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Molecular and Cellular Biology, June 2001, p. 4067-4074, Vol. 21, No. 12
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.12.4067-4074.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
B-Cell Maturation Protein, Which Binds the Tumor Necrosis Factor
Family Members BAFF and APRIL, Is Dispensable for Humoral
Immune Responses
Shengli
Xu and
Kong-Peng
Lam*
Institute of Molecular and Cell Biology,
Singapore 117609, Republic of Singapore
Received 18 January 2001/Returned for modification 28 February
2001/Accepted 20 March 2001
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ABSTRACT |
B-cell maturation protein (BCMA) is a member of the tumor necrosis
factor (TNF) receptor family and is expressed in B lymphocytes. BCMA
binds two TNF family members, BAFF and APRIL, that stimulate cellular
proliferation. BAFF in particular has been shown to influence B-cell
survival and activation, and transgenic mice overexpressing BAFF have a
lupus-like autoimmune disorder. We have inactivated BCMA in the mouse
germ line. BCMA
/ mice have normal B-cell
development, and the life span of mutant B lymphocytes is
comparable to that of wild-type B cells. The humoral immune
responses of BCMA/ mice to T-cell-independent antigens
as well as high and low doses of T-cell-dependent antigens are also
intact. In addition, mutant mice have normal splenic architecture, and
germinal centers are formed during an ongoing immune response. These
data suggest a functional redundancy of BCMA in B-cell physiology
that is probably due to the presence of TACI, another TNF
receptor family member that is expressed on B cells and that can also
bind BAFF and APRIL.
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INTRODUCTION |
Members of the tumor necrosis factor
(TNF) superfamily regulate a variety of cellular functions that include
proliferation, differentiation, and apoptosis. In particular, several
well-characterized members of the family such as TNF, lymphotoxins 
and 
, CD27 ligand (CD27L), CD30L, CD40L, OX40L, and FasL are known
to be critical regulators of the immune system and are essential for lymphoid cell development and selection, immune tolerance, and cell
death as well as immune responses against exogenous antigens (5,
7). Most TNF family members are synthesized as type II
transmembrane precursors, and their extracellular domains can be
cleaved to form soluble cytokines. However, both the soluble and the
membrane-bound forms of the TNF ligand can bind to type I transmembrane
receptors that contain one or more characteristic cysteine-rich motifs
and belong to the TNF receptor family (7, 26, 29).
Recently, a new member of the TNF superfamily has been identified and
termed BAFF (B-cell-activating factor belonging to the TNF family),
BLyS (B-lymphocyte stimulator), TALL-1 (TNF and apoptosis ligand-related leukocyte-expressed ligand 1), THANK (TNF homologue that
activates apoptosis, NF-
B, and c-Jun NH2-terminal kinase [JNK]), or zTNF4 (8, 19, 20, 23, 24). BAFF is expressed by monocytes and macrophages (21) as well as by T cells
and dendritic cells (23). It has been shown specifically
to bind to B cells (19, 23), suggesting that its receptor
is expressed on this cell type. BAFF is known to stimulate B-cell
proliferation and immunoglobulin secretion (19, 23) as
well as modulate the survival of peripheral B cells (1, 3, 15,
27). Consistent with its role in regulating B-cell physiology,
transgenic mice overexpressing BAFF develop a lupus-like autoimmune
disorder (8, 12, 16), and human with systemic lupus
erythematosus have elevated levels of BAFF in their blood
(37).
The receptors for BAFF were identified as BCMA (B-cell maturation
protein) and TACI (transmembrane activator and calcium modulator and
cyclophilin ligand), two orphan members of the TNF receptor family
(18, 25, 27, 32, 33, 35, 36). These two receptors are
expressed on resting and activated B cells (6, 14, 17, 19,
23). Engagement of BCMA activates JNK, p38 mitogen activated protein kinase (MAPK) and the transcription factors NF-B and Elk-1
(10), whereas cross-linking of TACI activates the
transcription factors NF-B and NF-AT (28). The
physiological relevance of these two receptors was demonstrated
by injecting soluble forms of either BCMA or TACI into mice. These
decoy receptors disrupted immune responses and splenic
architecture and prevented the accumulation of peripheral B cells
(8, 27, 35, 36). In addition, they could even alleviate
the autoimmune syndrome of lupus-prone mouse strains (8,
31).
