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* Laboratory of Immunology, Department of Clinical Biochemistry, Faculty of Chemical Sciences, National University of Córdoba, and
Laboratory of Immunogenetics, Faculty of Medicine, and
Department of Biological Chemistry, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina
Correspondence: Dr. Adriana Gruppi, Departamento de Bioqu
ica Cli
ica, Facultad de Ciencias Quicas, Universidad Nacional de Córdoba 5000, Cordoba CC61, Argentina. E-mail: agruppi{at}bioclin.fcq.unc.edu.ar
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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cytokine
production. Hence, the present study describes a potential mechanism by
which B cells can regulate T-cell function and survival.
Key Words: B lymphocytes • galectin-1 • Trypanosoma cruzi
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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134 amino acids, participates in key immunoregulatory
processes [5
6
7
8
9
]. It has been shown to induce apoptosis
of activated, mature T cells and particular subsets of nonselected and
negatively selected CD4lo CD8lo immature
thymocytes [5
, 6
, 10
]. We have
recently validated this observation in vivo using gene and protein
therapy strategies that showed that GAL-1 is able to suppress the
inflammatory and autoimmune responses via T-cell apoptosis in an
experimental model of rheumatoid arthritis [8
]. It has
recently been shown that GAL-1 antagonizes immunological functions that
require processive T-cell receptor (TCR) transduction and
costimulation, such as cytokine production, but permits those functions
that require only partial TCR 
-chain phosphorylation, such as
apoptosis [11
]. The presence of GAL-1 has been identified within the central and peripheral lymphoid organs in thymic epithelial cells [12 ], effector T cells [7 , 13 ], and activated macrophages [6 , 14 ]. However, expression and function of this ß-galactoside-binding protein within the B-cell compartment is a matter of controversy [13 , 15 ] and still remains to be ascertained. In the present study, we investigated the expression of GAL-1 on B cells and its immunoregulatory properties using Trypanosoma cruzi infection as a natural model of in vivo B-cell activation.
T. cruzi, the hemoflagellate protozoan parasite that causes Chagas’ disease, infects humans and other mammals primarily in Latin America [16 ]. The acute phase of the infection is characterized by an intense parasitemia accompanied by high cellularity in the lymphoid organs and a polyclonal B-cell activation [17 , 18 ].
Herein, we report the identification, purification, and regulated
expression of GAL-1 on highly activated B cells. This
ß-galactoside-binding protein produced by activated B cells was found
to induce T-cell apoptosis and influence interferon (IFN)-
production. Our study suggests an alternative immunoregulatory
mechanism triggered by B cells to shut off T-cell effector functions.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antibodies
The anti-GAL-1 polyclonal antibody (Ab) was kindly provided by
J. Hirabayashi and K. Kasai [19
]. Phycoerythrin-labeled
anti-mouse CD19, fluorescein isothiocyanate (FITC)-labeled anti-mouse
CD3, and FITC-labeled anti-mouse Mac-1 monoclonal antibodies (mAbs), as
well as the anti-mouse CD40 mAbs, were purchased from PharMingen (San
Diego, CA). The F(ab')2 anti-mouse µ mAb was
purchased from Cappel (Division of ICN Pharmaceuticals, Costa Mesa,
CA). Horseradish peroxidase-conjugated anti-rabbit immunoglobulin (Ig)
G was purchased from Sigma. Antibodies for cytokine determination
[IFN-, and interleukin (IL)-10] were provided by PharMingen.
Infection with T. cruzi
Mice, 6–8 weeks old (Comisión Nacional de Energía
Atómica, Buenos Aires, Argentina), were infected
intraperitoneally with 500 trypomastigotes from T. cruzi
(Tulahuén strain) as described by Zuñiga et al.
[20
]. Uninfected, normal littermates were used as
controls. Fifteen days after infection, the mice were killed by
cervical dislocation, and spleens were obtained.
Cell preparation and Percoll separation
Cell suspensions from spleens of infected and normal mice were
prepared by homogenization in a tissue grinder. Erythrocytes were lysed
by brief incubation in red blood cell lysis buffer (Sigma). Spleen
mononuclear cells (SMCs) were washed twice and resuspended in complete
RPMI 1640 medium containing 10% FCS, 50 µM ß-2-mercaptoethanol,
and 40 µg/mL of gentamicin.
