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- and ß-Chains of the IFN-
Receptor, and Triggers IFN--Mediated Apoptosis of Activated Human T Lymphocytes1
,
*
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy;
Division of Life Sciences, Cell Growth Regulation Laboratory, King’s College, London, United Kingdom; and
Department of Medicine, G. D’Annunzio University, Chieti, Italy
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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- and the ß-chains of the
IFN-
R on activated T lymphocyte membrane. None of these effects
depend on sugar binding: saturating amounts of lactose do not affect
the cell cycle block nor IFN-R up-modulation. The increased
expression of both chains renders ßGBP-treated T lymphoblasts
sensitive to IFN--induced apoptosis. Taken as a whole, these
findings suggest that ßGBP plays an important immunoregulatory role
by switching off T lymphocyte effector functions. They also provide the
first evidence of up-modulation of IFN-R expression on T lymphocytes
by a negative cell growth regulator. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(3, 5, 6). A more precise understanding of the mechanisms controlling T lymphocyte response can be sought through the characterization of other factors involved in its regulation. ß-galactoside-binding protein (ßGBP),3 a 15-kDa protein encoded by the LGALS1 gene (7, 8, 9), is a negative regulator of cell cycle that blocks the transition from S to G2 phase (7). ßGBP is physiologically released by fibroblasts (7), and its structure places it in the galectin family, of which the members are animal lectins characterized by their affinity for ß-galactoside residues (9, 10). ßGBP exists both as a monomer (7) and a homodimer (11, 12). These two molecular forms are in a state of equilibrium (13) and bind ß-galactoside residues on the cell membranes (14). Through its retention of associated cell surface ß-galactoside residues, the homodimer form (11, 13) displays a wide range of biologic activities involving cell adhesion and immune regulation (9, 10, 11, 12, 13, 14, 15, 16). Besides the binding to ß-galactosides residues, additional functions have been attributed to monomeric form. It has been reported, in fact, that the monomer interacts with a high affinity cell surface receptor on target cells, since its biologic activity is maintained even when the saccharide-binding site is masked by a glycan complex (7).
In this paper, the effects of monomeric ßGBP on the cell cycle
progression and expansion of activated normal and malignant human T
lymphocytes were examined. Even in the presence of lactose, ßGBP
markedly inhibited their proliferation by arresting them in the S and
G2/M phases. In addition, by up-regulating the expression
of both the - and ß-chains of their membrane IFN-R, it rendered
them sensitive to IFN--induced apoptosis (6).
These findings suggest that ßGBP plays an important immunoregulatory
role by switching off T lymphocyte effector functions. Moreover, they
provide the first evidence of up-modulation of IFN-R expression,
particularly that of its ß-chain, on T lymphocytes by a negative cell
growth regulator.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RPMI 1640, FCS, L-glutamine, penicillin,
streptomycin, gentamicin, and trypan blue dye were from Life
Technologies (Grand Island, NY); PHA, paraformaldehyde, RNase A, Tween
20, lactose, DMSO, and propidium iodide (PI) were from Sigma (St.
Louis, MO); PBS, BSA, ethanol, and sodium azide were from Merk
Chemicals (Milan, Italy); phycoerythrin (PE)-conjugated streptavidin,
biotin-conjugated rabbit anti-mouse Ig, mouse IgG1, and mouse IgG2a
control Ab were from Dako (Milan, Italy); mouse anti-IFN-R
IgG1 (R99) and rIFN- were a gift from Dr. G. Garotta (Human
Genome Sciences, Rockville, MD); mouse anti-IFN-Rß IgG2a
(C.11) was a gift from Dr. S. Pestka (Piscataway, NJ); cell culture
glassware was from Corning Costar (Cambridge, MA).
