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*
Departments of Pediatrics and Pathology, Women & Infants’ Hospital and
Department of Medicine, Rhode Island Hospital, Brown University, Providence, RI 02905;
Department of Pathology, Roger Williams Medical Center, Providence, RI 02908;
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; and
¶ Institut National de la Santé et de la Recherche Médicale Unité 131, Clamart, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain on their cell surface than the combined GC/M
subpopulation. The IL-10 receptor and the IL-2 receptor 
c chain were
almost equally expressed on both subpopulations. When cultured in
vitro, the addition of IL-4, but not IL-10, protected naive B cells
from apoptosis in the absence of activation and growth. However, IL-4
exerted no such effect on resting GC/M B cells. These data support the
hypothesis that IL-4 plays a pivotal role in the survival and
maintenance of resting human naive B cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To establish in vitro models to understand intrinsic differences between naive human B lymphocytes and their GC/M counterparts, current research has focused on characterization and isolation of distinct B cell subpopulations from the secondary lymphoid organs (9, 18). It has been possible to follow the development of GC and M B cells by defining the changes in surface molecule expression (5, 19). Indeed, it has been shown that naive B cells, characterized by IgD+CD23+CD38-CD44+CD95-, acquire a partial GC phenotype when their CD40 and Ag receptors are triggered (14). Moreover, GC B cells, distinguished by their surface phenotype of IgDlowCD23-CD38+CD44-CD95+, can also develop memory or plasma cell characteristics in the context of cytokine-mediated signaling and gp39 (CD154)-CD40 interactions (13, 15, 20, 21). The GC to M transition is characterized by the surface phenotype IgD-CD23-CD38-CD44+CD95+ (4, 15). We recently began to delineate intrinsic differences between naive human B cells and GC/M B cells and demonstrated that naive B cells, when activated by triggering CD40 and B cell Ag receptor, underwent robust DNA synthesis in response to IL-4, but to a much lesser extent to IL-2 or IL-10 (22). In contrast, activated combined GC/M subpopulation responded to all of these cytokines, albeit with variable proliferation index (22). However, the question arises about the milieu that supports the maintenance of the naive B cell pool in the absence of activation and rapid proliferation, a situation reminiscent of the primary follicles. In this regard, specific expression of CD23, the low-affinity lgE receptor, on freshly isolated naive B cells is intriguing (23). CD23 up-regulation has been shown to be transcriptionally controlled by IL-4 or EBV (24, 25, 26). In addition, IL-4 up-regulates expression of class II MHC and IL-4R on total resting B cells (27, 28). Given these observations, we propose that IL-4 uniquely influences and regulates the survival of B cells, particularly of naive human B cells, in the absence of activation or proliferation.
In the present study, we employed highly purified naive and GC/M human
tonsillar B cell subpopulations to ascertain the role of IL-4 and IL-10
in regulating their in vitro survival. We report that naive B cells
exhibited much slower propensity to apoptosis than GC/M B cells and
that IL-4 protected unstimulated naive, but not GC/M, B cells from in
vitro cell death. Curiously, IL-10 had no effect on naive B cells,
irrespective of the presence of its receptor on these cells. The
IL-4R chain was significantly detected on naive B cells, whereas the
IL-2 common -chain (IL-2Rc) was similarly expressed
on both subpopulations. Thus, maintenance of the functional receptor
and partial competence of IL-4-mediated signaling may be the mechanisms
whereby this cytokine supports the survival of naive B cells in the
absence of stimulation.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All cell culture experiments were performed in RPMI 1640 supplemented with penicillin (50 U/ml)/streptomycin (50 µg/ml) and 10% FCS (Life Technologies, Grand Island, NY). Cells were incubated at 37°C/5% CO2 and seeded at a density of 1 x 106 cells/ml. Activation of B cells was achieved by using anti-CD40 Ab derived from hybridoma cells secreting the anti-human CD40 Ab G28.5 (American Type Culture Collection, Manassas, VA), immunobeads covalently bound to rabbit anti-human lgM specific for µ-chains (Irvine Scientific, Santa Ana, CA) or soluble anti-IgM (F(ab')2) fragments of rabbit anti-human lgM Ab specific for µ-chains (Dako, Carpenteria, CA). Anti-human CD40 Ab was further purified and characterized as described previously (22). Recombinant human IL-2 and IL-4 were obtained from Genzyme Genetics (Cambridge, MA). Recombinant human IL-10 was purchased from R&D Systems (Minneapolis, MN). Anti-human IgA (clone G20-59), anti-human IgG (clone Gl 8-145), anti-human CD38 (clone HIT2), and anti-human IgD (clone IAG-2) were purchased from PharMingen (San Diego, CA). Rat anti-mouse IgG1 magnetic microbeads and CS+ separation columns were obtained from Miltenyi Biotec (Auburn, CA).