For B-cell purification, monocytes were removed from SMCs by plastic adherence (1 h of incubation at 37°C in 10-cm-diameter petri dishes) and T cells were depleted by magnetic cell sorting using anti-Thy 1.2-coated magnetic beads (Dynal, Compiégne, France) according to the manufacturer’s instructions. This procedure yielded >95% CD19+ B cells, as determined by fluorescein-activated cell sorter (FACS) analysis. B cells obtained from T. cruzi-infected and normal mice were fractionated in low- and high-density B cells to obtain cells with different activation grades. Briefly, purified B cells were layered on a Percoll gradient and centrifuged for 15 min at 4°C and 1,200 g. The cells localized at the upper phase (50–60% Percoll interphase) corresponded to low-density (large) B cells. The cells found at the 60–66% Percoll interphase corresponded to high-density B cells (small B cells).
Flow cytometry analysis
To determine the purity of the B-cell preparation, freshly
isolated B cells were washed three times with Hanks’ balanced saline
solution containing 1% bovine serum albumin and 0.1%
NaN3 and preincubated with anti-mouse CD32/CD16
mAb for 1 h at 4°C to block nonspecific trapping of Ig through
Fc receptors. Cells were then incubated with phycoerythrin-labeled
anti-mouse CD19, FITC-labeled anti-mouse CD3, and FITC-labeled
anti-mouse Mac-1 mAbs (1 µg/106 cells) for 30 min at
4°C and analyzed in a Cytoron Absolute® cytometer (Ortho Diagnostic
Systems, Raritan, NJ).
To analyze intracellular GAL-1, cells were washed twice and permeabilized overnight by incubation with 70% ethanol and further exposure to 0.05% Tween 20 for 10 min at room temperature. Cell surface GAL-1 expression of nonpermeabilized B cells was analyzed in parallel. The cells were then incubated with a 1:100 dilution of the anti-GAL-1 Ab and a 1:100 dilution of an FITC-labeled anti-rabbit IgG (Sigma) and processed for FACS analysis as described above. Results were analyzed using the WinMDi software (http://facs.scripps.edu/software.html).
Purification of GAL-1 from activated B cells
Gal-1 was purified from activated B cells as previously
described [6
, 21
]. Briefly, infected B
cells (2 x107) were washed twice with
phosphate-buffered saline (PBS) and lysed in 1 mL of an ice-cold buffer
solution consisting of PBS supplemented with 2 mM dithiothreitol and 2
mM EDTA containing protease inhibitors (1 mM phenylmethylsulfonyl
fluoride, 1 mM benzamidine, 2 mM sodium orthovanadate, 2 µg/mL of
aprotinin, and 2 µg/mL of leupeptin), 1% Nonidet P-40, and 50 mM
lactose. The material was then subjected to affinity chromatography on
a lactosyl-agarose matrix and specifically eluted with PBS supplemented
with 2 mM dithiothreitol and 2 mM EDTA plus 100 mM lactose. Fractions
monitored for protein content at 280 nm that displayed hemagglutinating
activity [22
] were concentrated by ultrafiltration using
Ultrafree-15 centrifuge filter tubes (Millipore Corp., Bedford, MA).
For biological assays, GAL-1 was further subjected to fast protein
liquid chromatography on a Superose 12 HR 10/30 column (Pharmacia LKB,
Uppsala, Sweden) to avoid potential contamination with
higher-molecular-weight ß-galactoside-binding proteins such as GAL-3
[21
, 23
].
In vitro B-cell stimulation
B cells (2 x105/well) were cultured in a volume
of 2 mL in flat-bottom 24-well tissue culture plates (Corning
Glassworks, Corning, NY) for 18 h in the presence of LPS
(20µg/mL), F(ab')2 anti-µ (10 µg/mL), anti-CD40 (7.5
µg/mL), or F(ab')2 anti-µ plus anti-CD40. Cells
cultured in medium alone were used as an in-vitro-stimulation control.
To investigate GAL-1 secretion, serum-free conditioned medium from B
cells cultured for 18 h in the presence of F(ab')2
anti-µ plus anti-CD40 was 20-fold concentrated and analyzed by
Western blot analysis using the specific polyclonal Ab.