Recombinant human ßGBP
The cDNA enclosing the full length coding sequence (L. Mallucci
and V. Wells, international patent application W092/07938) of the human
ßGBP protein was isolated by screening a human lung fibroblast cDNA
library in 
gt 11 (Stratagene, Cambridge, U.K.) using a full length
murine ßGBP cDNA (7). The human cDNA was first subcloned
into puc 19 vector using a Kpn-SstI fragment. The
sequence encoding the human ßGBP cDNA was then amplified by PCR using
forward primer 5'-G TCA ATC ATG GCT TGT GGT CTG GTC-3' and reverse
primer 5'-GT TCA GTC AAA GGC CAC AC-3' and directly cloned into the
eukaryotic cloning vector pCR3.1 using Escherichia coli
strain TOP 10F'. The extracted plasmid was transfected in COS1 cells
and the recombinant protein purified by immunoaffinity chromatography
following procedures described previously (7). The
competing sugar (100-mM lactose) was used after preincubation with the
ßGBP solutions for 20 min at room temperature.
Normal and malignant T lymphocyte cultures
Human PBL from heparinized venous blood from healthy donors were isolated by Lymphoprep gradient (Ficoll Type 400, Pharmacia, Uppsala, Sweden) centrifugation and stimulated (1 x 106/ml) with 2.5 µg/ml PHA (Sigma). The cells resulting after 3 days of culture (94–98% CD3+) received 50 U/ml r-IL2 (EuroCetus, Milan, Italy). After a further 3 days, they were treated with ßGBP, and r-IL2 was added. Cells were examined every 24 h.
ST4 (CD1+, CD2-, CD3-, CD4-, CD8+, CD25-), PF382 (CD1+, CD2-, CD3-, CD4-, CD8+, CD25-), and Jurkat (CD1+, CD2+, CD3+, CD4+, CD8-, CD25-) are previously described human T cell lines (5).
Cell proliferation assay
PHA-activated T lymphocytes (1 x 106/ml) were cultured in complete medium supplemented or not with ßGBP at different doses. At 24, 48, and 72 h, a small aliquot of the cell suspension was removed; 50 µl of this was mixed with 10 µl of trypan blue dye, and viable cells were counted. The results are expressed as the arithmetic mean of cell numbers from triplicate cultures. The experiments were performed with six donors and representative experiments are shown.
[3H]TdR uptake
PHA-activated T lymphocytes (1 x 106/ml) were cultured in triplicate in round-bottom 96-well plates in the presence or absence of 400 ng/ml ßGBP. After 66 h, the cultures were pulsed with 1 µCi [3H]TdR (Amersham, Milan, Italy). After 6 h, the cells were harvested on a glass fiber filter and [3H]TdR uptake was evaluated by Matrix-96 beta counter (Canberra-Packard, Milan, Italy). The results are expressed as the arithmetic mean ± SD of total cpm from triplicate cultures.
Cell cycle analysis
DNA staining for cell cycle analysis was performed as previously described (17). Briefly, 1 x 106 cells were resuspended in 0.875 ml of cold PBS and 0.125 ml of cold 2% paraformaldehyde solution, then incubated for 1 h on ice. The fixed cells were washed and gently resuspended in 1 ml of 0.2% Tween 20 in PBS at room temperature. The mixture was incubated for 20 min at 37°C. One milliliter of PBS supplemented with 2% FCS and 0.1% NaN3 (PBS-azide) was added, and the suspension was spun for 5 min at 1300 rpm. After the supernatant was decanted, DNA was stained by incubating the cells in 1 ml of PBS-azide containing 10 µg/ml PI and 11.25 Kunitz U of RNase for at least 30 min in the dark. DNA content was analyzed by flow cytometry.
IFN-R expression analysis
Cell surface expression of the - and ß-chains of IFN-R
was assessed by flow cytometry analysis. The -chain was detected
with the murine IgG1 mAb R99, which is specific for this chain
(5, 6). The ß-chain was detected by using a murine IgG2a
mAb (6). Staining was followed by biotinylated rabbit
anti-mouse Ig and streptavidin-PE. Membrane Ag expression was
analyzed with a FACScan flow cytometer (Becton Dickinson, Milan,
Italy). Each analysis represents the results from 10,000 events.
