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Departments of
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Microbiology and
Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032
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Abstract |
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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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The decision to become a plasma cell occurs at varying times and in different sites during a humoral immune response (4). Exposure of B cells to T-independent (TI)3 Ags activates proliferation and formation of foci of Ab-forming cells (AFC) in periarteriolar lymphoid sheaths (PALS) of secondary lymphoid organs. These plasma cells secrete Abs with relatively low affinity for Ag, usually of the IgM class, and are short-lived. Following exposure to T-dependent (TD) Ags, two distinct paths of B cell development are possible. The first is similar to the TI response and involves rapid clonal expansion of activated B cells which form foci of AFC in the T cell-rich areas of lymphoid organs, providing immediate Ag clearance. These early foci of AFC, which mainly produce low-affinity Abs, peak 8–10 days after immunization and then regress rapidly (5, 6). The alternate developmental choice for TD-activated B cells is entry into a lymphoid follicle to establish a germinal center (GC) (5, 7, 8). GC B cells, in association with follicular dendritic cells and TH cells, undergo rapid proliferation, somatic hypermutation, and affinity maturation. B cells that exit the GC adopt one of two fates: they become either memory cells or plasma cells (9, 10, 11). Plasma cells, that develop in the GC, migrate to the bone marrow (12, 13, 14) where they secrete high-affinity Abs and where they may persist for many months in the absence of further proliferation (1, 15, 16). Upon secondary exposure to TD Ags, circulating or marginal zone memory cells proliferate both in T cell-rich regions and in GCs of spleen and lymph nodes. This secondary response leads rapidly to development of plasma cells secreting Abs with high affinity for Ag (17).
Little is known about the molecular mechanisms that determine the
development of B cells following exposure to cognate Ag, particularly
those involved in the choices between a short-lived plasma cell vs GC
development or plasma vs memory fate following the GC reaction. We are
studying the role of a transcriptional repressor called B lymphocyte
maturation protein-1 (Blimp-1) in terminal B cell development. Although
several transcription factors (NF-
B/Rel, BSAP, PU.1, Spi-B, and
Aiolos) are important for early steps in B cell lymphopoiesis and
others (Oct-2, OCA-B, IRF4, E2A, and Bcl-6) are required for activated
or GC B cells (18, 19), Blimp-1 is the only transcription
factor known to be expressed in B cell lines representing mature or
plasma cells but not in lines representing earlier stages of B cell
development (20, 21).
Blimp-1 is a 98-kDa protein containing five Kruppel-type zinc fingers that confer sequence specific DNA binding (22, 23). Based on studies in B cell lines, Blimp-1 has been postulated to be a master regulator of terminal B cell differentiation. In the BCL-1 lymphoma model of differentiation from a mature B cell to a plasma cell, ectopic expression of Blimp-1 is sufficient to cause terminal differentiation evidenced by loss of surface Ig, IgM secretion, expression of syndecan-1 on the cell surface, and cessation of cell division (20, 24, 25). Blimp-1 acts as a direct transcriptional repressor of the c-myc gene (24) and the CIITA gene4 in B cells.
Although studies in cell lines suggest that Blimp-1 is likely to play a key role in plasma cell development, the expression pattern of Blimp-1 in normal B cells has not been studied. The data reported here show that Blimp-1 is expressed in plasma cells resulting from TI Ags, in plasma cells from both primary and secondary responses to TD Ags, and in long-lived plasma cells resident in the bone marrow. This is consistent with its previously suggested role as a regulator of terminal B cell differentiation. In addition, we show that Blimp-1 is not expressed in memory cells but is expressed in a small subset of GC B cells that have a partial plasma cell phenotype. These data suggest that expression of Blimp-1 is important for the commitment of GC B cells to a plasma cell fate.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (The Jackson Laboratory, Bar Harbor, ME) mice 8–10 wk old were immunized i.p. with 25 µg of (4-hydroxy-3-nitrophenyl)acetyl (NP)-Ficoll in 0.1 ml of saline (0.85% NaCl) or 100 µg of NP-keyhole limpet hemocyanin (KLH) alum precipitated (Biosearch Technologies, Novato, CA) in 0.2 ml of saline. Secondary immunization was done with 100 µg of alum-precipitated NP-KLH. Four weeks elapsed between primary and secondary immunization.