SDS-PAGE and Western blot analysis
Sodium dodecyl sulfate-polyacrylamide gel electrophoresis
(SDS-PAGE) was performed in a Miniprotean II electrophoresis apparatus
(Bio-Rad) as described by Laemmli [24
]. Briefly, lysates
corresponding to stimulated and nonstimulated B cells from normal or
infected donors (100 µg of protein each) were diluted in sample
buffer and resolved on a 15% separating polyacrylamide slab gel. After
electrophoresis, the separated proteins were transferred onto
nitrocellulose membranes and probed with a 1:1,000 dilution of the
anti-GAL-1 Ab. Blots were then incubated with 1 µg/mL of horseradish
peroxidase-conjugated anti-rabbit IgG, developed using enhanced
chemiluminescence detection, and finally exposed to Amersham Hyperfilm
(Uppsala, Sweden) for 3–5 min. Recombinant GAL (rGAL)-1 was used as a
positive control for immunodetection. Control of specific
immunoreaction was performed by incubation of the blots with a rabbit
preimmune serum without detecting any reactivity. The anti-GAL-1 Ab was
found to be monospecific because it did not recognize rGAL-3 in Western
blot assays. Prestained protein molecular-weight markers were run in
parallel.
To analyze the purity of the preparation after chromatography, the eluted fraction was resolved on a 10% Tricine gel by the method described by Schagger and von Jagow [25 ] and visualized by silver staining [26 ]. Immunodetection was performed as described above.
Apoptosis assay
To elucidate whether GAL-1 produced by infected B cells mediates
T- or B-cell apoptosis, both cell populations were exposed to the
action of this ß-galactoside-binding protein. T cells
(2x106 per well) obtained from SMCs depleted from B cells
by magnetic cell sorting using anti-B220-coated magnetic beads (Dynal)
were cultured for 18 h in the presence of medium alone or with
concanavalin A (Con A) (7.5 µg/mL). A purified B-cell population
obtained as described above (2 x106 cells per well)
was cultured for 18 h with medium alone or in the presence of an
F(ab')2 anti-µ Ab (10 µg/mL). After 18 h of
incubation, resting and activated T and B cells were washed and exposed
to purified GAL-1 (3 µg/mL) for 6 h. Samples were finally
processed for apoptotic cell detection by propidium iodide staining by
the procedure described by Nicoletti et al. [27
]. The
hypodiploid DNA content was analyzed on a Cytoron Absolute® cytometer
(Ortho Diagnostic Systems).
Cytokine determination
After 24 h of cell culture, supernatants of resting and
activated T and B cells were collected for cytokine determination.
Levels of IFN- and IL-10 were detected by a capture enzyme-linked
immunosorbent assay following the procedure described by the
manufacturer (PharMingen). Each sample was assayed in triplicate, and
the values were expressed as mean optical densities read at 490 nm in
an enzyme-linked immunosorbent assay reader (Bio-Rad).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To assure the accurate identification of this protein and further explore its immunological properties and functions, GAL-1 was purified by affinity chromatography from activated B cells obtained from T. cruzi-infected mice as described in Materials and Methods. The hemagglutinating activity was determined in fractions of high optical densities. As we expected, the most potent inhibitors were sugars bearing a ß-D-galactoside configuration such as thiodigalactoside and lactose, resembling the carbohydrate-binding properties of other members of this protein family (data not shown). The active fraction was resolved by SDS-PAGE, showing two bands of 14,500 and 29,000 Da, which corresponded to the monomeric and dimeric forms of this protein (Fig. 1C , lane 2). The starting material, consisting of total proteins of activated B cells, was also resolved by SDS-PAGE (Fig. 1C , lane 1). To discriminate between the dimeric structure of GAL-1 and other members of the galectin family, a Western blot analysis was performed using the anti-GAL-1 Ab (Fig. 1D) . Both the 14,500- and 29,000-Da protein bands were recognized in the eluted active fraction by the specific Ab (lane 1). rGAL-1 was used as a positive-immunoreaction control (Fig. 1D , lane 2).
FACS analysis showed that this homodimeric protein was mainly localized at the cytosolic compartment (Fig. 2 ). As shown in Figure 2A 2a slight difference regarding cell surface GAL-1 expression was observed between nonpermeabilized CD19+ B cells from infected and control mice. When cells were permeabilized, a significant shift was observed in the B-cell population obtained from infected mice, as shown by the mean fluorescence values (Fig. 2B) . It should be pointed out that CD19+ B cells, which highly express GAL-1, present a blast morphology, as judged by the forward-scatter profile.
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To investigate whether B cells export this protein to the extracellular medium, B cells from infected mice were exposed to F(ab')2 anti- and anti-CD40 stimulation in serum-free conditioned medium. Supernatant was then collected, concentrated, and processed by Western blot analysis. Because GAL-1 was found to be present in FCS, serum-free conditioned medium was used in our experiment. A single protein band was detected in 20-fold-concentrated supernatants, indicating that GAL-1 is released to the extracellular milieu by highly activated B cells (Fig. 3E , lane 1). As a control, 20-fold concentrated cell culture medium (RPMI-1640) was processed in parallel (lane 2).