Evaluation of apoptosis
Apoptosis was evaluated by fluorochrome labeling of DNA strand breaks by means of the terminal deoxynucleotidyl transferase (TdT) assay, using the Apo-Direct kit from PharMingen (San Diego, CA). This procedure allows the detection of apoptotic cells simultaneously with their DNA content (18). Fixation and staining were performed according to the manufacturer’s instructions. Briefly, 1 x 106 cells per sample were suspended in 0.5 ml of PBS. Cell suspensions were supplemented with 5 ml 1% paraformaldehyde in PBS and placed on ice for 15 min. Cells were then washed twice in 5 ml PBS, and 5 ml of ice-cold 70% ethanol was added. The samples were stored at -20°C until use. Each sample was incubated for 60 min at 37°C with TdT and FITC-dUTP in a reaction buffer. The cells were then washed, resuspended in 1 ml of PI and RNase solution, and incubated for 30 min at room temperature. Samples were analyzed by flow cytometry within 3 h of staining.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PHA-activated T lymphocytes (94–98% CD3+) from six
healthy donors were cultured in medium containing 50 U/ml IL-2 and
ßGBP (4–400 ng/ml) for 72 h. A dose-dependent ßGBP inhibition
of IL-2-induced proliferation was observed when their expansion was
evaluated by direct cell counting (Fig. 1
A). The IL-2-independent
proliferation of three malignant T cell lines, ST4, PF382 and Jurkat,
was also inhibited by ßGBP (data not shown).
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B) and apoptotic (Fig. 2A) T cells.
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, A and
B). Effect of ßGBP on the IL-2-dependent cell cycle progression of activated T lymphocytes
Since 400 ng/ml (27 x 10-9 M) ßGBP abolished
T lymphoblast proliferation but had no effect on viability, its
influence on the cell cycle was next evaluated through cytofluorometric
analysis of DNA content by PI staining (Fig. 2A). At the
beginning of the cultures established in medium supplemented with IL-2,
few PHA-activated T lymphoblasts were in the S and G2/M
phases (cycling cells), the remainder being in the
G0/G1 phases. The numbers of cycling cells
increased progressively after 24 and 48 h. After 72 h, they
dropped to the start levels (Fig. 2A, upper panels). This
pattern suggests that T lymphoblasts responded to IL-2 by expanding
3.5-fold (Fig. 1A) and then returned to a steady state with
most of them in G0/G1 phases. The presence of
400 ng/ml ßGBP induced a dramatic inhibition in cell number but no
striking differences in DNA content for the first 48 h of culture.
(Fig. 2A, lower panels).
The ST4, PF382, and Jurkat cell cycle was also arrested in S/G2 phase by ßGBP (data not shown).
Saturation with 100 mM lactose did not change the cell cycle in the
presence or absence of 400 ng/ml ßGBP (Fig. 2B), showing
that its blocking effect does not depend on its sugar-binding
properties.
Effect of ßGBP on the IL-2-dependent [3H]TdR uptake of activated T lymphocytes
Negative regulation of cell proliferation by ßGBP is due to its
ability to arrest cells between the S and G2 phases
(7). The inhibition of cell expansion due to the presence
of ßGBP strongly suggests that ßGBP impairs the growth of T
lymphocytes by accumulating them in S and G2/M phases, as
previously reported for fibroblasts (7). The discrepancy
in S and G2/M distribution observed after 72 h between
T lymphocytes cultured in the presence (42%) or absence (24%) of
ßGBP (Fig. 2A, 72 h, upper vs lower
panel) was not due to enhanced growth, but to arrest in
S/G2 phases. To confirm that the increase in numbers of
cells in S/G2 was due to arrest by ßGBP, the
[3H]TdR uptake of IL-2-responding T lymphocytes cultured
in the presence or absence of ßGBP was evaluated.
