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Unité d’Immunogénétique Cellulaire, Département de Médecine Moléculaire, Institut Pasteur, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To understand the pleiotropic functions of IL-2 at the molecular level,
we previously characterized IL-2-inducible genes using a cDNA
subtraction approach (5). Of these genes, those coding for
cytoskeleton proteins (
tubulin and 
catenin),
oncogene-regulating proteins (CTCF, JIF-1), and transcriptional factors
(E2F4, CREB, ZhX-1) were further studied in vivo using
IL-2-/- animals. These genes are underexpressed
in the spleens and lymph nodes
(LNs)4 of
IL-2-/- mice, suggesting that they may play a
role in determining the phenotype of IL-2-/-
animals by influencing gene expression, oncogene regulation, and
cellular adhesion that may lead to abnormal lymphocyte activation.
Alternatively, the phenotype of IL-2-/- mice
may be explained by impaired Fas- or TNF-mediated cell death (6, 7).
IL-2 has been shown to play a dual role during specific T cell activation. Its presence is initially mandatory for clonal expansion and later for sensitizing T cells to activation-induced cell death (AICD; Ref. 8). A number of recent reports have indicated that FLIP (also known as FLICE/caspase-8 inhibitory protein) plays an important role in the control of AICD (9). In vitro, the down-regulation of FLIP after T cell activation is mediated by IL-2, and no such effect is observed in cells from IL-2 knockout mice (10). By competitively inhibiting the binding of procaspase-8 to the adaptative molecule Fas-associated death domain protein (FADD), cellular FLIP (cFLIP) inhibits the Fas-mediated apoptosis pathway. The two forms of cFLIP (the long form (FLIPL) and the short form (FLIPS)) are inhibitory (11).
In this study, we compared the activation status and the proliferative and survival capabilities of lymphocytes from the LNs and spleens of IL-2-/- and IL-2+/- mice and tested the hypothesis that FLIP overexpression in vivo may contribute to the selectively altered phenotype of LN lymphocytes in IL-2-/- mice. This work further confirms the pleitropic effects of IL-2 at the molecular level.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-2+/- and
IL-2-/- mice on the 129/01A x C57BL/6
background were bred under routine conditions in the animal facilities
of the Pasteur Institute (Paris, France). All animals were 
2–3 mo
old at the time of analysis. IL-2-/- animals
were identified by PCR. Routine histology of major organs was performed
in most of the IL-2-/- animals.
MRL/lpr animals between 10 and 12 wk were obtained from
Harlan Laboratories (Gannat, France).
Flow cytometric analysis
Splenocytes and LN cells were used as single-cell suspensions. Lymphocyte subsets were characterized by staining with FITC-labeled mAb. When indicated, the activation of the different cell subsets was measured by adding PE-conjugated anti-CD69 mAb during the incubation period. Flow cytometry was performed using a FACScan flow cytometer and Lysis software (BD Biosciences, Mountain View, CA).
The following mAbs were prepared in the Pasteur Institute Department of
Immunology: FITC-conjugated anti-CD3 mAb (clone 2 C113.4),
FITC-conjugated anti-CD4 mAb (clone GK1.5), FITC-conjugated
anti-CD8 mAb (clone H35), FITC-conjugated anti-B220 mAb
(clone Ra3B2), FITC-conjugated anti-NK1.1 (clone PK136), and
FITC-conjugated anti-Mac-1 mAb (clone M1/70). FITC-labeled
anti-IL-2R mAb (clone 5A2) was characterized in the laboratory
and used as previously described (12). PE-labeled
anti-CD69 mAb (clone H1.2F3) was obtained from
PharMingen-Clinisciences (Montrouge, France).
Cell proliferation and cell survival assays
LN and spleen cells were cultured (105 cells/well) in 96-well flat-bottom microtiter plates in a final volume of 200 µl. Anti-CD3 mAb (clone 145-2C11; BD PharMingen, Paris, France) was used at 0.2 µg/ml. IL-2, IL-4, and IL-9 were used at the indicated concentrations. After a 48-h incubation, cultures were pulsed with [3H]TdR and harvested 16 h later.