GAL-1 produced by activated B cells triggers apoptosis of activated
T cells and influences T-cell cytokine production
Because it has been well established that GAL-1 regulates
the viability of lymphoid cells [5
, 6
,
8
, 10
, 28
], we asked whether
GAL-1 produced by B cells was able to modulate T- or B-cell
apoptosis. Con A-activated T cells obtained from normal mice were
highly susceptible to the action of this ß-galactoside-binding
protein, as judged by the marked increase in the level of apoptosis in
comparison to activated T cells cultured in the absence of GAL-1
(Fig. 4A
). Moreover, GAL-1 induced lower levels of apoptosis of resting T cells. As clearly depicted in Figure 4A
, exogenously added GAL-1
purified from infected B cells was not able to regulate the apoptotic
threshold of resting or activated normal B cells.
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by activated T
cells (Fig. 4B)
. In contrast, the production of IL-10 was not
significantly affected by exposure to this protein. In broad agreement
with the experimental evidence revealed in the apoptotic assays, GAL-1
was not able to affect cytokine production by activated B cells (data
not shown). Taken together, our results raise the possibility that activated B cells influence T-cell survival and function through the expression of GAL-1.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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By virtue of ß-galactoside-specific recognition, GAL-1 has been implicated in immunomodulatory processes [6 , 8 , 9 ], cell growth regulation [7 , 13 , 29 , 30 ], apoptosis [5 , 6 , 10 , 31 ], inflammation [32 ], and cell adhesion [33 ]. The presence of GAL-1 within the B-cell compartment has been a controversial subject. Although Allen et al. [15 ] identified the presence of GAL-1 in Epstein-Barr virus-immortalized B-lymphoblastoid cells, Blaser et al. [13 ] did not specifically detect this endogenous lectin in LPS-activated B cells. Therefore, in the present study, we used B cells from T. cruzi-infected mice, which exhibit a high degree of activation as a consequence of the infection, to study the expression of this ß-galactoside-binding protein. Given that GAL-1 has pleiotropic effects on the immune system, this study may be important for understanding immune regulation during B-cell expansion in response to infection.
By using a monospecific anti-GAL-1 Ab, we investigated the presence of this endogenous lectin in the B-cell compartment. Western blot and FACS analyses revealed the expression of GAL-1 on activated B cells from T. cruzi-infected mice but not on resting B cells obtained from normal mice, revealing a strong association between GAL-1 expression and the cell activation state. The purified protein exhibited all the biochemical properties that are shared by the GAL-1 family: (1) it was retained and further eluted from a lactosyl-agarose matrix; (2) it showed hemagglutinating activity on rabbit erythrocytes which was specifically inhibited by saccharides bearing a ß-D-galactoside configuration; and (3) it showed two protein bands of 14,500 and 29,000 Da, corresponding to the monomeric and dimeric forms of this protein, when analyzed by SDS-PAGE.
Galectin expression has been reported to be highly susceptible to modulation by diverse stimuli such as sodium butyrate [34 ], viral infections [35 ], tumor suppressor genes [36 ], and inflammatory agents [37 ]. In this sense, we have reported a differentially regulated expression of GAL-1 on resident, inflammatory, and activated macrophages [6 , 14 ].
Because B lymphocytes are highly adaptive cells that are able to modify their behavior in response to different environmental signals, we wondered whether B-cell-specific stimuli could modulate the expression of this protein. For this purpose, we selected different stimuli that act at different levels of B-cell physiology, TI and T-cell-dependent (TD) signals. TI stimuli can be further subdivided into TI-1 stimuli, which are intrinsically mitogenic in the mouse (such as LPS), and TI-2 stimuli, which are mediated by cross-linking of cell surface Igs such as F(ab')2 anti-IgM Ab [38 ]. We observed that stimulation of resting B cells from normal mice with F(ab')2 anti-µ or activation by LPS induced a slight increase in GAL-1 expression.
Unlike in a TI response, during a TD response, signals are provided by direct contact with an activated T-helper cell via CD40 expressed on B cells and gp39 (CD40L) expressed on activated T cells [39 , 40 ]. To mimic a TD response, we stimulated B cells using an Ab reactive with CD40. This signal induced a significant increase in GAL-1 expression, as evidenced by the appearance of the 29,000-Da dimeric form of GAL-1 on B cells from normal mice. This result indicates that T cells cooperating with B cells via CD40/CD40L interaction may trigger an up-regulation of GAL-1.