[3H]TdR uptake measures cells in the S phase, so T
lymphocytes cultured with ßGBP could display an enhancement of this
value after 72 h as the result of their accruing in
S/G2 phases.
When DNA synthesis was evaluated, a >60% increase in
[3H]TdR uptake was evident only in the presence of 400
ng/ml ßGBP (Fig. 3). The increase
induced by 400 ng/ml ßGBP was not affected by saturation of its
sugar-binding sites with 100 mM lactose (Fig. 3).
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R and
ß chain expression on activated T lymphocytes
We have previously shown that the intensity of the IFN-R -
and ß-chains’ expression on the T cell membrane decides whether
IFN- induces proliferation or apoptosis (6). Therefore,
the ability of ßGBP to modulate IFN-R chains was evaluated next.
Cytofluorometric analysis with the anti-IFN-R R99 mAb and
the anti-IFN-Rß C.11 mAb indicated that PHA-activated T
lymphocytes cultured for 72 h in the absence of 400 ng/ml ßGBP
expressed high -chain and barely detectable ß-chain levels (Fig. 4A, left panels). The presence
of ßGBP further enhanced the -chain expression and elicited a
marked expression of the ß-chain (Fig. 4A, right
panels).
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- and ß-chain-positive
cells also shows that ßGBP up-regulates the expression of both chains
(Fig. 4B). This increase began after 24 h and peaked
after 72 h. Once again, saturation with 100-mM lactose had no
effect. Similar results were obtained with the ST4, PF382, and Jurkat
lines (data not shown).
Apoptotic effects of IFN- on
ßGBP-treated activated T lymphocytes
The binding of IFN- to T lymphocytes expressing high amounts of
IFN-R ß-chain induces their apoptosis (6, 19). Since
ßGBP induced a substantial ß-chain increase, the extent to which
normal and malignant T cell apoptosis was enhanced by the addition of
IFN- was investigated.
PHA-activated normal T lymphocytes were first cultured for 72 h in
the presence or absence of 400 ng/ml ßGBP and then for a further
48 h in complete medium, with or without 1000 U/ml IFN-. No
apoptosis was detected by evaluating the induction of DNA strand breaks
with the TdT technique and PI staining when cells were cultured in
medium only (Fig. 5, upper
left), with IFN- alone (Fig. 5, upper right panel), or with ßGBP alone (Fig. 5, lower left), whereas it was dramatically evident in the
presence of ßGBP and IFN- (Fig. 5, lower right).
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-mediated
apoptosis came from experiments with ST4 malignant T cells cultured in
the presence or absence of 400 ng/ml of ßGBP for 48 h. DNA
content analysis showed an expected block in S/G2 phase
induced by ßGBP (Fig. 6, left). Cells were then washed
and cultured for a further 48 h in complete medium supplemented
(Fig. 6, right) or not (Fig. 6, middle) with 1000
U/ml of IFN-, and apoptosis was evaluated. No changes in apoptosis
or cell cycle were observed when cells previously cultured in the
absence of ßGBP (Fig. 6, upper left) were recultured in
the presence or absence of IFN- (Fig. 6, upper middle and
right panels). ST4 cells previously cultured in the presence
of ßGBP were blocked in S/G2 phases (Fig. 6, lower
left) and restarted their normal cycle when washed and recultured
in medium only (Fig. 6, lower middle). This indicated that
the ßGBP effect on cell cycle arrest disappears following its
removal. By contrast, the number of apoptotic cells soared to 60% when
they were recultured in medium supplemented with IFN- (Fig. 6, lower right). Similar results were obtained with the PF382
and Jurkat lines (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-chain IFN-R expression and thus
favors their bias toward IFN--mediated apoptosis (6, 19).
