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*
Laboratory of Cellular Immunology, Alton Ochsner Medical Foundation, New Orleans, LA 70121;
Department of Microbiology, Kangwon National University College of Medicine, Chunchon, Korea; and
Institute of Cell Signaling and School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham, United Kingdom
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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knockout mice that the initial
interaction between FDC and B cells is essential for GC formation
(9, 10). T cells expressing CD40 ligand (CD40L) at the
same time play a pivotal role in the GC reaction, as evidenced in
hyper-IgM patients (11) and in mouse models that are
deficient for CD40 (12) or CD40L (13, 14).
The signals for survival, proliferation, and differentiation of GC B
cells, however, are poorly understood, in part due to the lack of a
proper in vitro model to clearly analyze the cellular and
molecular interactions between B cells and FDC. Furthermore, the
identification of molecular signals that induce somatic mutation and
class switching has been hampered by the low viability of GC B cells
under conventional culture conditions without FDC and the polyclonality
of freshly isolated GC B cells. To overcome the practical difficulty in isolating pure FDC and to mimic the GC reaction in vitro, we have established an FDC line, HK, from human tonsils and used it to determine molecular and cellular requirements for GC B cells (15, 16, 17, 18, 19). HK cells indeed have functional features of FDC in delaying apoptosis and stimulating growth and differentiation of GC B cells. HK cells bind and prevent apoptosis of IgD-CD38+CD44- GC B cells preferentially and have costimulatory effects on the proliferation of CD40-stimulated GC B cells (16, 17). However, the individual roles of HK cells and CD40L in the proliferation and differentiation of GC B cells were not clearly defined, since both were required for optimum growth. In addition, GC B cells freshly isolated from tonsil are heterogeneous with regard to the stage of differentiation, mutation frequency, and Ig class (20) and are not ideal for characterizing the external signals operating at each stage of B cell differentiation in the GC. A monoclonal population of dividing cells would be devoid of such problems of freshly isolated GC B cells.
Burkitt’s lymphoma (BL) is a tumor with features of GC B cells (21), and group I BL lines retain those features in vitro. Gregory et al. (22) suggested the GC origin of BL cells by demonstrating the association with GC B cell-specific surface markers, CD10 and CD77. The BL cells display a homogeneous cell surface phenotype and are inclined to undergo spontaneous apoptosis unless cultured with appropriate stromal cells (23). In the present study we have chosen an EBV-negative group I BL cell line, L3055 (24, 25), to investigate molecular and cellular signals for the survival, proliferation, and differentiation of GC B cells at the clonal level. We show that L3055 cells express typical surface markers of centroblasts, exhibit a high propensity to undergo spontaneous apoptosis, but continuously proliferate without differentiation when cocultured with FDC clusters or HK cells. The addition of CD40L and IL-4 induces differentiation from centroblastic to centrocytic phenotype, and L3055 cells with the latter phenotype undergo CD95-mediated apoptosis. HK cells expand the L3055 cells rescued from B cell receptor (BCR)-mediated apoptosis by CD40L and a cytokine mixture (IL-2, IL-4, and IL-10). These data suggest important roles for FDC and T cells in the proliferation, differentiation, and selection of B cells in the GC.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The L3055 cell line was isolated from an HIV-negative 17-yr-old male of Arabic origin with an initial diagnosis of Burkitt-type acute lymphoblastic leukemia (24, 25). We subcloned L3055 cells by screening for the property of being HK dependent. L3055 cells were cultured in RPMI 1640 (Irvine Scientific, Santa Ana, CA) supplemented with 10% FCS (Life Technologies, Grand Island, NY), 2 mM glutamine, 100 U/ml penicillin G, and 100 µg/ml streptomycin (Irvine Scientific). HK cells were established and maintained as described previously (15).
