Laboratory of Biologic Cancer Therapy, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
Correspondence: Dr. Peter S. Goedegebuure, Department of Surgery, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: goedegep{at}msnotes.wustl.edu
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-chain signaling
cytokines, IL-2, IL-4, and IL-7, in activated T lymphocytes, whereas
the inflammatory cytokines including TNF-
and IFN- did not.
Galectin-3 expression and proliferation were down-regulated by
withdrawal of IL-2 and gamma irradiation. Anti-sense but not sense
phosphorothioated oligonucleotides for galectin-3 inhibited galectin-3
expression and blocked proliferation of T cells significantly. This
study suggests that up-regulation of galectin-3 plays an important role
in proliferation of activated T lymphocytes.
Key Words: common -chain signaling cytokines • proliferation • anti-sense
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Galectin-3 has several potential roles on immune cells in inflammatory processes. It down-regulates interleukin (IL)-5 gene expression in human eosinophils, the eosinophilic cell line EoL-3, peripheral blood mononuclear cells (PBMC), and in Ag-specific CD4+ T lymphocytes [6 ]. Although the expression and function of galectin-3 in several types of immune cells have been shown, not much is known about galectin-3 in relation to T lymphocytes.
Recently, it was shown that the human leukemia cell line, Jurkat-transfected with the galectin-3 gene, displayed higher growth rates than control transfectants and showed resistance to apoptotic signals [7 ]. However, because Jurkat cells do not express galectin-3, it is not clear what the exact function of galectin-3 is in normal cells under physiological conditions. It has not been shown whether galectin-3 is expressed in T lymphocytes, because immunohistochemistry on lymphoid organs and various lymphoid cell lines including EL4 cells by Northern blot analysis did not detect galectin-3 [8 , 9 ]. Thus, we investigated the expression and function of galectin-3 in primary T lymphocytes.
The data presented here demonstrate that galectin-3 is expressed in
activated T lymphocytes but not in resting T cells. The expression of
galectin-3 was enhanced by common -chain signaling cytokines, such
as IL-2, IL-4, and IL-7, and correlated with the proliferation of
activated T lymphocytes. Galectin-3 is located predominantly in
intracellular compartments but not on the surface and is secreted by
activated T lymphocytes. These findings on the presence and secretion
of galectin-3 in activated T lymphocytes may describe the roles of
galectin-3 in T lymphocytes and explain galectin-3-mediated
interactions between T lymphocytes and other immune cells.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lymphocyte preparation and culture
Spleen cells, lymph node lymphocytes, or thymocytes from C57BL/6
mice were prepared by mechanical disruption and hypotonic lysis of red
blood cells. To remove adherent cells, the cell suspensions were first
passed through nylon wool and subsequently incubated in a culture flask
for 2 h. The nonadherent cells were centrifuged on Lympholyte®-M
(Cedarlane, Ontario, Canada). After washing twice with Hanks’ balanced
saline solution (HBSS), the cells were used for surface or
intracellular staining and flow cytometry analysis. Typically,
5x107 spleen cells were retrieved from a single mouse.
Spleen cells were cultured in 2 ml culture medium (CM) in a 24-well
plate at 37°C in a 5% CO2 incubator. Culture medium was
RPMI 1640 containing 10% heat-inactivated fetal bovine serum (FBS), 2
mM fresh L-glutamine, 1 mM sodium pyruvate, 0.1 mM nonessential amino
acids, 100 international units (IU)/ml penicillin, 100 µg/ml
streptomycin (all from Bio-Whittaker, Walkersville, MD), and
5x10-5 M 2-mercaptoethanol (Sigma).