The ßGBP arrest of T cell cycle may have a broader physiologic
consequence. Its effect on the cycle of PHA-activated T lymphoblasts
and malignant T cell lines is a block at the S/G2
checkpoint. This block is no longer evident on T lymphoblasts 96 to
120 h of culture (data not shown). Further evidence of the
reversibility of this arrest was provided by its disappearance in ST4
cells when they were washed and ßGBP was removed (Fig. 6).
The discrepancy between the S and G2/M distribution and [3H]TdR uptake values observed in T lymphocytes cultured in the presence of ßGBP is only apparent. The observation that ßGBP induces the accumulation of T cells in S/G2 phases and thus blocks their progress through the cycle mirrors its control of the S/G2 checkpoint previously reported on fibroblasts, where it acts in the late S phase and arrests them in G2 (7). The increased [3H]TdR uptake of activated T cells in the presence of ßGBP appears to be the result of temporary accumulation of T cells in S/G2 phases as a consequence of their inability to exit from G2 and proceed into M phase.
The DNA content of resting T cells was unaffected (data not shown), presumably because ßGBP controls the S/G2 phase transition and thus can act only on proliferating cells (PHA-activated T lymphocytes or T cell lines), whereas resting T cells are nearly all in G0/G1.
Up-modulation of IFN-R - and ß-chain expression associated with
the ßGBP-mediated cell cycle inhibition appears to have important
consequences for the fate of T lymphocytes.
We have previously shown that induction of proliferation,
differentiation (20), or apoptosis (5, 6, 19)
of human T lymphocytes by IFN- depends on differences in the
expression of the IFN-R - and ß-chains on their membrane. High
expression of the -chain, in fact, favors only growth-promoting
signals (5, 20, 21), and high expression of both chains
favors apoptotic signals (6, 19).
In normal and neoplastic T lymphocytes, high IFN-R chain expression
is induced by serum (5) and IL-2 deprivation (6, 19), TCR ligation (6), and exposure to x-rays
(5) or chemotherapeutic drugs (22). Since
most of these treatments induce arrest in S and G2/M
(23, 24, 25), making T lymphocytes susceptible to
IFN--mediated apoptosis (5, 6, 19), our findings for
ßGBP effects suggest that up-regulation of IFN-R is a general
event related to T cell cycle arrest.
The ßGBP-dependent up-regulation of the two IFN-R chains and the
subsequent bias of T cells toward IFN--mediated apoptosis opens up a
new, molecularly defined way in which the fate of T cells encountering
IFN- is decided. Indeed, ßGBP, can be seen as a factor concurring
in the IFN- switch of the T cell program from proliferation to
apoptosis. Control of this switch may be of importance in many
immunologic scenarios, especially in autoimmune diseases, where the
tendency of Th lymphocytes to differentiate into Th1 cells and produce
large amounts of IFN- has already been indicated as a major
pathogenic mechanisms (26). The IFN-R complex is
functional in differentiated human Th1 and Th2 clones, with IFN-
mediating their autocrine or paracrine apoptosis only when its
ß-chain is highly expressed on their membrane (19). The
ability of ßGBP to convert IFN- signals from proliferative to
apoptotic could be a new way of switching off sustained activation of
Th1 lymphocytes in autoimmune diseases.
Modulation of ß-chain is a critical event during Th1/Th2
differentiation (27, 28, 29). The antiproliferative effect of
IFN- on Th2 cells (30) is due to their ability to
express ß-chain. Lack of this expression would seem to make Th1 cells
resistant to IFN- by preventing transduction of its signals
(27, 28). Present data suggest that ßGBP may play a
physiologic role in Th1/Th2 differentiation by favoring the
IFN--mediated apoptosis of Th cells with high levels of ß-chain
expression.
