
CD69 expression (
2-fold after 18 h of stimulation), and blast
transformation (data not shown). Despite the drastically reduced cell
death among NKT lymphocytes lacking functional Fas receptors, a
significant percentage remained apoptotic and was rescued by the
caspase inhibitor zVAD. These findings suggest that a second
caspase-dependent, but Fas-independent, pathway was involved in the
death of NKT cells stimulated with IL-12 plus IL-18.
Fas-dependent activation-induced cell death in vivo, after
treatment with the specific ligand of NKT lymphocytes, -GalCer
The results obtained to date raised the question of whether
activation-induced cell death of NKT lymphocytes occurred exclusively
in response to TCR-independent stimulation or whether TCR ligation
induced the same effect. To address this issue, we used the cognate Ag
-GalCer, whose function as a specific inducer of NKT cell activation
has been established both in vitro and in vivo (10, 24).
Within 18 h after a single injection of -GalCer, we observed
that NKT cells disappeared from both the spleen and the thymus, as
shown in Fig. 5A. The loss of
this population occurred after its functional activation in terms of
IL-4 and IFN- production, which was already detected 2 h
postinjection, when the frequency of NKT cells in the two organs was
not yet diminished (data not shown).
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-GalCer injection could be the
consequence of NK1.1 down-modulation rather than depletion. This
conclusion was not consistent with the fact that the number of
TCRßintCD122+ cells,
which have been characterized as NKT lymphocytes (1, 2),
diminished similarly after in vivo treatment with -GalCer (0.8%
TCRßintCD122+ cells
among TCRß+ splenocytes of mice having
received -GalCer vs 3.2% in vehicle controls). The proof that NKT
cells were actually undergoing apoptosis after injection of -GalCer
was provided by their binding of annexin V, which is an early event of
programmed cell death, while a much lower proportion of NKT cells was
labeled in vehicle controls (Fig. 5B).
Interestingly, in vivo treatment with -GalCer not only affects
peripheral NKT cells, but also depletes this population from the
thymus, which might have important implications for its steady state
and selection. A previous in vivo study has shown that administration
of anti-CD3 mAb, which activates both T and NKT cells, results in
the disappearance of the latter population from the spleen, but not
from the thymus (25). The lack of effect in this organ is
probably due to the inability of anti-CD3 mAb to stimulate thymic
NKT cells (6), conversely to -GalCer, which can
activate this thymic subset in vivo (our unpublished observations).
We investigated the involvement of the Fas pathway in NKT cell
depletion in vivo, again taking advantage of the Fas deficiency in
C57BL/6-lpr/lpr mice. The absence of functional Fas did not
prevent -GalCer-induced activation in terms of CD69 up-regulation
and IL-4 production in response to in vivo treatment (data not shown).
Yet, as shown in Fig. 6, it rendered NKT
cells insensitive to activation-induced cell death, implicating
Fas/FasL interactions in the disappearance of ligand-activated NKT
cells.
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ß+NK1.1+
splenocytes compared with controls (16.2 ± 4.3 x
105 vs 9.3 ± 2.7 x
105 cells for C57BL/6-lpr/lpr and
wild-type mice, respectively). In vivo, this slight accumulation of NKT
cells in old C57BL/6-lpr/lpr mice might be explained by the
implication of other death receptors (23) in the apoptosis
of these lymphocytes. It might also be argued that a marked
accumulation of NKT cells cannot be observed in Fas-deficient mice
because they are kept in pathogen-free conditions where exogenous
activation of NKT cells is unlikely.
In conclusion, our data provide evidence for a new Fas-dependent
mechanism controlling the life span of activated NKT cells in response
to the cognate Ag -GalCer as well as to TCR-independent (IL-12 plus
IL-18) stimulation. A strict surveillance of these autoreactive
effector cells seems requisite considering their functional capacities,
which ensure a prompt riposte during the early stages of the immune
response but may become harmful thereafter, causing damage to the
organism itself.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Maria C. Leite-de-Moraes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France.
3 Abbreviations used in this paper: -GalCer, -galactosylceramide; FasL, Fas ligand; SAV, streptavidin; PI, propidium iodide; CFSE, 5-(and 6-)-carboxyfluorescein diacetate, succinimidyl ester.
Received for publication March 28, 2000. Accepted for publication July 28, 2000.
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M. J. Smyth, N. Y. Crowe, D. G. Pellicci, K. Kyparissoudis, J. M. Kelly, K. Takeda, H. Yagita, and D. I. Godfrey Sequential production of interferon-gamma by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of alpha -galactosylceramide Blood, February 15, 2002; 99(4): 1259 - 1266. [Abstract] [Full Text] [PDF]
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) or medium (
) was determined daily for 3 days,
according to forward light scatter characteristics. Similar results
were observed in three separate experiments.