Activation of T lymphocytes
Spleen cells were activated by adding 5 µg/ml concanavalin A
(Con A; Sigma) or by placing the cells onto solid-phase anti-CD3 mAb
(hybridoma 145-2C11; ATCC)-coated flasks [10
]. After 2
days, the viable cells were purified by Lympholyte®-M and then
cultured at 1x106 cells/well in 2 ml CM in the absence or
presence of human recombinant (hr)IL-2 (a gift from Amgen, Thousand
Oaks, CA), granuloctye-macrophage colony-stimulating factor (GM-CSF),
tumor necrosis factor (TNF)-, IL-10, murine rIL-4, IL-7, interferon
(IFN)-, and ultrapure transforming growth factor (TGF)-ß (all from
Genzyme, Cambridge, MA) in 24-well plates. The number and viability of
cells were determined by the trypan blue exclusion test.
Flow cytometry analysis
For intracellular staining, cells were fixed in 4%
paraformaldehyde in phosphate-buffered saline (PBS) for 15 min at
4°C, washed twice, resuspended in HBSS, and then permeabilized by
incubation in BSS containing 0.1% saponin. The cells were incubated
with 2 µg anti-galectin-3 mAb for 30 min at 4°C and washed twice
with saponin-containing buffer. Staining was performed with incubation
in 0.5 µg anti-rat IgG-fluorescein isothiocyanate (FITC). After
intracellular staining, cell-surface staining was performed with 1 µg
anti-mouse CD4-phycoerythrin (PE), CD8-PE, or CD19-PE
(PharMingen, San Diego, CA). For propidium iodide (PI)-staining
analysis, cells were fixed in ice-cold 70% ethanol followed by
overnight incubation at -20°C. Cells were stained with PBS
containing 50 µg/ml PI, 0.1% Triton X-100, 0.5 mM
ethylenediaminetetraacetate (EDTA), and 50 µg/ml RNase A (Sigma) for
60 min at room temperature. The bromodeoxyuridine (BrdU, PharMingen)
incorporation assay was performed according to the manufacturer’s
instruction. Briefly, cells were incubated with BrdU (10 µM) for
2 h and treated with DNase (300 µg/ml). Incorporated BrdU was
labeled by 1 µg anti-BrdU Ab-PE and stained with 2 µg
anti-galectin-3 mAb and 1 µg anti-rat IgG-FITC. Flow cytometry
analysis of stained lymphocytes was performed on an Epics C cytometer
(Coulter, Hialeah, FL).
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS/PAGE) and Western blot analysis
SDS/PAGE was carried out on 12% or 14% polyacrylamide gels by
the method of Laemmli [11
]. Briefly, cells were lysed in
buffer consisting of 1% Triton X-100, 10 mM Tris (pH 7.4), 0.15 M
NaCl, 10 µg/ml aprotinin, 10 µg/ml leupeptin, and 25 µg/ml
phenylmethylsulfonyl fluoride (PMSF) for 5 min on ice. Cells were
centrifuged at 13,000 rpm for 10 min at 4°C, and the supernatant was
collected. An aliquot was mixed with equal parts of 2 x sample
loading buffer and was denatured at 100°C for 5 min. Protein
concentration in the lysates was determined using a protein assay kit
(Bio-Rad, Hercules, CA), and each sample was loaded at a concentration
of 100 µg/lane in the gel. After electrophoresis, proteins were
transferred onto nitrocellulose membranes and probed with 1.3 µg/ml
anti-galectin-3 mAb or 1 µg/ml anti-mouse CD3
Ab (Santa Cruz
Biotechnology, Santa Cruz, CA) and appropriate secondary antibodies.
The blot was developed by chemiluminescence (Amersham, Arlington
Heights, IL).
Detection of galectin-3 by using asialofetuin-Sepharose 4B
Asialofetuin was immobilized on CNBr-activated Sepharose 4B
according to the manufacturer’s instructions. To investigate the
binding affinity of galectin-3 to asialofetuin, 1 x
107-activated T lymphocytes were lysed. After
centrifugation at 13,000 rpm for 10 min at 4°C, the supernatant was
incubated with 10 µl asialofetuin-Sepharose 4B in the absence or
presence of 250 mM lactose or sucrose with bidirectional agitation at
4°C for 1 h. After the beads were washed three times with the
lysis buffer, the bound and subsequently eluted protein was analyzed by
Western blot using anti-galectin-3 mAb.