Interestingly, both BCMA and TACI also bind APRIL (a
proliferation-inducing ligand), another member of the TNF family that is closely related to BAFF (8, 11, 18, 22, 32, 33, 30,
36). APRIL has been shown to stimulate the proliferation of
tumors (9) and, recently, B cells (36). The
administration of recombinant APRIL to mice also led to an accumulation
of B cells in vivo (36), similar to the effect of the
administration of BAFF (19). Both APRIL and BAFF bind BCMA
or TACI with equivalent affinity (8, 18, 22, 32, 33, 36),
and it was not clear why there would be cross-interaction among the two
ligands and two receptors.
Given the existence of two TNF ligands, APRIL and BAFF, that can bind
independently to two TNF receptors, BCMA and TACI, it is difficult to
deduce the relative contribution of each individual component of this
dual receptor-dual ligand system to the regulation of B-cell physiology
and humoral immune responses in vivo. Indeed, it is not known if one
specific pair of ligand and receptor would play a more important role
physiologically. We therefore undertook to dissect the system by
selectively inactivating BCMA or/and TACI in the mouse germ line. In
this report, we document the generation and characterization of mutant
mice lacking BCMA.
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MATERIALS AND METHODS |
Generation of BCMA-deficient mice.
The cDNA for BCMA was
obtained by reverse transcription-PCR (RT-PCR) of RNA isolated from
mouse spleens, using the primers 5'-TCTTTCAGTGATCCAGTCCC-3'
and 5'-TCTCCTGACAGAAGGTTCTC-3', and verified by
sequencing. This cDNA is used to probe a mouse 129 genomic DNA library.
Restriction enzyme digestion, Southern blotting, and DNA sequencing
were used to map the genomic clone of BCMA. A targeting vector was
constructed to replace the third and final exon of BCMA with a
neo gene. A 4-kb HindIII-XhoI
fragment 3' and a 1.6-kb BamHI-BamHI fragment 5'
of the deleted exon were used as the long and short arms of homology,
respectively. The targeting vector was linearized and electroporated
into E14.1 embryonic stem (ES) cells, which were subsequently selected
with 300 µg of G418 (Gibco) per ml and 2 µM ganciclovir. DNA was
prepared from drug-resistant ES cell clones and digested with
HindIII. Homologous recombinants were identified by
Southern blotting using probe A (Fig. 1).
The frequency of targeting was 1:50. Two targeted ES cell clones were
injected into C57BL/6 blastocysts to generate chimeric mice for germ
line transmission of the mutant allele. BCMA/ mice were
analyzed at 6 to 10 weeks of age and were of mixed 129-C57BL/6
background.
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FIG. 1.
Gene inactivation of BCMA. (A) Partial restriction
endonuclease map of the wild-type allele, the targeting vector, and the
inactivated allele of BCMA (B, BamHI; E, EcoRI;
H, HindIII; X, XhoI; pBKS, pBluescript KS).
The black boxes represent exons. HindIII digestion of
the genomic DNA will yield fragments of 8 and 6 kb for the wild-type
and targeted alleles, respectively, as revealed by the external probe
A. (B) Southern blot analysis of HindIII-digested tail
DNA obtained from wild-type, BCMA+/ and
BCMA/ mice. (C) RT-PCR of splenic RNA samples obtained
from wild-type and BCMA/ mice. The 5' RT-PCR identified
the region corresponding to exon I of the gene. The housekeeping gene
GADPH is included as control.