Antibodies and reagents used in the study
FITC- or PE-conjugated anti-CD10 (W8E7), anti-CD23 (EBVCS-5), anti-CD23 (S5.2), anti-CD3 (SK7), anti-CD19 (4G7), anti-CD25 (2A3), anti-CD20 (L27), anti-CD38 (HB-7), goat anti-mouse Ig, and isotype controls were purchased from Becton Dickinson (San Jose, CA). FITC-conjugated anti-CD44 (F10-44-2) was obtained from BioSource International (Camarillo, CA); anti-CD86 (HA3.1F9) was obtained was from Genetics Institute (Cambridge, MA); FITC-conjugated anti-IgD (HJ9) was obtained from Sigma (St. Louis, MO); biotin-conjugated peanut agglutinin was obtained from Vector Laboratories (Burlingame, CA); FITC-labeled anti-CD95 (DX2), biotin-labeled anti-IgG (G18-145), and biotin-labeled anti-IgA (G20-359) were purchased from PharMingen (San Diego, CA); FITC- or PE-labeled streptavidin and anti-CD95 (CH-11) were obtained from Immunotech (Westbrook, ME); FITC-conjugated goat anti-mouse IgM was purchased from Southern Biotechnology Associates (Birmingham, AL); anti-IgM (SADA4.4) was obtained from American Type Culture Collection (Manassas, VA); the annexin V-FITC apoptosis detection kit was obtained from Trevigen (Gaithersburg, MD); and Transwell (0.4-µm pore size) was purchased from Corning Costar (Cambridge, MA). Anti-CD77 (5B5) was provided by Dr. M. Nahm (University of Rochester, Rochester, NY). Soluble human trimeric CD40L was provided by Dr. R. Armitage (Immunex, Seattle, WA) and used at 400 ng/ml, which was determined to give optimal proliferation of GC B cells. The IL-2 was obtained from Hoffmann-La Roche (Nutley, NJ). Recombinant human IL-4 was a gift from Schering-Plough (Union, NJ). The IL-10 was purchased from R&D Systems (Minneapolis, MN).
Isolation of FDC clusters
Fresh FDC clusters were isolated as described by Bosseloir et al. (26). After mincing the tonsil tissue into small pieces, an enzyme mixture of collagenase IV (2 mg/ml; Worthington, Freehold, NJ) and DNase (2 U/ml; Sigma) was used to digest the tissue three times at 37°C, 20 min each time. The cell suspension was separated by a Percoll density gradient with 0, 15, 35, 50, and 60% Percoll. The interface of 15–35% was collected and washed. A BSA density gradient of 0, 3, and 7.5% was then used to further purify fresh FDC clusters by centrifuging at 10 x g for 10 min at 4°C. The 7.5% phase containing FDC clusters was collected and used in the experiments.
Flow cytometry
Flow cytometric analysis was conducted on a FACScan (Becton Dickinson) with CellQuest software as described previously (17). The computer software FACSComp calibrated the cytometer with CaliBRITE beads (Becton Dickinson).
Coculture
HK cells irradiated with 3000 rad were prepared 1 day before L3055 cells were added to the wells of 24-multiwell plate. Coculture was performed under various conditions as indicated in the figures. A cytokine mixture of optimal concentrations of IL-2 (20 U/ml), IL-4 (100 U/ml), and IL-10 (50 ng/ml) was used throughout the experiments. Optimal concentrations of anti-IgM (10 µg/ml) and anti-CD95 (100 ng/ml) were used. Viable cells were enumerated by counting the cells with intact morphology after staining with trypan blue.
Statistical analysis
The statistical significance of differences was determined using Student’s t test, and p < 0.05 was considered significantly different.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To study molecular signals that operate at each stage of GC B cell
differentiation at the clonal level, it is necessary to determine
whether L3055 cells represent centroblasts. A detailed flow cytometric
analysis revealed that L3055 cells expressed CD10, CD20, CD38, CD77,
and peanut agglutinin binding, but not CD44 (Fig. 1
), extending the results reported
previously (27). These are the typical surface markers for
GC centroblasts (18, 28). L3055 cells did not express
surface Igs other than IgM. This phenotype remained constant for >1 yr
in culture, indicating that this cell line did not undergo class
switching to downstream isotypes.