These biologic effects of ßGBP position it as a new member of the
cytokine network. Cytokines act at low concentration and through
specific receptor interaction. The concentration range (27 x
10-11 -27 x 10-9 M) at which ßGBP
functions independently from the sugar binding we used is close to the
physiologic concentration at which cytokines act (10-9
-10-12 M) (31), rather than those of
lectinic proteins (12, 32). In addition, our data showed
that the effects of ßGBP are due to a specific receptor binding
distinct from a more general carbohydrate interaction, since the
effects of ßGBP are not affected by the addition of saturating
amounts of lactose. These data obtained on T lymphocytes confirm those
previously reported on fibroblasts showing that ßGBP-induced
inhibition of the exit of cells from G0 and G2
is not due to its lectin properties, since it binds with high affinity
(Kd of 10-10 M) to 
5 x
104 receptor sites per cell through molecular domains other
than those that link saccharide determinants (7).
In conclusion, the present data suggest that the LGALS1 gene
product has different mechanisms of action. It exists as both a dimer
and a monomer in a dose-dependent equilibrium (13). The
dimeric form is expressed in peripheral lymphoid tissues and the thymus
(11, 12, 32) and may be therapeutically active against
autoimmune diseases (15, 16) through direct deletion of
reactive T cells (16). The finding that this form directly
induces the apoptosis of activated T lymphocytes (12) and
thymocytes (32) further supports this possibility. In
contrast, we demonstrated that the monomer does not directly induce the
apoptosis of activated T cells, but biases them to an apoptotic
response to IFN-. Perillo et al., too, have shown that the dimer
induces apoptosis in T cells at a concentration 1 x
105-fold higher than that we used to obtain the
ßGBP-induced cell cycle arrest (12). Our dose was one at
which the equilibrium shifts toward the monomeric form. The 400 ng/ml
concentration (corresponding to 27 x 10-9 M) is
4000-fold lower than the estimated Kd of the
dimer to monomer (7 x 10-6 M) (13).
Therefore, our data strongly suggest that the monomeric form, although
it retains sugar-binding ability (13), can act in a
cytokine-like manner.
The immunomodulatory effects of the LGALS1 gene product may be finely controlled in vivo through regulation of the equilibrium between the cytokine-like monomeric form and the lectin-like dimeric form (14).
These findings thus provide further evidence that IFN-R expression
is modulated by a negative regulator of cell growth and point the way
to the elaboration of new therapeutic strategies for manipulating the
growth of autoimmune T cells by using ßGBP to force their
IFN--mediated apoptosis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprints requests to Dr. Francesco Novelli, Dipartimento di Scienze Cliniche e Biologiche, Ospedale S. Luigi Gonzaga, 10043 Orbassano, Italy. E-mail address:
3 Abbreviation used in this paper: ßGBP, ß-galactoside binding protein; LGALS1, lectin, galactoside-binding, soluble 1 (gene); IFN-R, -chain of IFN-R; IFN-Rß, ß-chain of IFN-R; PI, propidium iodide; TdT, terminal deoxynucleotidyl transferase.
Received for publication March 30, 1998. Accepted for publication April 23, 1998.
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A. Allione, P. Bernabei, M. Bosticardo, S. Ariotti, G. Forni, and F. Novelli Nitric Oxide Suppresses Human T Lymphocyte Proliferation Through IFN-{gamma}-Dependent and IFN-{gamma}-Independent Induction of Apoptosis J. Immunol., October 15, 1999; 163(8): 4182 - 4191. [Abstract] [Full Text] [PDF]
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 G. A. Rabinovich, G. Daly, H. Dreja, H. Tailor, C. M. Riera, J. Hirabayashi, and Y. Chernajovsky Recombinant Galectin-1 and Its Genetic Delivery Suppress Collagen-induced Arthritis via T Cell Apoptosis J. Exp. Med., August 2, 1999; 190(3): 385 - 398. [Abstract] [Full Text] [PDF]
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 R.-Y. Yang, D. K. Hsu, L. Yu, J. Ni, and F.-T. Liu Cell Cycle Regulation by Galectin-12, a New Member of the Galectin Superfamily J. Biol. Chem., June 1, 2001; 276(23): 20252 - 20260. [Abstract] [Full Text] [PDF]
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