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Examination of BCMA and TACI expression by RT-PCR.
Total RNA
was extracted from splenocytes of wild-type and BCMA/
mice by using TRIZOL reagent (GIBCO BRL) Five micrograms of the total
RNA was reverse transcribed into cDNA, using the Superscript preamplification system (GIBCO BRL) in a reaction volume of 20 µl.
The following primers were used to detect the presence of full-length
BCMA cDNA (545 bp, primers 1 and 2) or the portion corresponding to
exon I (278 bp, primers 1 and 3) of the BCMA cDNA: primer 1, 5'-TCTTTCAGTGATCCAGTCCC-3'; primer 2, 5'-CACTTTGCAAAGCAGTTGGC-3'; and primer 3, 5'-TTTGAGGCTCGTCCTTCAGG-3'. In addition, the expression of
TACI was examined in a semiquantitative manner using the primer 5'-ATGGCTATGGCATTC-3' and 5'-TCAGATCCCTGGTGCCTTCC-3'
in RT-PCR with various numbers of amplification cycles.
Glyceraldehyde 3-phosphate dehydrogenase (GADPH) was also amplified as
a control for the amount of template used in the RT-PCR.
Antibodies.
The antibodies used in flow cytometry and
immunohistochemistry, all purchased from PharMingen (San Diego,
Calif.), were anti-B220 (RA3-6B2), anti-immunoglobulin M (IgM)
(R6-60.2), anti-CD5 (53-7.3), anti-CD21/35 (7G6), anti-CD23 (B3B4), and
anti-Syndecan-1.
Flow cytometry analyses.
Single-cell suspensions were
obtained from the spleen and lymph nodes by dissociation of the tissues
with plastic mesh and rubber stoppers from 5-ml syringes. Peritoneal
cavity and bone marrow cells were obtained by injecting staining medium
(phosphate-buffered saline [PBS] containing 3% fetal bovine serum
and 0.1% sodium azide) into the peritoneal cavity and into the femur
and tibia, respectively, of each mouse. All cells were treated with red
blood cell lysing solution (0.15 M NH4Cl, 1 mM
KHCO3, 0.1 mM Na2EDTA) for 5 min at 4°C to
eliminate erythrocytes. For flow cytometric analyses, cells were
stained with optimal amounts of fluorescein isothiocyanate (FITC)-,
phycoerythrin, and biotin-conjugated antibodies for 10 min at 4°C and
subsequently washed twice with staining medium. Biotin-conjugated
antibodies were revealed by second step staining with
streptavidin-CyChrome. Flow cytometry analyses were performed on a
FACScan (Becton Dickinson, Mountain View, Calif.) using CellQuest software.
BrdU incorporation studies.
Wild-type and mutant mice were
fed continuously with water containing 1 mg of 5-bromo-2-deoxyuridinc
(BrdU) per ml over a period of 1 to 3 weeks. Peritoneal cavity and
splenic cells were harvested from the animals and surface stained with
anti-B220 and anti-IgM antibodies to identify B cells. The cells were
fixed for 30 min in 1 ml of ice-cold 70% ethanol and overnight in PBS containing 0.1% Tween 20 and 1% paraformaldehyde. Subsequently, the
cells were washed once in PBS and incubated for 10 min at room
temperature in a solution containing 150 mM NaCl, 5 mM
MgCl2, 10 µM HCl, and 300 µg of DNase I per ml.
Finally, the cells were stained intracellularly with the anti-BrdU
antibody (Becton Dickinson) for 20 min at room temperature, washed
twice in PBS, and analyzed on a FACScan.
Basal serum immunoglobulin levels.
To measure basal serum
immunoglobulin levels, enzyme-linked immunosorbent assay (ELISA) plates
were coated with rat anti-mouse Ig antibodies (5 µg/ml). Sera
obtained from wild-type and mutant mice were serially diluted and added
into the wells. After the washing and blocking steps, horseradish
peroxidase-coupled rat anti-mouse IgM, IgA, IgE, IgG1, IgG2a, IgG2b, or
IgG3 antibodies were added; this was followed by addition of the ELISA
substrate tetramethylbenzidine (Pierce). Levels of the various serum
immunoglobulins were quantified against known standards that were also
included in the assays.