Isolation of tonsillar B cell subpopulations
Human tonsillar B cells were isolated as described previously (22). In brief, tonsils were obtained after routine tonsillectomy and finely minced, and the resulting cell suspension was depleted of T cells by resetting with neuraminidase-treated sheep RBC and subsequent Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) gradient centrifugation. After adherence to plastic for 2 h to overnight at 37°C in a humidified atmosphere of 5% CO2, to remove non-B cells, B cells were further purified on discontinuous Percoll gradients (Pharmacia) according to density as previously described (22). Cells collected at the 70% layer represent high-density IgD+CD38- naive B cells (herein referred to as high-density B cells). Cells collected at the 60% layer represent low-density IgDlowCD38+ combined GC/M B cells (herein referred to as low-density B cells). Naive and GC/M subpopulations were further purified by negative and/or positive selection on magnetic microbead columns. Abs to human CD38, IgD, IgG, and IgA were used as required. Naive B cells were enriched from Percoll gradient-purified high-density cells by negatively selecting IgD+ cells followed by positive selection. GC/M B cells were enriched from low-density cells first by negative selection in an IgD+ reaction followed by positive selection by incubating cells with Abs to CD38, IgG, and IgA. Cells were first incubated for 15 min on ice with appropriate Abs. Rat anti-mouse IgG1 microbeads (Miltenyi Biotec) were added and cells were incubated for an additional 15 min on ice. The labeled cells were magnetically separated on Miltenyi CS+ columns using the VarioMACS (Miltyeni Biotec) magnetic separator. The purified cells were then collected and assessed for respective phenotypic characteristics by FACScan analysis (Becton Dickinson, Mountain View, CA).
FACScan analysis
Purified human tonsillar B cell subpopulations (1 x
106 cells/ml) were incubated with mouse
anti-human CD95-FITC (Immunotech, Marseille, France), rat
anti-human IgD-FITC (PharMingen), mouse anti-human CD38-FITC
(Immunotech), mouse anti-human CD19-PE (Becton Dickinson
Immunocytometry Systems, San Jose, CA), mouse anti-human
IL-2Rc-PE (PharMingen), or mouse anti-human IL-10R-PE
(PharMingen) for 30 min on ice in the dark. After washing twice with
PBS containing 2% FCS, cells were fixed in 0.5%
paraformaldehyde and analyzed with a FACScan flow cytometer.
To detect IL-4R chain, a high sensitivity immunofluorescence
staining was conducted as described elsewhere (29).
Briefly, purified human tonsillar B cells were incubated with a
biotinylated goat polyclonal Ab against IL-4R chain (R&D Systems)
followed by the sequential addition of biotin-conjugated anti-goat
IgG (Santa Cruz Biotechnology, Santa Cruz, CA) and PE-streptavidin
(Becton Dickinson Immunocytometry Systems) for 30 min each on ice in
the dark. Cells were washed twice with PBS + 2% FCS, fixed in 0.5%
paraformaldehyde, and analyzed by flow cytometry.
Proliferation assays
Purified human tonsillar B cells (1 x 105 cells/well) were seeded in 96-well round-bottom microtiter plates in a final volume of 200 µl. Cells were grown in 10% FCS and in the presence or absence of covalently linked anti-IgM beads (1:250 dilution) and anti-CD40 (1 µg/ml) plus IL-4 (20 U/ml), IL-2 (100 U/ml), or IL-10 (10 ng/ml). After 72 h in culture, cells were pulsed with 1 µCi/well [3H]thymidine for an additional 16 h, and incorporated radioactivity was measured.
Analysis of DNA fragmentation
Analysis of apoptosis by DNA fragmentation was performed as previously described using the apoptotic DNA ladder kit obtained from Roche Diagnostics (Mannheim, Germany) (30). Briefly, after culturing with appropriate cytokine and/or activator(s) for 24 or 48 h, cells were washed once in PBS, resuspended in 0.2 ml PBS, and brought to a final volume of 0.4 ml with binding buffer (10 mM Tris-HCl (pH 8.0), 10 mM urea, 6 M guanidine-HCl, and 20% Triton X-100 (v/v), pH 4.4). Samples were incubated for 10 min at room temperature where 0.1 ml isopropanol was added following vortexing. The resulting mix was passed through a filter tube and washed twice with washing buffer (20 mM NaCl, 2 mM Tris-HCl (pH 7.5), and EtOH). Purified DNA was obtained using elution buffer (10 mM Tris, pH 8.5) heated to 70°C and spun through the column at 8000 rpm for 1 min. DNA (20 µg in each lane) was separated on a 1.2% agarose gel and visualized by ethidium bromide staining.