Subcellular localization of galectin-3
Activated T lymphocytes were centrifuged, washed in HBSS, and
resuspended at a cell density of 5 x 107 cells/ml in
lysis buffer containing 10 mM Hepes (pH 7.4), 38 mM NaCl, 25 µg/ml
PMSF, 1 µg/ml leupeptin, and 1 µg/ml aprotinin [12
].
The cell suspension was homogenized using a Dounce homogenizer and
centrifuged at 900 g to pellet the nuclei. The postnuclear
supernatant was centrifuged at 130,000 g to pellet the
membrane compartments. The membrane and nuclear pellet were resuspended
in a volume of Triton X-100 containing lysis buffer equal to that of
cytosolic supernatant. The relative expression of galectin-3 and CD3
in cytosolic, crude membrane, and nuclear fractions was analyzed by
Western blot.
Anti-sense studies
Purified phosphorothioated sense and anti-sense
oligonucleotides were designed for the inhibition of galectin-3
expression in activated T lymphocytes. Sense oligonucleotides (5' AGG
AAA ATG GCA GAC AGC) specific for mouse galectin-3 gene
[9
] and the complementary anti-sense oligonucleotides
(5' GCT GTC TGC CAT TTT CCT) were synthesized and purified by Oligos
Etc. (Wilsonville, OR). Activated T lymphocytes pretreated with Con A
were prepared by Lympholyte®-M and then cultured with sense or
anti-sense oligonucleotides. The efficacy of oligonucleotides was
determined by flow cytometry analysis. Thymidine incorporation was
assessed after exposure to 1 µCi [3H] thymidine (ICN
Pharmaceuticals, Irvine, CA) during the last 18 h of culture. For
apoptosis analysis, annexin-V and PI staining were used. Cells were
stained using Annexin-V FITC kit (BioSource International, Camarillo,
CA) and analyzed by an Epics C cytometer (Coulter).
Statistical analysis
Each experiment was performed at least three times. The
statistical significance of the experimental data was evaluated by
Student’s t-test. P < 0.05 was accepted as
statistically significant.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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 View larger version (61K): [in a new window] |
Figure 1. Galectin-3 is expressed in activated T lymphocytes. Murine spleen cells
were double-stained for CD4 or CD8 (cell surface) and for galectin-3
(intracellular). Analysis was performed by flow cytometry. Resting
splenic CD4+ or CD8+ T lymphocytes do not
express intracellular galectin-3 (A and B). CD4+ and
CD8+ T lymphocytes activated with Con A (5 µg/ml) for
48 h and then cultured in IL-2-containing media (100 IU/ml) for
96 h express intracellular galectin-3 (C and D).
|
 View larger version (23K): [in a new window] |
Figure 2. Activation is required for galectin-3 expression in activated T
lymphocytes. Spleen cells at 2 x 106 cells/ml were
cultured in the absence or presence of plate-bound anti-CD3 mAb
(145-2C11) or 5 µg/ml Con A for 48 h and then cultured in the
absence or presence of 100 IU/ml IL-2. Cells were stained
intracellularly with anti-galectin-3 mAb followed by anti-rat IgG-FITC
and assayed by flow cytometry. Mean fluorescence intensity (MFI) and
percent-positive of each sample were obtained through subtraction of
value obtained using galectin-3 mAb from the value obtained using rat
IgG as primary Ab. *, P < 0.05; **, P < 0.01 as compared with the medium alone.