Immunizations of BCMA-deficient mice with antigens.
The ability of BCMA/ mice to mount a humoral
immune response was assessed by immunizing the animals with the hapten
4-hydroxy-3-nitrophenyl acetyl (NP) as described previously
(34). Wild-type and mutant mice were injected
intraperitoneally with 10 µg of NP25-Ficoll (NP-Ficoll)
in PBS to examine their immune responses to a T-cell-independent antigen. For the immune response to a T-cell-dependent antigen, mice
were immunized intraperitoneally with 200 or 5 µg of
alum-precipitated NP17-chicken globulin (NP-CG) in a high-
or low-dose vaccination protocol, respectively. For the secondary
immune response, all animals were challenged with 5 µg of
alum-precipitated NP-CG. Sera were collected from the mice at various
time points after immunizations to detect the presence of NP-specific
antibodies in an ELISA. To detect NP-specific antibodies, the ELISA
plates were coated with NP-bovine serum albumin (5 µg/ml; 50 µl/well) at 4°C overnight and subsequently blocked with (200 µl/well) 3% bovine serum albumin at room temperature for 2 h.
Preimmune and immune sera were added at various dilutions to the wells
of the ELISA plates at room temperature for 2 h; this was followed
sequentially by addition of horseradish peroxidase-coupled rat
anti-mouse antibodies and the ELISA substrate tetramethylbenzidine
(Pierce). The wells of the ELISA plates were washed with PBS containing
0.02% Tween 20 between each incubation step. Specific antibodies of
classes IgM and IgG3 and those of classes IgM and IgG1 were quantified for T-cell-independent and T-cell-dependent immune responses, respectively.
Immunohistochemistry.
Spleens from wild-type and
BCMA/ mice were snap-frozen in Tissue-Tek solution
(Sakura, Finetek). Cryostat sections 8 to 10 µm thick were prepared
on gelatin-coated slides and fixed in ice-cold acetone. The samples
were rehydrated, blocked for 1 h in staining buffer (0.1% Triton X-100
in PBS) containing 5% heat-inactivated rat serum, and subsequently
stained with FITC-and biotin-conjugated antibodies. The
biotin-conjugated antibodies were revealed with streptavidin-Texas red
(PharMingen). After the final washes, the slides were mounted in Gel
Mount (Biomeda, Foster City, Calif.) and examined by laser confocal
microscopy (MRC 1024; Bio-Rad).
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RESULTS |
Generation of BCMA-deficient mice.
BCMA was recently
identified as a receptor for BAFF and APRIL, two TNF family members
that play an important role in B-cell activation (8, 18,
25). To determine if BCMA is required for the in vivo
development and activation of B lymphocytes, we have inactivated the
receptor in the mouse. BCMA-deficient mice were generated by deleting
the third exon of the bcma gene, which codes for amino acids
92 to 185 of the protein (Fig. 1A). This targeting strategy leads to
the removal of most of the intracellular domain of BCMA which includes
the region (amino acids 119 to 143) that is required for the binding of
TNF receptor-associated factors, the activation of NF-B, JNK, and
p38 MAPK, and the induction of Elk-1 (10).
The deletion of exon III in mutant mice was verified by Southern
blotting (Fig.
1B). To ensure that BCMA is indeed inactivated,
RT-PCR
was performed on RNA isolated from the spleens of mutant
mice, using
primers that correspond to exon I and to the full-length
cDNA of BCMA.
As shown in Fig.
1C, neither the full-length BCMA
message nor a
truncated version that would be encoded by exons
I and II was detected
in samples obtained from the mutant mice.