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A, their presence resulted in
a >20-fold increase in cell recovery at the optimum number of HK
cells. The dependence of L3055 cells on HK cells for survival and
growth was not ascribed to low cell density, because increasing the
cell density did not abrogate the requirement of HK cells (Fig. 2B). The HK-dependent growth of L3055 cells is reminiscent
of a functional feature of centroblasts isolated from tonsils
(16). The FDC clusters freshly isolated from tonsil were
also capable of providing survival and growth signal to L3055 cells in
a dose-dependent manner (Fig. 2C), suggesting that the
effect of HK cells on L3055 cells indeed reflected an important
functional feature of FDC.
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The GC is comprised of Ag-activated T cells as well as B cells and FDC (2). Because T cells participate in GC reactions by direct cell to cell contact and by secreting cytokines (29), we used the defined signals of activated T cells, such as CD40L, IL-2, IL-4, and IL-10, to characterize HK cell signals in the proliferation of centroblasts.
When cultured alone, L3055 cells did not grow, and viable cells were
rarely detected after a 4-day culture (Fig. 3). In contrast, HK cells supported
growth remarkably, yielding a 24-fold increase in cell recovery. CD40L
and the cytokine mixture, either alone or in combination, yielded only
a 2- to 5-fold increase in the number of viable cells. When HK cells,
CD40L and the cytokines were added together, the recovery of L3055
cells increased to 14-fold. However, this value was 40% less than that
obtained by the addition of HK cells alone, suggesting that CD40L and
the cytokines inhibited growth of L3055 cells in the presence of HK
cells.
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). During this period of culture, the
numbers of recovered cells were comparable under each condition. Cells
were stained with FITC-labeled annexin V and propidium iodide (PI) and
analyzed on a FACScan. Apoptotic cells lose membrane phospholipid
asymmetry and bind annexin V on the surface, which is thought to be an
early marker of apoptosis (30). Late apoptotic cells or
dead cells do not exclude PI and become PI+. In
the absence of HK cells, 43% of the L3055 cells were annexin
V+ PI+ and 20% became
annexin V+ PI- (total,
63% annexin V+). The presence of HK cells
reduced annexin V+ PI+
cells to 17% and annexin V+
PI- to 6% (total, 23% annexin
V+). The addition of the cytokine mixture alone
did not change the results significantly, but the addition of CD40L
gave rise to results similar to those observed with HK cells regardless
of whether the cytokines were added. Annexin V-
PI- viable cells were 74% in the presence of HK
cells and 75% in the presence of CD40L plus the cytokines (the
upper panels of Fig. 4, A and B).
These results suggest that CD40L and HK cells prevent spontaneous
apoptosis of L3055 cells. However, CD40L plus cytokines poorly
supported cellular proliferation, because the cell recovery was only
20% of that with HK cells alone (Fig. 3
). These data indicate that HK
cells provide signals both to prevent spontaneous apoptosis and to
support cellular proliferation, whereas CD40L prevents spontaneous
apoptosis but poorly stimulates the growth.
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In vivo administration of soluble Ags induces significant apoptosis of B cells in the GC (31, 32), even though Ags presented by FDC are thought to select B cells with high affinity receptors. However, the functional roles of BCR signal, FDC, and T cells in determining the fate of GC B cells have not been defined clearly. To analyze the roles of the individual factors in Ag-induced apoptosis and selection in the GC, the effect of anti-IgM on L3055 cells was examined under various culture conditions containing HK cells, CD40L, or the cytokine mixture.