Propidium iodide staining
The percentage of apoptotic cells was determined by analyzing the nuclear content by flow cytometry as described previously (30). Purified tonsillar human high-density and low-density B cells were incubated either alone (10% serum) or in the presence of IL-4 or IL-10 for 24 or 72 h. Cells were harvested and resuspended in 1.5 ml hypotonic fluorochrome solution (50 µg/ml propidium iodide in 0.1% sodium citrate plus 0.1% Triton X-100) and incubated for 30 min at room temperature in the dark. DNA content was then analyzed by flow cytometry. Debris was excluded from analysis by raising the forward scatter threshold. Apoptotic cells were defined as those having hypodiploid nuclei emitting fluorescence in channels 10–200 and were enumerated as a percentage of the total population.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To evaluate intrinsic phenotypic characteristics of naive and GC/M
B cells, highly purified tonsillar B cells (see Materials and
Methods) were stained with various cell surface markers. Flow
cytometry shows that the naive B cell subpopulation (high-density
fraction) predominately expressed the surface markers IgD and CD23.
This subpopulation lacked expression of the GC/M surface markers CD95
and CD38 (Fig. 1
A).
Conversely, the GC/M B cell subpopulation (low-density fraction)
displayed high levels of CD38 and CD95 on their surface (Fig. 1A). Both subpopulations represented highly purified B cells
as demonstrated by >95% staining for the pan B cell marker CD 19
(Fig. 1A). These results are typical of those obtained from
several independent preparations and agree with published observations
(31, 32).
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B, the high-density (naive) B cell fraction was found to be
a homogeneous population of small sized cells showing a single peak
with a forward scatter of 
100 mean channel units. However, the
low-density (GC/M) B cell fraction was a heterogeneous population
representing cells of various sizes, showing a forward scatter of 140
mean channel units with a large fraction scattered >150 mean channel
units. These results further confirm that isolated naive and GC/M B
cells represented highly purified subpopulations. IL-4R expression differs between naive and GC/MB cell subpopulations
It has been reported that unfractionated resting tonsillar human B
cells express low levels of IL-4R (29). However, the
precise nature of a subpopulation that may express this receptor is not
well defined. To address this question, unstimulated high-density and
low-density B cell subpopulations were stained with a polyclonal Ab
against the IL-4R chain and analyzed by FACS. An indirect labeling
technique was used to enhance the sensitivity of IL-4R detection as
described in Materials and Methods. As shown in Fig. 2A, the high-density fraction
expressed significantly more IL-4R on its surface (25.3%) as
opposed to the low-density fraction (6.2%). Importantly, activation of
these subpopulations with anti-IgM + anti-CD40 for 24 h
resulted in a marked increase in IL-4R expression in both
subpopulations, 66.2% on high-density and 45.7% on low-density B
cells, respectively.
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c
chain. As shown in Fig. 2B, both subpopulations exhibited
significant expression of IL-10R and IL-2Rc. These data
are representative of several independent tonsil specimens and suggest
that although unstimulated naive (high-density) and GC/M (low-density)
B cells express IL-10R and IL-2Rc in a similar fashion,
they differ in their display of the IL-4R chain. IL-4 protects naive, but not GC/M, B cells from spontaneous cell death
We hypothesized that resting naive B cells were intrinsically
programmed to respond to IL-4 in the absence of activation and
proliferation. Because IL-4 has been shown to act as a survival factor
for resting T cells and to protect chronic lymphocytic leukemia B cells
from spontaneous apoptosis (33, 34), we used the measure
of apoptosis as an approach to test the ability of IL-4 as a survival
factor for resting naive and GC/M B cells. Here, enriched high- and
low-density tonsillar B cells were either cultured alone or in the
presence of IL-4 or IL-10 for 0, 24, or 72 h, and apoptosis was
measured by propidium iodide staining. At 0 h, neither
high-density nor low-density B cells showed any significant cell death
(Fig. 3). It is important to note that a
significant portion of the low-density population was in
G2-M phase of the cell cycle at time 0 h.