Antibodies
Rabbit polyclonal anti-Blimp-1 was kindly provided by Mark
Davis (20). Anti-CD138 (antimouse syndecan-1) and
anti-B220 were purchased from PharMingen (San Diego, CA);
anti-peanut agglutinin (PNA) and anti-PNA-biotin were obtained
from Vector Laboratories (Burlingame, CA); anti-Ki-67 (clone
TEC-3), anti-CD10 (clone 56C6), anti-CD20 (clone L26),
anti-CD138 (antihuman syndecan-1), and anti-CD23 were purchased
from Serotec; HRP-streptavidin and alkaline phosphatase
(AP)-streptavidin were obtained from Dako (Carpinteria, CA);
anti-
and all secondary Abs, biotin or AP conjugated, were
purchased from Southern Biotechnology Associates (Birmingham, AL);
anti-CD3-biotin and anti-CD20-FITC were obtained from Becton
Dickinson (Mountain View, CA); anti-CD38-biotin was obtained from
Caltag (South San Francisco, CA); and anti-IgD-FITC was purchased
from Dako.
Immunohistochemistry
Spleens were removed at indicated times after immunization and fixed in 1% paraformaldehyde overnight at 4°C, embedded in paraffin blocks, and processed by routine methods. Dewaxed sections were microwaved in 10 mM EDTA (pH 8) for 15 min (26), cooled, blocked with 3% human AB serum (Sigma, St. Louis, MO), and incubated overnight with appropriate dilutions of primary Abs and control sera. Sections were stained by a double-immunoenzyme technique using the biotin-avidin-peroxidase system and AP system. First, a rabbit anti-mouse Blimp-1 polyclonal (1:1000) or control serum was used. The sections were washed in washing buffer (TBS: 50 mM Tris (pH 7.5) and 0.1% Tween 20) and counterstained with 1:200 diluted, biotin-conjugated, mouse and human serum-adsorbed goat anti-rabbit Ab (Southern Biotechnology Associates). Finally, HRP-streptavidin was added and, after washing, developed with aminoethylcarbazole (Sigma). After color development the sections were incubated with the second primary Ab for 2–16 h at room temperature, at the dilutions suggested by manufacturers. Following washing, sections were incubated with the appropriate secondary Ab either biotin or AP conjugated (1:200 dilutions); in the former case, sections were finally incubated with streptavidin-AP (1:300 dilution). AP was developed by fast blue and napthol AsBi-phosphate (Sigma) substrate. Slides were lightly counterstained with hematoxylin.
Double immunofluorescence to detect Blimp-1 and Ki-67
Following treatment of paraffin-embedded spleen sections as described for immunohistochemistry, sections were blocked in TBS-3% serum for 10 min at room temperature. Blimp-1 antiserum (1:1000 dilution) was incubated overnight. Sections were washed five times with TBS-0.1%Tween 20 and incubated for 45 min with anti-rabbit IgG-biotin conjugated; following quenching of endogenous peroxidase, streptavidin-HRP (1:500 dilution) was added for 45 min. The Blimp-1 signal was enhanced with the tyramide amplification system (NEN Life Science Products, Boston, MA); sections were incubated with TBS-1% BSA prior addition of tyramide-biotin diluted 1:500 into Holmes buffer for 30 min. At this step, rat anti-Ki-67 (1 µg/ml) was added for overnight incubation. After washing, sections were incubated with FITC (tetramethylrhodamine isothiocyanate)-conjugated goat anti-rat (red color) Ig. A second round of primary and secondary Ab incubation (1 h each) was performed, followed by a 45-min incubation with streptavidin-7-amino-4-methylcoumarin-3-acetic acid to detect Blimp-1 (blue color). After final washings, coverslips were applied on sections using Vectashield (Vector Laboratories).
Double immunofluorescence to detect Blimp-1 and IRF4
Double immunofluorescence was performed on human tonsil sections by incubating fixed slides with the two primary Abs: rabbit anti-Blimp-1 and mouse anti-IRF4 (27). After overnight incubation, sections were washed and stained with both tetramethylrhodamine isothiocyanate-conjugated goat anti-rabbit Ab and FITC-conjugated goat anti-mouse Ab. A second round of primary and secondary Ab incubation (1 h each) was performed to enhance specific staining. After final washings, coverslips were applied on sections using Vectashield (Vector Laboratories).