No viable L3055 cells were recovered after a 4-day culture containing
both anti-IgM and HK cells (Fig. 3), indicating that L3055 cells
underwent anti-IgM-induced apoptosis, and HK cells did not prevent
it. There was a significant recovery of L3055 cells (465%) when CD40L
and the cytokine mixture were present. The addition of anti-IgM to
this culture resulted in 60% less cell recovery (175%). When HK cells
were added to CD40L and the cytokine mixture, however, the cell
recovery obtained in the presence of anti-IgM was comparable to
that in the control culture without anti-IgM (1250 vs 1400%,
respectively). To detect an early sign of apoptosis induced by
anti-IgM, L3055 cells were cultured under various conditions for
6 h as described previously (Fig. 3), and two-color analysis on a
FACScan was performed. The addition of anti-IgM in the absence of
HK cells reduced annexin V-
PI- viable cells from 36 to 24%, which occurred
with a concomitant increase in annexin V+
PI- early apoptotic cells from 20 to 28% (Fig. 4A). This result is indicative of the early onset of
anti-IgM-induced apoptosis. In contrast, CD40L plus the cytokine
mixture rendered L3055 cells resistant to anti-IgM killing during
the 6-h culture, as addition of anti-IgM did not reduce annexin
V- PI- viable cells (75
to 75%). Similar results were obtained in the presence of HK cells
(Fig. 4B). The addition of anti-IgM decreased the
annexin V- PI- viable
cells (74 to 65%) with a concomitant increase in annexin
V+ PI- early apoptotic
cells (6 to 14%). These cells became resistant to apoptosis in the
culture containing CD40L and the cytokine mixture (82 vs 84%).
Collectively, these results suggest that HK cells do not prevent
anti-IgM-induced apoptosis but provide growth signals to L3055
cells, while CD40L plus the cytokine mixture blocks BCR-mediated
apoptosis but poorly stimulates the growth. L3055 cells receive the
resistance signal from CD40L plus cytokines and the growth signal from
HK cells, as demonstrated in the comparable cell recoveries regardless
of anti-IgM addition.
Those cells undergoing Ag-induced apoptosis in vivo
(31, 32) may be GC B cells that encounter Ag in the early
stage of GC entrance before the encounter with Ag-activated T cells.
The in vivo experiments did not identify whether
centroblasts or centrocytes were sensitive to Ag-induced apoptosis. To
investigate this question, L3055 cells were first cultured with CD40L
and the cytokine mixture in the presence of HK cells for 4 days to
induce differentiation and then exposed to anti-IgM for 20 h.
L3055 cells cultured without CD40L and the cytokine mixture were used
as a control population. Viable cells were significantly decreased in
both populations by the addition of anti-IgM (78 to 14% and 76 to
10%; Fig. 5). L3055 cells cultured with
CD40L and the cytokine mixture for 7 days retained the susceptibility
to anti-IgM (data not shown). Both populations were protected from
anti-IgM-induced apoptosis when CD40L and the cytokine mixture were
present at the time of anti-IgM addition. These results suggest
that both centroblasts and centrocytes are susceptible to Ag-induced
apoptosis and that both populations are protected from Ag-induced
apoptosis by Ag-activated T cells.
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The order of B cell differentiation in the GC has been well
characterized by surface Ag expression and localization in tonsil
(33). Centroblasts in the GC differentiate to centrocytes
and then to memory B or plasma cells. To determine the roles of the
individual factors directing differentiation of centroblasts,
phenotypic change was examined after a 4-day culture of L3055 cells
under various conditions. As shown in Fig. 6, the addition of CD40L plus cytokines,
particularly IL-4, resulted in a drastic change in the phenotype. The
effect of CD40L or cytokines was moderate when added alone. After
stimulation with CD40L and IL-4, however, CD77, the typical marker of
centroblasts was down-regulated, while a marker of centrocytes, CD95,
was up-regulated. Consistent with the report that BL were CD95-negative
tumors (34), L3055 cells did not express CD95 before
stimulation. However, the addition of IL-4, but not IL-2 and IL-10, to
CD40L enhanced the induction of CD95 and CD23. CD23 is highly expressed
in the light zone of the GC (35), possibly on centrocytes.
Down-regulation of CD10, CD20, and CD38 was also observed in L3055
cells after culture with CD40L and IL-4 (data not shown). This result
was similar to the changes observed with centroblasts freshly isolated
from tonsil (18). The activity of IL-4 was specific and
unique in the transition of the L3055 phenotype, because the presence
or the absence of IL-2 or IL-10 did not affect the results (data not
detailed). HK cells did not play a critical role in the modulation of
this phenotypic change (Fig. 6).