This correlates with the forward scatter analysis shown in Fig. 1B, indicating that a number of these cells are at various
stages of cell division in vivo. However, by 72 h of
culture, both high- and low-density B cells underwent spontaneous
apoptosis, with 44 and 46.4% cell death, respectively (Fig. 3).
Interestingly, high-density B cells showed a lesser propensity for
apoptosis than low-density B cells. Fig. 3A shows that at
24 h, only 9.3% of the high-density B cells were hypodiploid
(apoptotic) as opposed to 40.1% of the low-density B cells (Fig. 3B). The addition of IL-10 alone did not significantly
improve the viability of high-density subpopulation. However, IL-10
provided some protection for low-density B cells at 24 h,
reducing the apoptotic death rate from 40.1% when cultured alone to
23.4% when treated with IL-10 (Fig. 3B). This protection
however dissipated by 72 h (Fig. 3B). In contrast,
treatment with IL-4 resulted in a marked protection of high-density,
but not low-density, B cells from apoptosis. After 72 h, there was
only 15% cell death in the comparable IL-4-treated high-density
subpopulation as compared with 42.4% cell death in the low-density
subpopulation (Fig. 3B). This differential ability of IL-4
to protect high-density, but not low-density, B cells from apoptosis
may be associated with the varying expression of IL-4R on their cell
surface and/or partial signaling competence of naive B cells to respond
to this cytokine.
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We hypothesized that the inability of IL-4 to protect low-density
B cells in Fig. 3B was perhaps because of a second signal
requirement. We and others have shown that low-density B cells are
stimulated to proliferate in response to IL-4 when activated with
anti-IgM and/or anti-CD40 (11, 22). Therefore, we
next aimed to evaluate 1) the dose-dependent inhibition of apoptosis in
both high- and low-density B cells and 2) the conditions which result
in protection of low-density B cells. Resting high- and low-density B
cells were cultured for 24 or 48 h in the presence of varying
concentrations of IL-4, and apoptosis was measured by DNA fragmentation
analysis or propidium iodide staining (only DNA fragmentation at 48-h
time point shown here). IL-4 was able to protect resting high-density B
cells from apoptosis in a dose-dependent manner, with concentrations of
20 ng/ml giving maximum protection, whereas no IL-4-mediated inhibition
of apoptosis in resting low-density B cells was observed even at the
highest dose (Fig. 4A).To test
whether low-density B cells were protected from apoptosis by IL-4 in
the presence of coactivators, we conducted DNA fragmentation analysis
with cells cultured for 48 h in the absence or presence of IL-4
alone or in combination with anti-IgM and anti-CD40. As shown
in Fig. 4B, IL-4 alone was not able to protect low-density B
cells from apoptosis, agreeing with the results from Figs. 3B and 4A. However, coactivation of low-density B
cells with anti-IgM and anti-CD40 resulted in a significant
reduction in apoptosis (Fig. 4B). This protection was
further enhanced by the addition of IL-4 (Fig. 4B). These
results suggest that costimulation with activators such as anti-IgM
and anti-CD40 renders low-density B cells capable of responding
to IL-4.
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To assess whether protection of unstimulated high-density B cells
was associated with concurrent cell growth, purified high- or
low-density B cells were assayed for
[3H]thymidine incorporation for 72 h in
the presence or absence of IL-4 or IL-10 alone or in combination with
anti-IgM and/or anti-CD40. Stimulation with IL-4 or IL-10 alone
did not result in any significant proliferation in high- or low-density
B cells (Fig. 5). Moreover, activation
with either anti-IgM or anti-CD40 alone or in combination did
not result in any significant proliferation. However, in low-density B
cells, maximal proliferation in response to IL-4 or IL-10 occurred when
these cells were coactivated with anti-IgM and anti-CD40 (Fig. 5).This robust proliferative response to IL-4 after coactivation
correlates with the reduced apoptosis observed in Fig. 4B
and supports the idea that low-density B cells require a costimulatory
signal to respond to IL-4. Conversely, under conditions of
coactivation, IL-4, but not IL-10, was capable of inducing significant
proliferation in high-density B cells (Fig. 5). It is important to
point out that these experiments have been repeated several times and
that these results are consistent with our published findings
(22). Thus, the data presented in
Figs. 3–5 suggest that
IL-4 can act as a survival factor for high-density B cells without
inducing cellular proliferation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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chain and IL-4 signaling competence. This notion is supported
by the observations that despite significant display of its receptor on
naive B cells (Fig. 2), IL-10 did not protect these cells from
apoptosis (Fig. 3). IL-10 has been shown to prevent spontaneous death
in resting GC B cells (35, 36). However, our data revealed
only a partial and transient protection of GC/M B cells by this
cytokine (Fig. 3). It is possible that resting GC and M cells will show
a distinct response to IL-10 and thus a mixture of these subpopulations
will only partially respond to IL-10.