The most striking finding of our study was that expression of GAL-1 was highly increased when B cells were simultaneously stimulated with both F(ab')2 anti-µ and anti-CD40 Abs. To extrapolate this finding to a physiological situation, we might speculate that B cells that receive signals resembling binding of soluble antigens and T-cell cooperation could activate their biosynthetic machinery and express the highest levels of GAL-1.
A different situation was found when we analyzed GAL-1 expression on B cells obtained from T. cruzi-infected mice. These cells expressed the monomeric and dimeric forms of GAL-1 at levels comparable to those found on normal B cells stimulated with both F(ab')2 anti-µ and anti-CD40 Ab. Because the protozoan infection is a powerful stimulating signal per se, these cells were probably activated in vivo via BCR and CD40. Restimulation of highly activated B cells from T. cruzi-infected mice with several TI and TD signals up-regulated GAL-1 to different extents. Moreover, we found that when B cells received maximal stimulation, GAL-1 was externalized to the extracellular milieu.
Because it had been established that GAL-1 induces apoptosis of activated T cells [5 , 6 , 8 ] and immature thymocytes [10 ], we asked whether GAL-1 expression on B cells could regulate lymphoid-cell viability. GAL-1 produced by B cells was able to specifically regulate T-cell survival. We found that GAL-1 induced higher levels of apoptosis for activated T cells than for nonactivated T-cells. This observation could be ascribed to increased susceptibility of activated T cells to GAL-1, as has been previously shown [5 ]. However, we do not rule out the possibility of an additive effect of B-cell-derived GAL-1 and activated-T-cell-derived GAL-1 [13 ]. Although it will be relevant to demonstrate, using a coculture system, that B-cell-derived GAL-1 induces T-cell apoptosis, this experimental approach is confounded by the fact that B cells might signal T cells to up-regulate GAL-1, which makes it extremely difficult to discriminate between B-cell-derived GAL-1 and GAL-1 produced by T cells after B-cell signaling. Therefore, we attempted to separate this lectin from activated B cells to demonstrate that GAL-1 derived from B cells is responsible for T-cell apoptosis. T cells from GAL-1 in knockout mice would also be useful to address this issue.
B cells were refractory to GAL-1-mediated apoptosis. However, Fouillit et al. [41 ] have recently found that GAL-1 regulates CD45-mediated signaling in Burkitt lymphoma cell lines. This finding is relevant to the difference between nontransformed antigen-stimulated B cells and a transformed B-cell line.
In light of our observations, an attractive possibility is that activated T cells signal B cells via CD40-CD40L and cause them to overexpress GAL-1. Because activated T cells are the main target of GAL-1, one might speculate that GAL-1 expression by B cells could be an alternative immunoregulatory mechanism to shut off T-cell effector functions.
Finally, we observed that GAL-1 was able to down-regulate IFN-
production by T cells. Accordingly, by using a gene therapy strategy in
an experimental model of rheumatoid arthritis, we have recently
demonstrated that GAL-1 induced apoptosis of T-helper type 1 cells,
skewing the balance toward a T-helper-type-2-polarized immune response
[8
]. Given that Chung et al. [11
] have
recently shown that GAL-1 can down-regulate IL-2 production in a manner
independent of its proapoptotic properties, the possibility that GAL-1
might be regulating IFN- production not just by killing
IFN--producing cells should also be considered. Our results are
particularly interesting in the context of T. cruzi
infection. Because IFN- is implicated in the control of parasite
replication [42
, 43
], its down-regulation
may contribute to the immunopathogenesis of this infectious process.
Moreover, recent data demonstrate that clearance of apoptotic bodies by
T. cruzi-infected macrophages promotes parasite replication
[44
]. Therefore, GAL-1 released during T.
cruzi infection could be implicated in the process of T-cell
apoptosis [45
, 46
], thus favoring the
chronic establishment of the parasite in the host. Further experiments
are required to elucidate the role of GAL-1 in the resetting of the
immune response during infections with intracellular microorganisms.
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ACKNOWLEDGEMENTS |
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Received November 27, 2000; revised February 26, 2001; accepted February 28, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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- and ß-chains of the IFN- receptor, and triggers IFN--mediated apoptosis of activated human T lymphocytes J. Immunol. 161,2114-2123-chain phosphorylation and antagonizes processive TCR signal transduction J. Immunol. 165,3722-3729 dependent J. Immunol. 151,4200-4209[Abstract]
induces macrophages activation and prevents acute disease, immunosuppression, and death in experimental Trypanosoma cruzi infection J. Immunol. 140,4342-4350[Abstract]
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