In situ TUNEL assay
The TUNEL assay was performed using an in situ detection kit following the manufacturer’s instructions (Boehringer Mannheim GmbH, Mannheim, Germany) with the following modifications. Tonsil sections were fixed and stained with Blimp-1 Ab as described in immunohistochemistry methods. Sections were then labeled with 50 µl (3-fold diluted in appropriate buffer) of the TUNEL reaction mixture for 60 min at 37°C, washed, and then incubated for 30 min with 50 µl of converter AP. The slides were rinsed and incubated for 10 min at room temperature with 100 µl of fast blue/napthol AsBi phosphate solution.
Isolation of IgD-, CD38-, CD20+ memory cells
Human tonsils taken from patients during routine tonsillectomy were finely minced and the resulting cell suspension was subject to depletion of T cells by rosetting with sheep RBC. Partially purified B cells were incubated for 20 min with biotin-conjugated mouse Abs against CD3, CD38, and IgD and with FITC-conjugated mouse Ab against CD20. Following washes, cells were incubated for 15 min with streptavidin-APC. FITC-CD20+, APC-(CD38/CD3/IgD)-, FITC-CD20-, and APC-(CD38/CD3/IgD)high were sorted using FACStar (Becton Dickinson Immunocytometry Systems, San Jose, CA). Sorted cells were cytocentrifuged for 5 min at 800 rpm on microscope slides, dried at room temperature for 1 h, fixed for 10 min in 10% buffered Formalin and 10 min in methanol, and then stained with Blimp-1 polyclonal Ab as described for immunohistochemistry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We wished to confirm Blimp-1 expression in plasma cells formed in
vivo during an immune response and also wished to determine whether
Blimp-1 expression varied in plasma cells formed during a TI or TD
response. A recent report using in vitro culture has suggested that
Blimp-1 expression is limited to TI responses (28). To
determine whether Blimp-1 is expressed in short-lived, low-affinity
plasma cells generated in response to a TI Ag, mice were immunized with
NP (3) coupled to Ficoll (NP-Ficoll). This immunogen
produces a TI response which is genetically restricted in C57BL/6 mice
to production of Abs that predominately contain light chains
(14).
Mice were sacrificed 10 days after immunization and paraffin-embedded
spleen sections were stained with Abs recognizing Blimp-1, chains,
and syndecan-1 (Fig. 1
). The specificity
of Blimp-1 antiserum used in all our experiments was confirmed by
blocking with recombinant Blimp-1 protein before immunohistochemistry
(data not shown). Blimp-1+ (nuclear staining
shown in red) and syndecan-1+ (surface staining
shown in blue) cells were detected in PALS of the spleen where foci of
AFC are normally found (Fig. 1A). Ninety-four percent of the
syndecan+ cells present in the PALS were
Blimp-1+ and 97% of
Blimp-1+ cells were found to be
syndecan+. These cells represent Ig-secreting
plasma cells (29). When spleen sections were stained for
expression of light chain, large clusters of
+ cells (blue staining) were detected in the
PALS of immunized mice but not in control mice, where
+ cells represented <5% of Ig-expressing
cells (data not shown). Thus, the + cells
represent plasma cells that resulted from immunization with the TI Ag
NP-Ficoll. Nuclear Blimp-1 expression was detected in 85% the
+ cells (red nucleus surrounded by cytoplasmic
staining for ) and 94% of the syndecan+ cells
(Fig. 1B). Analysis of serial sections showed that some
cells appear to be Blimp-1- because the plane of
the section does not pass through the center of the nucleus, thus not
allowing detection of Blimp-1. These data show that Blimp-1 is
expressed in plasma cells derived from a TI response to NP-Ficoll.
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To investigate the expression of Blimp-1 in plasma cells resulting from a TD Ag, C57BL/6 mice were immunized with NP hapten conjugated with KLH. Splenic sections were analyzed by immunohistochemistry at intervals during the response.
Ten days after immunization, clusters of Blimp-1+
cells (nuclear staining shown in red) were observed in PALS and red
pulp of the spleen. Ninety-seven percent of
Blimp-1+ cells were
syndecan-1+ (Fig. 2A). B cells showing strong
expression of B220 (B220high) (surface staining
shown in blue) were negative for Blimp-1 expression
(left, Fig. 2B), whereas
B220-/low cells were
Blimp-1+(Fig. 2B), consistent with a
plasma cell phenotype (17).