For cell survival assays, single-cell suspensions (106/ml) were prepared from a pool of mesenteric, inguinal, and popliteal LNs, or from spleens taken from IL-2-/- and IL-2+/- mice. Propidium iodide (150 µg/ml) was added to the cell suspension and the lymphocytes were analyzed for size and granulometry (forward light scatter/side light scatter) using a FACScan flow cytometer. This easily distinguishes dead from live cells (13).
Western blot analysis
Lysates were prepared from the spleens and LNs of IL-2-/- and IL-2+/- mice and analyzed as already described (7, 14). After electrophoresis on a 12% polyacrylamide gel, the proteins (100 µg/sample) were transferred to Immobilon membranes (Millipore Corporative, Paris, France). The immunoblots were incubated with rabbit anti-cFLIP polyclonal Abs (Alexis, Paris, France). After incubation with goat anti-rabbit peroxidase-conjugated Abs (1/5000; Southern Biotechnology Associates, Birmingham, AL), reactive protein bands were visualized by ECL (Amersham Pharmacia Biotech, Piscataway, NJ).
cFLIP protein expression levels were quantified by densitometry.
-Actin on the same blots was measured using mAb (clone C-2, IgG1, 3
µg/ml; Santa Cruz Biotechnology, Santa Cruz, CA) and
peroxidase-conjugated anti-mouse Abs (1/10,000; Amersham, Les Ulis,
France). Bands corresponding to the amount of cFLIP or -actin were
measured using NIH Image software (National Institutes of Health,
Bethesda, MD). The cFLIP signal was normalized to that of -actin and
the cFLIP/-actin ratio calculated.
Semiquantitative RT-PCR
This technique has already been used in the laboratory in the past (15, 16). Total RNA was extracted from the spleens and LNs of IL-2-/-, IL-2+/-, and MRL/lpr mice using RNA PLUS reagent (Quantum Bioprobe, Montreuil, France). The first-strand cDNA was synthesized from 1 µg of mRNA using oligo(dT)12–18 (25 ng/µl) by incubating the mixture at 70°C for 10 min followed by quick chilling on ice. The following were then added according to the manufacturer’s instructions: 5 x first-strand buffer, dNTP mix, avian myeloblastosis virus reverse transcriptase (Promega, Lyon, France), and RNAsin (2 U/µl; Promega) to a final volume of 20 µl. The mixture was sequentially incubated at 42°C for 60 min, 95°C for 5 min, and cooled to 4°C. cDNA mixture (2 µl) was used for PCR amplifications using gene-specific primers. The reactions were performed using a Thermal Cycler (PerkinElmer, Wellesly, MA).
The PCR products were size fractionated on 1.5% agarose gel,
transferred onto Hybond-N+ membranes (Amersham),
and hybridized with specific probes. For semiquantitative analyses,
gels were exposed on Kodak storage phosphor screens (Kodak, Rochester,
NY), and the radioactive signal was measured using a
PhosphorImager (Molecular Dynamics, Sunnyvale, CA). -Actin and
IL-2R
, which are constitutively expressed in all lymphomononuclear
cells, were used as internal controls. A semiquantitative analysis of
cFLIP mRNA expression was obtained by dividing the radioactive signals
for cFLIP mRNA by the radioactive signals for -actin mRNA or
IL-2R mRNA and expressing the result as a ratio, i.e.,
FLIPL/-actin or
FLIPL/IL-2R.
The sequence of the primers and probes used are as follows.
FLIPL: sense, 5'-TATGCAAGTATGGCCCAACA-3';
antisense, 5'-CAGGCTGAGGCTGTATTTC-3'; and probe,
5'-GACTCTAAGCCCCTGCAACC-3'. FLIPS: sense,
5'-TGGATCCAGACTGGACGAGAACCTGGCTG-3'; antisense,
5'-TGTGAATTCTTATTACATCTCTGAGACTGGT-3'; and probe
5'-TGAGAGAGGCCAGCTCTCTTTTGCT-3'. IL-R: sense,
5'-TCCAGCTTCGATCTCTGTTGCTCCG-3'; antisense,
5'-CAAGGTCCTCATGTCCAGTGCGA-3'; and probe, specific cDNA fragment.