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). These results are
in line with our previous report that CD40-stimulated tonsillar
centroblasts are susceptible to anti-CD95-induced killing
(17). The resistance of the unstimulated L3055 cells may
be due to the absence of CD95 expression (Fig. 6). Hence, the
phenotypic and functional analysis suggests that L3055 cells have the
capacity to differentiate from centroblast to centrocyte in response to
CD40L and IL-4. HK cells did not affect the differentiation of L3055
cells by CD40L and IL-4.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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For the purpose of understanding molecular signals that regulate
apoptosis, proliferation, and differentiation of human GC B cells,
in vitro experiments have been conducted by using freshly
isolated GC B cells (38, 39, 40). GC B cells, which easily
undergo spontaneous apoptosis, require an essential survival signal,
CD40L. However, even in the presence of exogenous cytokines, CD40L
poorly supports the growth of GC B cells, rendering an extensive
experiment difficult (17). To solve this problem several
laboratories, including ours, have successfully established FDC-like
cell lines (15, 41, 42, 43). For example, the presence of an
FDC cell line, HK, gives rise to a >5-fold increase in cell recovery
relative to that in the control culture (17). The HK cells
alone do not maintain proliferation of GC B cells in the absence of T
cell help. In contrast, L3055 cells continue to proliferate
unaccompanied by a significant phenotypic change. This observation
suggests that an important function of FDC is to maintain the
proliferation of centroblasts in the dark zone, probably in the absence
of T cell help. It has recently been demonstrated that the initial
interactions between Ag-activated B cells and FDC are essential for GC
formation in the absence of T cells (9, 10), suggesting
that L3055 cells may have been derived from such early activated B
cells committed to form GC. L3055 cells differentiate in response to
CD40L and IL-4, indicating the distinct functions of FDC and T cells in
GC formation. Centroblasts proliferate massively in the dark zone of
the GC, where T cells are rare (44). In this location,
activated B cells may stimulate maturation of FDC precursors via
lymphotoxin- as suggested previously (9, 10), and
mature FDC, in turn, may provide proliferation signals to centroblasts.
The centroblasts may differentiate into centrocytes when they encounter
activated T cells. FDC appear to stimulate the survival and
proliferation of centroblasts without differentiation, while T cells
trigger differentiation of FDC-supported centroblasts. T cell-derived
signals seem to dominate over the signals from HK cells. Thus, our data
clearly delineate distinct functions of FDC and Ag-activated T
cells.
Both centroblastic and centrocytic L3055 cells underwent anti-IgM-induced apoptosis, while only the latter was sensitive to CD95-mediated killing. Apoptosis induced by anti-IgM was efficiently prevented by CD40L and HK cells. These data underscore the complex interactions among FDC, B, T cells, and Ag in the selection and apoptosis of GC B cells. First, the data suggest that autoreactive B cells, which may arise by somatic mutation at the stage of massive proliferation of centroblasts (33), are eliminated upon the recognition of self-Ags in the microenvironment where cognate T cells are not available, whereas Ag-specific B cells survive in the environment where cognate T cells are available. These results extend earlier observations of Holder et al. (24). Second, centrocytes also undergo apoptosis upon BCR cross-linking, because the treatment with anti-IgM induces apoptosis of L3055 cells following differentiation to centrocytes by CD40L plus IL-4. This result is in agreement with a previous report that BCR-mediated apoptosis is targeted to centrocytes (5). Although elimination of Ag-reactive GC B cells was demonstrated in vivo (31, 32), whether centroblasts or centrocytes were the target of Ag killing was not clear. Our findings suggest that both centroblasts and centrocytes have the propensity to undergo BCR-mediated apoptosis upon the recognition of Ag. However, Ag-specific centrocytes are protected and expanded by signals from activated T cells and FDC, respectively, as suggested by the resistance and growth of L3055 cells in the presence of HK cells, CD40L, and the cytokine mixture. Hence, our data emphasize the important function of FDC in the expansion of the Ag-specific B cells. Third, the present data suggest that CD95-mediated apoptosis operates in centrocytes, but not in centroblasts. CD95-mediated apoptosis is not operational in the early stage of the GC reaction to ensure massive proliferation of centroblasts to provide a large repertoire, but it becomes operational in the elimination of Ag-nonspecific B cells in the stage of centrocytes.