|
-chain signaling
cytokines-chain signaling cytokines, such
as IL-4 and IL-7, enhanced galectin-3 expression significantly
(P<0.01), whereas other cytokines including inflammatory
cytokines, IFN-, TNF-, GM-CSF, TGF-ß, and IL-10 did not affect
the expression level (Table 1
). Furthermore, IL-2, IL-4, and IL-7 increased the viability of
activated T lymphocytes significantly, whereas the other cytokines had
no effect. The effects of the common -chain signaling cytokines on
galectin-3 expression and T cell viability were similar for Con A- and
anti-CD3 mAb-activated T lymphocytes. These observations suggest that
activated T lymphocytes require specific cytokines, such as IL-2, IL-4,
or IL-7, for survival, which is associated with an increased expression
of galectin-3. |
View this table: [in a new window] |
Table 1. Effects of Various Cytokines Including IL-2, IL-4, and IL-7 on
Intracellular Galectin-3 Expression and Viability of Activated T
Lymphocytes
|
 View larger version (20K): [in a new window] |
Figure 3. Galectin-3 is expressed in activated T cells and has binding affinity
to asialofetuin with lactose specificity. (A) Western blot analysis of
cell lysates using anti-galectin-3 mAb. T cells were stimulated with 5
µg/ml Con A and incubated in IL-2-containing medium. (B) Enhancement
of galectin-3 in T cells activated with 5 µg/ml Con A for 48 h.
Analysis was started when T cells were transferred into medium plus 100
IU/ml IL-2 (lane 1, t=0). (C) Galectin-3 molecules from activated T
lymphocytes were assayed for their specificity for galactoside
residues. Total cell lysate from 2.5 x 106 cells was
analyzed in lane 1. Lysates from 1 x 107 cells were
mixed with asialofetuin-conjugated beads (lanes 2–4) in the absence
(lane 2) or presence (lane 3) of lactose or sucrose (lane 4) at 250 mM.
The bound and subsequently eluted protein was probed with
anti-galectin-3 mAb in Western blot.
|
 View larger version (27K): [in a new window] |
Figure 4. Galectin-3 is expressed predominantly in intracellular compartments.
The surface expression level of galectin-3 was measured by flow
cytometry in thymocytes, resting spleen cells, T lymphocytes activated
for 1 week with Con A/IL-2, and pancreatic tumor cells, Capan I, as
positive control (A). The activated T lymphocytes were incubated in the
presence of 100 U/ml IL-2. Cell lysates were separated into nucleus,
cytosolic, and membrane fractions and analyzed by Western blot with
anti-galectin-3 mAb or anti-CD3 Ab (B).
|
 View larger version (57K): [in a new window] |
Figure 5. Galectin-3 is secreted by activated T lymphocytes spontaneously, and
the secretion can be enhanced by calcium ionophores. Activated T
lymphocytes stimulated with Con A/IL-2 for 1 week were incubated in
medium alone (lane 1), with calcium ionophore A23187 (lanes 2+3) or
with ionomycin (lanes 4+5) for 3 h. Each supernatant was harvested
by centrifugation and then assayed for the amount of secreted
galectin-3 molecules by Western blot analysis.
|
 View larger version (18K): [in a new window] |
Figure 6. IL-2 withdrawal decreases galectin-3 expression and viability in
activated T lymphocytes. Activated T lymphocytes, which were
pre-activated with 5 µg/ml Con A and then cultured in IL-2-containing
media (100 IU/ml) for more than 5 days, were used. After washing the
cells twice with PBS, the cells were incubated in medium alone for
48 h. The viability was determined by trypan blue exclusion, and
MFI was calculated after intracellular staining (A). The percentage of
cells with hypodiploid DNA content was determined by flow cytometry
analysis after staining with 50 µg/ml PI (B).
|
-chain signaling cytokines,
IL-2, IL-4, and IL-7, showed different effects on cumulative cell
number, whereas these cytokines showed a similar effect on T cell
viability from days 2–6 after activation of lymphocytes. At the same
time, galectin-3 expression correlated with an increase of the
cumulative cell number. Although at day 2, the cells treated with IL-4
were similar in cell number and galectin-3 expression as those treated
with IL-2 at days 4 and 6, cell number and galectin-3 expression were
higher in the IL-2-supplemented culture than in the IL-4- or
IL-7-supplemented cultures (Fig. 7
). Although the viability of IL-7-supplemented cultures was similar
to that of IL-2- or IL-4-supplemented cultures (88–95%), the cells
treated with IL-7 did not increase in cell number and galectin-3
expression (Fig. 7)
.