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light
chain (32) and use the V186.2 VH
gene segment (30). The pattern of the response is also
well characterized (5). Six days after immunization, foci
of + cells appear in the extrafollicular areas
of lymphoid organs along one face of the T cell-rich areas of the PALS;
these represent short-lived plasma cells that survive for a few days
and secrete low-affinity IgM (5). These foci decrease in
size after day 8; the cells become increasingly dispersed and lose
their intimate association with the PALS (5).
When spleen sections obtained from mice 6 days after immunization were
analyzed by immunohistochemistry, clusters of
+ Blimp-1+ cells were
observed along the PALS (Fig. 2
C). These cells are also
syndecan-1+ (Fig. 2D) and most likely
represent short-lived plasma cells that arise during the early phase of
a TD response (17). +
Blimp-1+ cells were also detected 12 and 15 days
after immunization in PALS (data not shown) and red pulp when the
+ cells start to lose intimate association
with PALS (5). Thus, Blimp-1 is expressed in the
short-lived terminally differentiated plasma cells that arise during
the primary immune response to the TD Ag NP-KLH. Spleen sections from
immunized animals were also stained to detect cytoplasmic expression of
non-IgM isotypes in plasma cells. Blimp-1 protein was observed in the
nuclei of IgG1+ and IgA+
plasma cells (data not shown). Thus, Blimp-1 expression is not limited
to the IgM-secreting cells and Blimp-1 is expressed in plasma cells
that have undergone isotype switching. Blimp-1 was also observed in
syndecan+ plasma cells in human tonsils (see Fig. 7), adenoids (data not shown), and lymph nodes (Fig. 2E).
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F). Thus, Blimp-1 is expressed in
long-lived plasma cells that home to the bone marrow. Blimp-1 is expressed in plasma cells formed during a secondary immune response but not in memory B cells
The GC reaction produces memory B cells as well as plasma cells.
Upon secondary stimulation with Ag, memory cells proliferate and
differentiate into Ig-secreting plasma cells. To understand the
involvement of Blimp-1 in response to secondary stimulation, C57BL/6
mice, previously immunized with NP-KLH, were boosted 1 mo after primary
immunization. This immunization protocol gives a strong secondary IgG1
response (34). Spleen sections from boosted animals, along
with spleen sections from control mice (not boosted), were analyzed for
cytoplasmic IgG1 (blue) and nuclear Blimp-1 (red). Spleens from animals
receiving a secondary immunization show large clusters of
IgG1+ plasma cells (Fig. 3) not observed in control mice (data not
shown). These clusters of IgG1+ cells, most
likely derived from secondary immune response, were mainly
Blimp-1+ (Fig. 3, higher magnification). Thus,
Blimp-1 is expressed in plasma cells that arise from a secondary immune
response to NP-KLH.
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Serial sections of tonsils were stained with Abs against the surface
markers CD10, CD138, CD23, CD20, and Blimp-1 as indicated in Fig. 4. Since Blimp-1 is abundantly expressed
in epithelial cells (D. Chang and C. Angelin-Duclos, unpublished data),
the tonsillar epithelial regions were easily identified by strong
staining for Blimp-1 (in red). In Fig. 4A, the section was
stained with a mixture of antisera against CD10, CD138, CD23 (surface
staining in blue), and Blimp-1 (nuclear staining in red). Cells that
stain blue on the surface with this mixture of Abs are naive, GC, or
secreting B cells but are not memory B cells. As expected, some of
these cells express Blimp-1. In Fig. 4B, the section was
stained with anti-CD20 (surface staining in blue) and
anti-Blimp-1 (nuclear staining in red). Clusters of
CD20+ cells within the tonsillar epithelium (see
boxed region, Fig. 4B), that were negative for
CD10, CD138, and CD23 (see boxed region, Fig. 4A)
have a memory cell phenotype (35). These cells do not
express Blimp-1 although
Blimp-1+CD20- cells,
presumably plasma cells, were observed in other areas of the
section.
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) were stained for
expression of Blimp-1. The
IgD+CD3+CD38+CD20-
fraction contained Blimp-1+ cells which are
probably plasma cells
(CD38+CD20-) and provide a
positive control in this experiment; however, no
Blimp-1+ cells were observed in the
CD20+IgD-CD38-
fraction. Thus, we conclude that Blimp-1 is undetectable, and unlikely
to be expressed, in memory B cells.