-Actin: sense, 5'-TGGAATCCTGTGGCATCCATGAAAC-3'; antisense,
5'-TAAAACGCAGCTCAGTAACAGTCCG-3'; and probe, specific cDNA
fragment.
Statistics
Mean ± SD are reported. Student’s t test was used to evaluate the significance of the results.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The enlargment of the LNs in IL-2-/-
animals was analyzed over time (Table I
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By measuring the total number of cells, it was found that cervical LNs
were more enlarged at 1 mo than 3 mo old (Table I). By contrast,
paraaortic LNs were more enlarged 3 mo after birth. The data show that
the cells from the LNs of IL-2-/- animals were
always more numerous than from the LNs of
IL-2+/- animals. The ratio was always >2 and
the difference was found to be statistically significant
(p < 0.05). It is striking that compared with
the spleens of IL-2+/- animals, the total cell
content of spleens from IL-2-/- mice was less
increased (Table I). The ratio was always <2 and the difference was
not statistically significant (p > 0.05).
These results were verified by measuring the weight of the LNs and
spleens from IL-2-/- and
IL-2+/- animals (Table I).
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A). However, the
activation status of the lymphocytes was different in the two strains
(Fig. 1B). A very high proportion (69%) of the LN
lymphocytes from the IL-2-/- mice expressed the
CD69 activation marker, whereas only a small proportion (16%) of these
cells were positive when prepared from IL-2+/-
animals. These results were confirmed by analyzing
CD3+ lymphocytes from both strains. When the
expression of CD69 was compared between CD4, CD8, and B cells from the
LNs and spleens of IL-2-/- and
IL-2+/- mice, a striking difference was also
observed. All the cell subsets were activated in the LNs of
IL-2-/- animals compared with
IL-2+/- animals. In contrast, the expression of
CD69 by these three subsets was comparable in the spleens of
IL-2-/- and IL-2+/-
mice.
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and Fig. 1C) indicate that
lymphoproliferation predominates in the LNs of
IL-2-/- mice and that all the major lymphocyte
subsets are activated in the corresponding secondary lymphoid
organ. Comparison of the reactivity and survival capacity of lymphocytes from IL-2-/- and IL-2+/- mice
The capacity of the lymphocytes to proliferate in response to
suboptimal anti-CD3 concentrations (0.2 µg/ml) was evaluated in
the presence of a limited concentration of IL-2 (2 nM) unable to induce
alone a detectable T cell proliferation. The results presented in Fig. 2A demonstrate that LN cells from
IL-2-/- mice showed a greater capacity to
proliferate than LN cells from IL-2+/- animals
(p < 0.002). In contrast, under the same
experimental conditions, spleen cells from
IL-2-/- and IL-2+/-
animals proliferated equally well.
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B). Surprisingly, LN T cells
from IL-2-/- animals showed a substantial
proliferative capacity in response to IL-2 in the absence of any
costimulatory signal. This IL-2 proliferation was specific because IL-4
and IL-9 did not induce any [3H]TdR
incorporation under the same experimental conditions (Fig. 2, C and D). As expected, IL-2R was detected at
the cell surface of IL-2-/- lymphocytes after
they have been induced to proliferate by IL-2 (Fig. 2E).
It has been demonstrated that lymphocytes from
IL-2-/- mice are more resistant to Fas-mediated
apoptosis than the corresponding cells from
IL-2+/- mice (6). In this study, we
examined the ability of IL-2-/- lymphocytes to
survive in vitro (Fig. 3). Whole LN cells
from IL-2-/- or IL-2+/-
animals were followed in culture in the absence of any stimulation. The
LN cells from IL-2-/- mice survived longer than
those from IL-2+/- animals (Fig. 3A).
This is not the consequence of spontaneous, measurable proliferation in
the LN cultures from IL-2-/- mice (Fig. 3B). In contrast, spleen cells from
IL-2-/- and IL-2+/- mice
survived equally well. It should be noted that the spleen cells
survived for a shorter period than the LN lymphocytes.