This suggests that the
bcma loci have been successfully disrupted
in the mutant
mice and that no aberrant or truncated protein is
likely to be
generated.
Normal B-cell development in BCMA-deficient mice.
BCMA is expressed only in B lymphocytes (6, 14) and thus
may play an important role in B-cell development and/or activation. To
determine the effect of BCMA inactivation in early B-cell development, we analyzed the bone marrow cells of mutant and wild-type mice by flow
cytometry. As shown in Fig. 2A,
B220+ IgM pre-B cells as well as
B220+ IgM+ immature B cells are found in
equivalent proportions in BCMA/ and wild-type mice. In
addition, the populations of mature recirculating B220high
IgM+ cells are also comparable in the wild-type and mutant
animals. Thus, the data indicate that BCMA is not required for the
development of early B cells. This is not surprising, as BCMA is
expressed only at the mature stage of B-cell differentiation (6,
14).
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FIG. 2.
B-cell populations in BCMA/ mice,
determined by flow cytometry analyses of B-cell populations found in
bone marrow (A), spleens (B and C), and peritoneal cavities (D) of
wild-type and BCMA/ mice. Only IgM+ B cells
are shown in panel C. Numbers indicate the percentages of cells within
the lymphocyte forward and side scatter gates (A, B, and D) and
percentages of IgM+ B cells for (D). The data shown are
representative of more than five analyses.
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Since only B cells in the peripheral lymphoid organs express BCMA and
its ligand BAFF is expressed by T cells and dendritic
cells
(
23), which are known to interact with B cells, we next
examine if the compositions of the various B-cell subpopulations
found
in the spleens of mice are altered in the absence of this
protein. It
has been reported that the treatment of mice with
soluble BAFF expands
certain B-cell subpopulations such as the
marginal zone B cells in the
spleen (
1,
27). As shown in
Fig.
2B,
2C, and
3, splenic B cells found in the mutant
mice are
indistinguishable with respect to phenotype or subpopulation
distribution
from those in wild-type animals. The
B220
+ IgM
+ B cells are present within
normal range in BCMA
/ mice compared to wild-type mice
(Fig.
2B). In addition, the different
subpopulations of immature,
follicular, and marginal zone B cells,
defined by their relative
expression of the CD21/35 and CD23 antigens,
are also unchanged (Fig.
2C and
3).
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FIG. 3.
Distribution of various B-cell populations in spleens of
BCMA/ mice. The distribution of marginal zone (MZ),
immature (Im), and follicular B cells as defined in Fig. 2C was
examined in four wild-type (white boxes) and five mutant (black boxes)
mice and expressed as percentage of total splenic B cells.
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Next, we examine if the absence of BCMA would affect the development of
the CD5
+ B cells that reside predominantly in the
peritoneal cavity of
mice, given that its ligand BAFF is also produced
and secreted
by monocytes and myeloid cells (
21) that are
found in sizeable
numbers at this location. CD5
+ B cells
can be distinguished from normal B cells by their expression
of the CD5
antigen. As seen in Fig.
2D, CD5
+ B cells are also found in
the peritoneal cavities of BCMA
/ mice, suggesting that
this B-cell subset is not perturbed by
the inactivation of
BCMA.
Finally, enumeration of the B cells in the bone marrow, spleens, lymph
nodes, and peritoneal cavities of BCMA
/ mice indicates
that their numbers are comparable to those of
wild-type animals (data
not shown). This suggests that the absence
of BCMA has no effect on the
size of the peripheral B-cell populations.
Taken together, the data
indicate that a BCMA deficiency does
not alter the maturation of B
cells or the distribution of the
various subsets of peripheral B
cells.
BCMA-deficient and wild-type B cells have comparable life
spans.