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During a TD response, plasma cells (that express Blimp-1) and
memory cells (that do not express Blimp-1) are produced by GCs. When
murine GCs were analyzed, we found that a small but reproducible subset
of the PNA+ GC B cells was
Blimp-1+ (Fig. 6A). During the primary immune
response to NP-KLH, GCs are observed in the spleen at day 5, reach
maximum expansion at day 12, and persist until at least day 20
(5, 37). To determine when Blimp-1+
cells appeared during GC formation, spleen sections from mice immunized
with NP-KLH were analyzed 5, 8, 12, 15, and 22 days after immunization
for expression of Blimp-1 (red nuclear staining) and PNA (blue surface
staining). Both the total number of Blimp-1+
cells per GC and the frequency of Blimp-1+ cells
in GCs were low at days 5 and 8, high at day 12, and then fell rapidly
by day 15 (Table I). This pattern
suggests that Blimp-1+ cells, once formed, do not
remain in the GC.
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+ (blue staining) cells (Fig. 6B),
confirming that these cells resulted from immunization with NP-KLH. In
the Blimp-1+ + cells,
staining was stronger than in the majority of GC cells and appeared
to be localized to the cytoplasm rather than on the surface, showing
that these cells were secreting Ig.
GC centroblasts undergo very active proliferation whereas centrocytes
do not divide. Based on the Blimp-1-dependent repression of
c-myc transcription and cessation of proliferation observed
in the BCL-1 cell model, we expected that Blimp-1 expression in the GC
would be limited to centrocytes. To test this hypothesis, we used Ab to
Ki-67, a nucleolar protein present only in dividing cells
(38) to distinguish GC centroblasts (large cells) from
centrocytes (small cells, Ki-67-). Surprisingly,
two-color immunofluorescence, using Blimp-1 and Ki-67 Abs, revealed
that at least half of the Blimp-1+ GC cells were
Ki-67+ (Fig. 6, C–E). Thus, our data
show that some of the Blimp-1+ cells in the GC
are proliferating centroblasts.
GCs in human tonsils and adenoids were also examined, and Blimp-1
expression was observed in 
15% of CD10+ GC
cells. To characterize these cells further, human tonsils were stained
for expression of CD10 and Bcl-6 (characteristic of GC B cells); CD138
and IRF4 (characteristic of Ig-secreting plasma cells), CD23
(characteristic of mature mantle B cells and follicular dendritic
cells), and CD20 (characteristic of pre-B, resting, activated, or
memory B cells, but not plasma cells) (39, 40, 41). Fig. 7, A–D, shows serial sections
of a tonsillar GC and extrafollicular regions stained for Blimp-1 (red)
and for CD10, CD138, CD20, or CD23 (in blue), and Fig. 7
(E–G) shows a tonsillar GC stained for Blimp-1 and IRF-4.
Blimp-1+ plasma cells were observed outside the
follicles (Fig. 7B); in addition, 15% of the
CD10+ GC cells were
Blimp-1+ (Fig. 7A). Frequently the
Blimp-1+ cells in human GCs were organized in
clusters, possibly around a follicular dendritic cell (see boxed
regions in A–D). These clustered
Blimp-1+ cells are CD10+
(Fig. 7A), CD138+ (Fig. 7B), CD20- (although a few are
positive) (Fig. 7C), CD23- (Fig. 7D), IRF4+ (Fig. 7, E–G),
and Bcl-6- (data not shown). Expression of CD138
and IRF4 and loss of expression of Bcl-6 and CD20 are characteristic of
plasma cells rather than GC cells or memory cells.
Enforced expression of Blimp-1 in cultured lines representing pre-B or
mature B cell developmental stages causes apoptosis (24, 42). Therefore, we wondered whether Blimp-1 expression in GC B
cells was associated with apoptosis. In situ TUNEL assay was performed
on the human tonsil sections in combination with Blimp-1 staining. Most
Blimp-1+ (red nuclear staining) cells were not
TUNEL+ (Fig. 7H). Because we were
technically unable to detect both Blimp-1 and dUTP incorporation using
double immunofluorescence, we cannot rule out the possibility that some
TUNEL+ cells may be
Blimp-1+. However, by analyzing serial sections
that were single stained with Blimp-1 or TUNEL (data not shown), we
conclude that many/most Blimp-1+ cells are not
TUNEL+. In addition, none of the
Blimp-1+ cells have an apoptotic morphology.