 View larger version (18K): [in a new window] |
Figure 7. Increase of cumulative cell number is associated with galectin-3
expression. Activated T lymphocytes stimulated with Con A (5 µg/ml)
for 48 h were cultured in the absence or presence of 100 IU/ml
IL-2, 250 U/ml IL-4, or 250 U/ml IL-7 for 6 days. Each
cytokine-containing medium was replaced with new medium containing an
equal amount of cytokine every 2 days. The cell number was counted by
trypan blue exclusion (A), and galectin-3 staining (B) was performed as
described in Materials and Methods.
|
 View larger version (23K): [in a new window] |
Figure 8. Irradiation blocks T cell proliferation and decreases galectin-3
expression. Activated T lymphocytes, which were incubated in 100 IU/ml
IL-2, 250 U/ml IL-4, or 250 U/ml IL-7 for 6 days after Con A
stimulation, received 1000 rad irradiation. The cells were cultured
24 h after irradiation and measured for intracellular galectin-3
by flow cytometry. The number represents MFI.
|
1.6x105,
P<0.05 at 5x105 cells/ml), but sense
oligonucleotides did not (Fig. 9B) .
 View larger version (20K): [in a new window] |
Figure 9. Inhibition of galectin-3 expression by anti-sense oligonucleotides
decreases the proliferation of activated T lymphocytes. Activated T
lymphocytes pretreated with Con A were incubated in the presence of
IL-2. The cells were treated with 10 µM sense or anti-sense
oligonucleotides for 2 days and then analyzed for galectin-3
expression. The number represents MFI (A). Activated T lymphocytes were
cultured in 10 µM concentration of sense or anti-sense
oligonucleotides at various cell concentration for 2 days (B). The
[3H]-thymidine incorporation was measured after exposure
to 1 µCi [3H] thymidine during the last 18 h of
culture. Results are normalized to control cells, grown in medium
only.
|
 View larger version (43K): [in a new window] |
Figure 10. Galectin-3 is expressed at higher level in BrdU-positive cells than in
BrdU-negative cells. Activated T lymphocytes pretreated with ConA were
cultured in the absence or presence of IL-2 (100 U/ml) for 2 days.
Cells were incubated with BrdU at a concentration of 10 µM for the
last 2 h and labeled with anti-BrdU Ab-PE, anti-galectin-3 mAb and
anti-rat IgG-FITC.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-chain signaling cytokines
such as IL-2, IL-4, and IL-7. To investigate the function of galectin-3 in activated T lymphocytes, we designed anti-sense oligonucleotides specific for murine galectin-3 [9 ]. Anti-sense oligonucleotides inhibited the up-regulation of galectin-3 by IL-2, whereas sense oligonucleotides tested at the same concentration did not affect galectin-3 expression. Previous results demonstrated that galectin-3 transfected into Jurkat cells modulated the growth and apoptosis of Jurkat cells [7 ]. Thus, proliferation and apoptosis analysis were performed by thymidine incorporation, annexin-V, and PI staining in the presence of sense or anti-sense oligonucleotides. Anti-sense oligonucleotides inhibited the proliferation of activated T lymphocytes significantly at various cell concentrations (Fig. 9) . However, we did not detect any evidence of apoptosis in spite of the multiple attempts.
Several possibilities might explain this discrepancy. First, it is possible that the effect of galectin-3 down-regulation by anti-sense oligonucleotides may be overcome by anti-apoptotic molecules, such as bcl-2 and bcl-xL, which are increased sharply by IL-2 in activated T lymphocytes [15 ]. Although binding affinity of galectin-3 for bcl-2 was demonstrated [7 ], it is not clear that bcl-2 binds galectin-3 functionally in activated T lymphocytes. Second, there are significant differences between the two experimental systems. Whereas Jurkat cells do not express galectin-3 naturally, activated T lymphocytes express significant amounts of various anti-apoptotic molecules. Thus, it is possible that anti-apoptotic effects observed in Jurkat cells may not appear in activated T lymphocytes treated with IL-2, because Jurkat cells are well-known to be sensitive to various apoptotic signals. Taken together, our results suggest that galectin-3 is involved in proliferation of activated T lymphocytes mainly, although it is still possible that galectin-3 has anti-apoptotic effects.