Resting naive B cells may indeed differ from GC/M counterparts in their
survival, growth, and cytokine signaling. Indeed, naive B cells undergo
apoptosis in a delayed manner as compared with GC/M B cells (Fig. 3).
Furthermore, we recently reported that naive B cells, when activated
through CD40 and IgM cross-linking, significantly responded to only
IL-4 for growth stimulation (22). In these experiments,
IL-4 was able to induce cyclin D3 and eliminate cyclin-dependent kinase
inhibitor p27. In resting naive B cells, the absence of IL-4-mediated
growth stimulation could be attributed to the maintenance of p27
(37). Thus, it appears that a significant expression of
the IL-4R chain on resting naive B cells may be a part of hierarchy
to certain cytokines. This notion is supported by defective expression
of functional IL-4R on Ag-experienced IgE-producing B cells
(38). Furthermore, recent observations by Corcione et al.
(39) that naive, GC, or M B cell subsets differ in their
selective utilization of TNF- receptor strengthens this
hypothesis.
IL-4 is a key cytokine that induces growth in activated B cells,
promotes Ab responses, and polarizes CD4 T cell functions
(40, 41, 42, 43). All of these effects strictly depend on the
signal transduction through binding to the IL-4R, which is composed of
at least two chains, IL-4R (140-kDa) chain and IL-2Rc
(75-kDa) chain (44, 45). The data shown here present a
paradigm in that although naive B cells express a complete receptor
complex, IL-4-mediated protection of these cells from apoptosis occurs
in the absence of DNA synthesis (Figs. 3 and 5). In this regard, it has
been recently demonstrated that distinct sequence motifs within the
cytoplasmic tail of the IL-4R are involved in regulating protection
from apoptosis and cell growth (46, 47, 48). Moreover,
inhibition of IL-4-mediated apoptosis does not depend on STAT6
activation (46, 47). In agreement with these observations,
IL-4 has been shown to protect resting T cells in a STAT6-independent
manner (33). Thus, it is possible that in resting naive B
cells, IL-4-mediated apoptosis inhibition involves mechanisms
independent of STAT6-docking regions. These studies are currently being
investigated in our laboratory.
What is the biological significance of IL-4-mediated survival of naive
B cell pool? Surprisingly, IL-4 knockout mice do not exhibit any gross
aberrations in B cell functions and GC architecture, except for the
lack of IgE production and gut mucosal Ab responses (49).
In contrast, chronic overproduction of IL-4 is thought to be associated
with humoral autoimmunity in mice (50), suggesting
increased B cell numbers and/or responses associated with the
autoimmune pathology. One explanation for normal B cell survival and
maintenance in the absence of IL-4 is the functional presence of IL-13.
Interestingly, the expression of IL-13 receptor 1-chain was found to
be the highest on naive B cells (51). Thus, simultaneous
disruption of IL-4, IL-13, and other redundant B cell cytokines may
result in poor B cell viability, in particular naive B cells. Another
important role of IL-4 in naive B cell biology may be its unique
participation in inducing their migration (52). Thus, it
is possible that by protecting naive B cells from apoptosis and by
inducing their migration, IL-4 increases the number of naive B cells in
a site-specific manner. Indeed, a very recent report clearly suggests
that IL-4 increases splenic B cell number through enhanced migration of
circulating B cells and increased B cell life span
(53).
In summary, our data indicate that resting naive and GC/M human B cells exhibit intrinsic differences as demonstrated by their disparate IL-4R expression as well as differential propensity for apoptosis and survival in responses to IL-4 and IL-10. Importantly, our data suggest that IL-4 may be a crucial regulator of the increased presence of resting B lymphocytes, particularly naive B cell subpopulation, in lymphoid organs.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Surendra Sharma, Women & Infants’ Hospital, Brown University, 101 Dudley Street, Providence, RI 02905.
3 Abbreviations used in this paper: GC, germinal center; M, memory; c, common .
Received for publication October 22, 1999. Accepted for publication August 24, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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receptors (CD23) on normal human B lymphocytes. J. Exp. Med. 165:1459.
1 induced apoptosis in normal human B cells and lymphoma B cell lines. Oncogene 11:1615.[Medline]
l expression on B cells, T cells and monocytes and its regulation by IL-13 and IL-4. Eur. J. Immunol. 28:4286.[Medline]
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