Among the cytokines produced by the GC T cells (45), the functional role of IL-4 was remarkable. The IL-4 induced differentiation of centroblastic L3055 cells into cells with centrocyte phenotype by up-regulating CD23 and CD95 and down-regulating CD10, CD20, CD38, and CD77. This is the direct effect of IL-4 on L3055 cells, as the presence or the absence of HK cells does not alter the result. These data suggest that T cells play a critical role in the differentiation of B cells in the GC by secreting IL-4 in addition to CD40L. Given the similar effects of IL-4 on L3055 cells and centroblasts freshly isolated from tonsil (18), IL-4 appears to be an essential cytokine for GC B cell differentiation. This may explain why IL-4 gene-targeted mice cannot form GC (46), and B cells in IL-4-transgenic mice display hyperactivity (47).
In conclusion, the data presented in this paper suggest that FDC (HK) and T cells (CD40L and cytokines) have distinct roles in the course of GC B cell differentiation. FDC provide unique signals for the survival and massive proliferation of centroblasts, while T cells trigger the differentiation of centroblasts and eliminate Ag-nonspecific B cells via CD95. FDC appear to cooperate with T cells in the selection step by expanding Ag-specific B cells prevented from undergoing BCR-mediated apoptosis. Further investigation with the L3055 cell line may help to elucidate molecular and biochemical events of class switching and somatic mutation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Yong Sung Choi, Laboratory of Cellular Immunology, Alton Ochsner Medical Foundation, 1516 Jefferson Highway, New Orleans, LA 70121. E-mail address:
3 Abbreviations used in this paper: GC, germinal center; FDC, follicular dendritic cells; BL, Burkitt’s lymphoma; CD40L, CD40 ligand; PI, propidium iodide; BCR, B cell receptor.
Received for publication August 4, 1999. Accepted for publication October 13, 1999.
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T. Bonnefoix, J.-Q. Mi, P. Perron, M. Callanan, C. Semoun, M. Favre, J.-C. Renversez, M.-F. Sotto, D. Leroux, and J.-J. Sotto Terminal plasmocytoid differentiation of malignant B cells induced by autotumor-reactive CD4+ T cells in one case of splenic marginal zone B-cell lymphoma Blood, January 1, 2002; 99(1): 388 - 390. [Full Text] [PDF]
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X. Zhang, L. Li, J. Jung, S. Xiang, C. Hollmann, and Y. S. Choi The Distinct Roles of T Cell-Derived Cytokines and a Novel Follicular Dendritic Cell-Signaling Molecule 8D6 in Germinal Center-B Cell Differentiation J. Immunol., July 1, 2001; 167(1): 49 - 56. [Abstract] [Full Text] [PDF]
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T. Suzuki, N. Kiyokawa, T. Taguchi, T. Sekino, Y. U. Katagiri, and J. Fujimoto CD24 Induces Apoptosis in Human B Cells Via the Glycolipid-Enriched Membrane Domains/Rafts-Mediated Signaling System J. Immunol., May 1, 2001; 166(9): 5567 - 5577. [Abstract] [Full Text] [PDF]
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 L. Li, X. Zhang, S. Kovacic, A. J. Long, K. Bourque, C. R. Wood, and Y. S. Choi Identification of a Human Follicular Dendritic Cell Molecule That Stimulates Germinal Center B Cell Growth J. Exp. Med., March 20, 2000; 191(6): 1077 - 1084. [Abstract] [Full Text] [PDF]
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