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and 3 demonstrate that LN lymphocytes
from IL-2-/- mice have a greater ability to
proliferate and survive in vitro than LN lymphocytes from
IL-2+/- animals. No such difference was found
between spleen lymphocytes from the two mouse strains under study. LN cells from IL-2-/- mice express more FLIP than those from IL-2+/- mice
Cell extracts prepared from IL-2-/- and
IL-2+/- LN cells were subjected to Western blot
analysis using anti-FLIP Ab. Fig. 4A presents the results of a
typical analysis of cell extracts prepared from five
IL-2-/- and seven
IL-2+/- animals. The Ab recognized a 55-kDa band
readily detectable in the LN cell extracts from the
IL-2-/- mice. The same band was expressed at a
far lower intensity in the LN cell extracts from the
IL-2+/- animals. As a control, we analyzed the
expression of -actin by Western blotting. Data concerning -actin
expression confirmed the different intensities of FLIP
expression in IL-2-/- and
IL-2+/- animals.
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-actin ratio as indicated in Materials
and Methods (Fig. 4B). The ratio in
IL-2-/- was 2.5-fold that in
IL-2+/- mice, and the difference was
statistically significant (p < 0.014). When
the same analysis was performed with cell extracts from spleens of
IL-2-/- and of IL-2+/-
animals, the ratios were found to be comparable (Fig. 4C). FLIPL and FLIPS mRNA expression in the LNs and spleens of IL-2-/- and IL-2+/- mice
FLIP expression was further quantified at the mRNA level by
analyzing FLIP mRNA expression using semiquantitative RT-PCR. Fig. 5A presents the data obtained
with mRNA preparations from the LNs, spleens, and thymuses of
IL-2-/- and IL-2+/-
mice. FLIPL mRNA was clearly overexpressed in the
LNs of IL-2-/- when compared with the LNs of
IL-2+/- mice. In contrast, the spleens and
thymuses from IL-2-/- and
IL-2+/- mice expressed comparable levels of
FLIPL mRNA. Some variability in the
FLIPL mRNA levels was observed in the different
experimental groups. The results for FLIPL mRNA
expression were quantified (Fig. 5B), and the ratio was
calculated using -actin mRNA as an internal marker. The results show
that the LN cells from IL-2-/- animals
expressed five times more FLIPL mRNA than those
from IL-2+/- animals, whereas spleens from both
strains expressed comparable levels. In a similar manner to
spleen, the thymuses from IL-2-/- and
IL-2+/- animals expressed comparable levels of
FLIPL mRNA.
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mRNA as internal marker because this gene,
like -actin, is constitutively expressed. Fig. 6A confirms that
FLIPL mRNA is overexpressed in the LN cells from
IL-2-/- animals. The results obtained with
IL-2-/- and IL-2+/- mice
were statistically different (p < 0.003). This
analysis also confirmed that spleen cells from
IL-2-/- and IL-2+/- mice
express similar amounts of FLIPL mRNA. We also
verified that FLIPS mRNA follows the same pattern
of expression as FLIPL mRNA (Fig. 6B).
Because LN cells from IL-2-/- mice are
overactivated (Fig. 1), it was important to verify that FLIP mRNA
overexpression was not dependent on lymphocyte activation. To do this,
we compared FLIPL mRNA expression in LN cells
from IL-2-/- and MRL mice which express an
intact IL-2 gene but show abnormal T cell activation (17).
The data shown in Fig. 6C clearly demonstrate that FLIP mRNA
overexpression correlates with a lack of IL-2, not with lymphocyte
activation. The results reported in Figs. 5 and 6 establish that in the
absence of IL-2, FLIP mRNA is overexpressed in the LNs of
IL-2-/- mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The role of FLIP in the control of T cell death has already been
documented. FLIP expression levels have been found to be initially
up-regulated then down-regulated in primary T cells after antigenic
stimulation. TCR ligation-induced down-regulation of FLIP has been
correlated with sensitization of the T cells to AICD
(18, 19, 20, 21, 22). FLIP inhibits the Fas-mediated pathway. Fas
signaling is initiated by oligomerization of the receptor by Fas
ligand. The cytoplasmic domain of cross-linked Fas then binds
the adaptative molecule FADD. This is followed by the binding of
procaspase-8 to FADD throughout the interaction of death effector
domains (DEDs). Caspase is then activated leading to a cascade of
catalytic caspase activation culminating in apoptosis. Owing to its
structural homology with caspase-8, FLIP competitively inhibits the
binding of procaspase-8. In procaspase-8, the
FLIPL has two DEDs followed by a caspase-like
sequence, whereas the FLIPs has only the two DEDs. Furthermore, an
unanticipated role played by FLIPL has recently
been described in the regulation of the transcription NF-
B and in
extracellular signal-regulated kinase-mediated gene expression, and
thus, in the regulation of the proliferation and/or differentiation of
Fas-stimulated cells (23).