Therefore, the data show that expression of Blimp-1 in GC B cells is
not obligatorily associated with apoptosis.
In summary, we show that a subset of GC B cells expresses Blimp-1 in both mouse and human. These cells are not apoptotic and some of them are proliferating. In mice, their numbers peak at day 12 following immunization with NP-KLH and they do not accumulate in the GC thereafter. Although GC markers, PNA, or CD10 are expressed on these cells, they also express CD138 and IRF4, but not Bcl-6 and appear to be secreting Ig, suggesting acquisition of a partial plasma cell phenotype.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blimp-1 is present in plasma cells but not in memory cells
During a primary response, two types of plasma cells are formed.
Outside of the follicles, short-lived plasma cells producing IgM with
low affinity for Ag (29) provide the first response to TD
Ags and the only response to TI Ags. In response to TD Ags,
longer-lived plasma cells secreting IgG or IgA with higher affinity for
Ag are formed after B cells undergo affinity maturation and isotype
switching. Long-lived plasma cells in the bone marrow are thought to be
derived from plasma blasts that exit the GC (14, 43, 44).
High-affinity isotype-switched plasma cells are also formed from memory
cells in a secondary immune response. Blimp-1 was present in plasma
cells in the PALS, resulting from a primary response to either TI or TD
Ags, and in plasma cells arising from a secondary response to a TD Ag.
In addition, the presence of Blimp-1 in GC B cells (Fig. 6) further
confirms that Blimp-1 is induced during a TD response.
The small percentage of Blimp-1+ syndecan- cells may represent precursors of the AFC in which the syndecan marker is not yet expressed. A similar precursor can be found in the GC where a small percentage of Blimp-1+ syndecan- cells is also observed. Blimp-1 expression in these cells may represent one of the early signals required for differentiation into short-lived AFC.
Blimp-1 was also present in the long-lived plasma cells resident in the bone marrow. It has been suggested that Blimp-1 in short-lived plasma cells is associated with apoptosis due to repression of the anti-apoptotic gene A1 (43), and this possibility is consistent with our data. However, since Blimp-1 is also expressed in long-lived plasma cells, its expression is not necessarily associated with apoptosis in all plasma cells. Expression of Blimp-1 in all types of plasma cells is consistent with the presence of Blimp-1 in murine plasmacytoma and human myeloma cell lines and with its induction during terminal differentiation of BCL-1 cells to a plasma cell phenotype.
However, our results differ from a previous report in which an antisense strategy was used to inhibit Blimp-1 expression in cultured splenocytes (28). In this study, Blimp-1 appeared to be required for a TI but not for a TD response when splenocytes were treated in vitro with anti-CD40 mAb and IL-4. It seems likely that differences between stimulation of splenocytes in culture and an immune response in vivo account for the apparent discrepancy, particularly since the role of CD40 in a TD immune response and its role in plasma cell terminal differentiation is still debated (46, 47, 48, 49, 50). It is also formally possible that even though Blimp-1 is expressed in plasma cells formed during a TD response in vivo, it is not required for that response. The final resolution of this question awaits B cell-specific deletion of the Blimp-1 gene in vivo.
Our studies on human tonsils revealed no evidence for Blimp-1 in
CD20+CD23-CD138-CD10-
memory cells found in the epithelial area of tonsils (Fig. 4) or in
purified populations of memory cells (Fig. 5). Thus, it is clear that
Blimp-1 is not expressed in most memory cells. This finding is similar
to that of Nagumo et al. (51), who also reported lack of
Blimp-1 in CD20+ cells purified from human PBLs.
Given our understanding that Blimp-1 induces Ig secretion and represses
c-myc and class II MHC expression, it is reasonable that
memory cells, which retain surface Ig and class II MHC expression
(35, 52) and retain the ability to proliferate, do not
express Blimp-1.
Blimp-1+ cells in the GC may be committed to a plasma cell fate
Finding Blimp-1 in a subset of GC B cells, in both murine spleen and human tonsils and adenoids, was unexpected based on the previously observed expression pattern of Blimp-1 in B cell lines. The majority of Blimp-1+ GC cells are viable and some are positive for Ki-67, a marker of proliferating cells. Thus, Blimp-1 does not cause apoptosis in these cells as it does when ectopically expressed in B cell lines representing earlier stages of development (24, 42).