Because galectin-3 had been found on the surface of
thioglycollate-elicited macrophages, it is known to be related with
inflammation [1
, 13
]. Surprisingly,
galectin-3 expression in T cells is increased sharply by common
-chain signaling cytokines, such as IL-2, IL-4, and IL-7, but not by
various inflammatory cytokines including IFN- and TNF-. This
observation suggests that galectin-3 may be involved in another,
physiological immune response including activated lymphocytes. The
observation that common -chain signaling cytokines increase the
viability and proliferation of activated T lymphocytes is consistent
with previous studies [15
, 16
].
Galectin-3 is a member of the family of animal lectins with ß-galactoside binding affinity. Although galectin-1 and galectin-3 are included in the same family, the two proteins demonstrated different effects on lymphocytes. Recombinant human galectin-1 induces apoptosis in thymocytes and activated T lymphocytes and inhibits IL-2 production [17 , 18 ].
We demonstrated here that activated T lymphocytes secreted galectin-3 spontaneously, and the secretion could be enhanced by calcium ionophores. To evaluate the effects of secreted galectin-3, we measured the proliferation and viability of activated T lymphocytes in the presence of anti-galectin-3 mAb or control antibody. However, we did not detect significant effects of anti-galectin-3 mAb at a range of 1–10 µg/ml (unpublished results). The expression level of intracellular galectin-3 in viable cells treated with and without ionophores was similar (unpublished results). Therefore, it seems that the rate of synthesis of galectin-3 has increased, but the newly synthesized protein does not accumulate in the cells. The amount of secreted galectin-3 was decreased rapidly from the cells after IL-2 withdrawal by Western blot analysis (unpublished results). Therefore, IL-2 withdrawal-induced apoptosis is unlikely a result of secreted galectin-3.
Galectin-3 has been shown to be an adhesion molecule that binds to the extracellular matrix including laminin [19 ]. Galectin-3 is expressed on the surface of macrophages and tumor cells and closely correlated with the formation of tumor metastasis [5 , 13 , 20 ]. To investigate the presence of surface galectin-3 on T lymphocytes, we measured the expression level on thymocytes, resting spleen cells, and activated T lymphocytes by flow cytometry analysis. In our study, no galectin-3 molecules were detected on the surface of lymphocytes in spite of the multiple attempts. However, the finding that galectin-3 is released from activated T cells spontaneously suggests that secreted galectin-3 may be involved in the adhesion of activated T lymphocytes to other immune cells.
Intracellular galectin-3 in activated T lymphocytes is distributed in
the nucleus, cytosol, and membrane compartments. The nuclear and
cytosolic localization of galectin-3 was demonstrated previously
[2
, 21
]. In our study, galectin-3 was
detected in membrane fractions as well as nuclear and cytosolic
fractions. CD3 molecules used as control were detected in nuclear
and membrane fractions (Fig. 4) . The observation that CD3 molecules
are localized in the nucleus is in agreement with previous observations
by Nakano et al. [22
]; CD3 is present in
the nuclear fraction, and the expression is increased upon T cell
activation.
This study is the first to show the expression and function of
galectin-3 in normal T lymphocytes. In summary, galectin-3 expression
is induced by activation signals including TcR-mediated activation and
enhanced by common -chain signaling cytokines, IL-2, IL-4, and IL-7.
Galectin-3 is located predominantly in intracellular compartments not
on the cell surface, and intracellular galectin-3 plays an important
role in the proliferation of activated T lymphocytes.
Received June 28, 2000; revised November 22, 2000; accepted November 22, 2000.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax, bcl-xs) gene expression Eur. J. Immunol. 26,294-299[Medline] chain of the T cell receptor complex J. Biol. Chem. 271,6483-6489This article has been cited by other articles:
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