Overexpression of FLIP in the LNs of IL-2-/-
animals has been described in this study at both the mRNA and protein
levels. Using semiquantitative RT-PCR and either -actin or IL-2R
as internal controls, we demonstrated that FLIP mRNA levels in the LNs
of IL-2-/- animals are 2- to 5-fold greater
than those in the LNs from IL-2+/- mice.
In contrast, FLIP levels are comparable in both strains for the spleen
and for the thymus. This latter result is in agreement with our
previous data showing that IL-2 does not affect gene expression in this
primary organ (5, 16). Furthermore, we demonstrated that
FLIPL and FLIPS mRNA follow
the same pattern of expression. It is worth noting that FLIP
overexpression is not linked to lymphocyte activation because
lymphocytes from MRL mice do not overexpress the corresponding mRNA.
This is a critical result because MRL and IL-2-deficient mice have a
comparable phenotype, including an apoptosis defect (due to Fas ligand
mutation in MRL mice) and lymphoproliferation, but the IL-2 gene is
intact in MRL mice (24, 25). Therefore, these results
clearly establish the role played by IL-2 in the in vivo regulation
of FLIP.
Preferential overexpression of FLIP in the LNs of
IL-2-/- mice seems to correlate with many
immunological characteristics defined in the IL-2-deficient phenotype.
LN size is preferentially increased in IL-2-/-
mice, whereas the enlargement of the spleen is small and not
statistically significant (Table I). The cellular expansion found in
the LNs of IL-2-/- mice does not alter the
proportion of the different subsets and all the lymphocytes are
concerned by the activation process (CD69 expression). In contrast,
expression of the CD69 marker by spleen lymphocytes is comparable in
IL-2-/- and IL-2+/-
mice. This corresponds to background lymphocyte activation we observe
systematically in the mice from our animal facilities. We also noted
spontaneous NF-B activation in the LNs from
IL-2-/- mice (data not shown). The Western
blots we conducted were unable to detect any processed FLIP responsible
for the induction of the proliferative signals (23).
However, spontaneous NF-B activation may, at least in part, explain
the increased susceptibility of the T lymphocytes from
IL-2-/- mice to proliferate in response to
limited amounts of anti-CD3 and IL-2. In the course of this
investigation, we noted that lymphocytes from
IL-2-/- mice proliferated intensely in response
to IL-2 alone. In the absence of IL-2, some signaling circuits may be
induced and are ready to function on exposure to this cytokine.
At the cellular level, overexpression of FLIP may explain the increased
ability of lymphocytes from IL-2-/- mice to
survive in vitro (Fig. 3) and their resistance to Fas-induced
apoptosis, as previously described (26). In vivo, this may
induce resistance to AICD and lead to autoimmune reactions, which are a
hallmark of the IL-2-deficient phenotype (26, 27, 28).
However, differents results suggest that LN T cells from
IL-2-/- mice may be controlled by normal
regulatory circuits. In transfer experiments, wild-type cells of
hemopoietic origin present in the same animal are able to prevent
hyperactivation of LN cells from IL-2-/- mice
(29).
Different mechanisms have been put forward to explain the phenotype of
IL-2-/- mice. A lack of
CD4+CD25+ "professional
suppressor" T cells has been suggested as a possible mechanism
responsible for autoimmune reactions in IL-2-/-
mice (29, 30, 31, 32). Their absence in
IL-2-/- mice might also explain the
uncontrolled lymphocyte activation. In contrast, our data suggest that
the IL-2-/- phenotype is under multigenic
control (5, 7). We have previously identified
IL-2-inducible genes coding for cytoskeleton proteins ( tubulin and
catenin), oncogene-regulating proteins (CTCF, JIF-1), and
transcriptional factors (E2F4, CREB, ZhX-1). Under some conditions,
underexpression of catenin may lead to faulty adhesion and release
of lymphocytes from normal regulatory control by cell-cell contact.