Centroblasts are highly proliferative and probably receive multiple mitogenic signals that activate c-myc transcription. We hypothesize that Blimp-1-dependent repression of c-myc transcription may be overcome by these signals so that centroblasts express Blimp-1 as well as c-Myc. In centroblasts, Blimp-1 may regulate other target genes, such as A1 (43) or CIITA.4 Once B cells leave the dark zone or the GC, strong proliferative signals that activate c-myc transcription may be lost, allowing Blimp-1 to repress c-myc transcription, leading to cessation of cell cycle that accompanies terminal differentiation.
Blimp-1+ cells in the GC appear to represent a
dynamic transition from a GC phenotype (CD10+ or
PNA+, CD20+,
CD138-, surface Ig) to an AFC phenotype
(CD10- or PNA-,
CD20-, Bcl-6-,
IRF4+, CD138+, Ig
secreting). In both human and murine GCs, the
Blimp-1+ cells were predominately
syndecan-1+ (70%); in the mice immunized with
NP-KLH, expression in Blimp-1+ GC cells was
cytoplasmic, consistent with cells secreting Ig rather than expressing
Ig on the surface. The
Blimp-1+CD10+ GC cells
in tonsils were predominately
CD138+IRF4+CD20-Bcl-6-CD23-,
a phenotype associated with AFC. AFC have been observed in the GC
previously (53, 54, 55, 56, 57). More recently IRF4, which is required
for formation of Ig-secreting cells (58), was shown to be
expressed in a subset of GC B cells with an AFC phenotype
(27). Indeed, we found that IRF4 and Blimp-1 are expressed
in the same subset of GC cells. The existence in the GC of this
Blimp-1+IRF4+ subset with
an AFC phenotype implies that the fate decision between memory cells
and AFC occurs before B cells leave the GC.
Blimp-1+ cells appear in the GC early in the
primary response and peak at day 12; thereafter, they disappear rapidly
(Table I). This timing is consistent with previous reports that AFC are
produced in the GC earlier than the bulk of memory cells (54, 59, 60, 61, 62). The data also suggest that, once formed,
Blimp-1+ cells do not accumulate in the GC but
exit rapidly. This observation leads to the interesting possibility
that expression of Blimp-1 is important for the decision of an AFC to
exit the GC as well as with commitment to an AFC phenotype.
Further study on the role and regulated expression of Blimp-1 is likely to illuminate important aspects of AFC differentiation in the GC. In particular, it will be important to determine whether induction of Blimp-1 in the GC is stochastic or instructed. Cytokine-dependent induction of Blimp-1 mRNA in cell culture models suggests that it may be instructed (20, 24). Furthermore, studies with primary cultures of human tonsillar B cells suggest that CD40/CD40 ligand signals favor memory cell differentiation and block plasma cell differentiation (36). Consistent with an instructive model, treatment with CD40 ligand blocks Blimp-1 induction as well as plasma cell differentiation in the CH12 cell line (50). Plasma cell differentiation appears to be driven by signals from OX40 ligand, CD27, and cytokines, including IL-10, IL-3, and IL-6 (10, 51, 63, 64). In addition, a recent report suggests that a threshold level of Ag affinity is required for development of AFC but not memory cells (62) although another study did not observe this requirement (65). Thus, signaling via B cell receptor may be important for Blimp-1 induction. It will be important to learn if one or a combination of these signals induces expression of Blimp-1 in GC B cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kathryn Calame, Department of Microbiology, Columbia University, 701 168th Street, New York, NY 10032.
3 Abbreviations used in this paper: TI, T independent; AFC, Ab-forming cell; PALS, periarteriolar lymphoid sheath; TD, T dependent; GC, germinal center; Blimp-1, B lymphocyte-induced maturation protein-1; NP, (4-hydroxy-3-nitrophenyl)acetyl; KLH, keyhole limpet hemocyanin; PNA, peanut agglutinin; AP, alkaline phosphatase.
4 J. Piskurich, Y. Lin, Y. Wang, K. Lin, J. Ting, and K. Calame. Submitted for publication.
Received for publication June 28, 2000. Accepted for publication August 28, 2000.
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2a variable region. Cell 24:625.[Medline]
switch, and light chain expression. J. Exp. Med. 187:1169.This article has been cited by other articles:
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