Similarly, underexpression of CTCF and JIF-1 and low levels of
transcriptional factors (E2F4, CREB, ZhX-1) may under some
circumstances increase the susceptibility of lymphocytes to activation
and proliferation in IL-2-/- mice. More
recently, we found that TNF-, TNF-, and lymphotoxin-
are underexpressed in vivo in IL-2-/- mice, and
under some conditions, this may also contribute to the uncontrolled
proliferation of their lymphocytes. Hence, we propose that regulatory
dysfunction of multiple IL-2-regulated genes may be involved directly
or indirectly in the lymphoproliferation seen in
IL-2-/- mice.
The respective roles played by FLIP and other genes regulated by IL-2 deserve further discussion. Because all of the IL-2-induced genes described previously are equally underexpressed in the LNs and spleens of IL-2-/- animals, this suggests that FLIP overexpression is very critical in the in vivo selective LN lymphoproliferation described in this study. Underexpression of the genes previously described by our laboratory would be necessary but not sufficient to observe the lymphoproliferation. By contrast, FLIP overexpression would be required to reduce susceptibility to apoptosis and induce the activation and lymphoproliferation observed in the LNs of IL-2-/- mice. In this context, it is also interesting to compare the characteristics of IL-2-deficient mice and recently generated FLIP transgenic animals. In these mice, FLIP has been placed under the CD2 promotor (9). Peripheral T cells in these FLIP transgenic animals are like IL-2-/- T lymphocytes protected against Fas-induced apoptosis in vitro. However, unlike IL-2-deficient mice, FLIP transgenic animals do not show an accumulation of activated T cells in vivo. This strongly suggests that constitutive expression of FLIP in T cells is not always sufficient to elicit alone the lymphoproliferation observed in IL-2-/- mice. Our observation that lymphocyte expansion in IL-2-/- mice involves all the lymphocyte subsets suggests that FLIP must be overexpressed in more than one cell type to explain the IL-2-/- phenotype. However, a direct role of FLIP overexpression in vivo has been suggested by demonstrating autoimmunity as a consequence of retrovirus-mediated expression of FLIP in T lymphocytes (33). Altogether, this suggests that a balance between cFLIP down-regulation by IL-2 and regulatory dysfunction of IL-2-inducible genes is involved in the control of the lymphoadenopathy observed in IL-2-/- mice.
This study has shed additional light on the complex network of regulatory functions directly or indirectly controlled by IL-2, and further supports the notion that the pleiotropic molecular effects of IL-2 are under multigenic control.
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Acknowledgments |
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Footnotes |
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2 Current address: Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Louis Pasteur Avenue, Boston, MA 02115.
3 Address correspondence and reprint requests to Dr. Jacques Thèze, Unité d’Immunogénétique Cellulaire, Departement d’ Immunologie, Institut Pasteur, 25-28 rue du Docteur Roux, 75724 Paris Cedex 15, France. E-mail address: jtheze{at}pasteur.fr
4 Abbreviations used in this paper: LN, lymph node; AICD, activation-induced cell death; cFLIP, cellular FLIP; FLIPL, long form of cFLIP; FLIPS, short form of cFLIP; FADD, Fas-associated death domain protein; DED, death effector domain.
Received for publication March 20, 2002. Accepted for publication July 26, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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expression: further analysis in the IL-2 knockout model, and comparison with TNF-, lymphotoxin-, TNFR1 and TNFR2 modulation. Int. Immunol. 13:135. T lymphocytes for apoptosis. Nature 353:858.[Medline]
B inhibitor IB. Mol. Cell. Biol. 19:6345.-chain expression is independently regulated in primary and secondary lymphoid organs. J. Immunol. 161:1977.B and Erk signaling pathways. Curr. Biol. 10:640.[Medline]
chain, resistance to clonal deletion and IL-2 dependency. Int. Immunol. 10:371.This article has been cited by other articles:
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