Recently, it has been reported that BAFF mediates the
survival of peripheral B lymphocytes (1, 27). Therefore,
we performed BrdU-labeling studies in vivo to determine if the life
span of B cells is altered in the absence of BCMA. The life span of B cells is reflected by the turnover of the B-cell population in the
periphery, which is measured by a change in the fraction of B cells
that have incorporated BrdU over a period of time (4). An
increased in the fraction of BrdU+ B cells would suggest a
shortened life span, and vice versa. Mice were continuously fed with
BrdU-containing water for a period of 1 or 3 weeks. As shown in Fig.
4, the fraction of IgM+ B
cells in the spleen and peritoneal cavity that have incorporated BrdU
is comparable between mutant and wild-type animals over a 1-week
period. There seems to be a slightly higher turnover of the B-cell
population in the peritoneal cavity of BCMA/ mice
compared to wild-type mice over a 3-week labeling period; however, this
difference is not detected in the splenic B-cell population. Taken
together, the data suggest that the average life span of B lymphocytes
is not significantly altered in the absence of BCMA.
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FIG. 4.
Turnover of wild-type and BCMA-deficient B cells. Mice
were continuously fed with BrdU in drinking water for a period of 1 or
3 weeks. B220+ IgM+ splenic and peritoneal
cavity B cells were stained for intracellular BrdU content. Groups of
four wild-type (white box) and five mutant (black box) mice were
analyzed for each time point.
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BCMA-deficient mice have normal humoral immune responses.
Treatment of normal mice with soluble BAFF leads to elevated levels of
serum immunoglobulins (19), and transgenic mice
overexpressing BAFF develop a lupus-like syndrome characterized by the
presence of autoantibodies (8, 12, 16). In addition, the
administration of a soluble form of BCMA to mice inhibits
(36), whereas treatment of mice with recombinant BAFF
enhances (3), humoral immune responses. These findings
together suggest that both BCMA and its ligand BAFF are involved in
B-cell responses to antigens. To assess if the B cells in
BCMA-deficient mice are functionally normal, we first examine the basal
immunoglobulin levels in the sera of mutant mice. As shown in Fig.
5, the serum concentrations of the
various classes of immunoglobulins such as IgM, IgG1, IgG2a, IgG2b,
IgG3, and IgA as well as those of IgE (data not shown) are within the
normal range, suggesting that there is no overt general activation or
anergy of B lymphocytes in BCMA/ mice.
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FIG. 5.
Basal serum immunoglobulin levels in
BCMA/ mice. The concentrations of various serum
immunoglobulin isotypes were measured by ELISA, and the value for each
wild-type (open circles) and mutant (filled circles) mouse was
plotted.
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Antigens that elicit an antibody response from B cells can be
classified as T cell independent or T cell dependent according
to
their dependency on CD4
+ T-cell help. To determine
if BCMA
/ mice could mount efficient immune
responses against exogenous
antigens, we first immunized the mice with
a T-cell-independent
antigen, NP-Ficoll. The primary antibody response
to NP-Ficoll
is mainly of the IgM and IgG3 class. As shown in Fig.
6, BCMA
/ mice are able to
respond to T-cell-independent antigen, and the
mutant B cells secrete
equivalent if not slightly higher IgM and
IgG3 antigen-specific
antibodies compared to wild-type animals
a week after the initial
challenge with NP-Ficoll.
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FIG. 6.
BCMA/ mice have normal
T-cell-independent immune responses. Wild-type (open circles) and
mutant (filled circles) mice were immunized with 10 µg of the
T-cell-independent antigen NP-Ficoll. The amount of antigen-specific
antibodies of the IgM and IgG3 class was measured in an ELISA 8 days
after the challenge. The value for each mouse was plotted. Preimmune
sera were negative for the antigen-specific antibodies and are not
shown.
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For the T-cell-dependent immune response, we immunized the mice with
either a high or a low dose of the antigen NP-CG for
the primary
response and rechallenged the mice 45 days later with
a low dose of the
same antigen for the secondary response. The
antibody response to NP-CG
is mostly of the IgM and IgG1 class.
In the high-dose immunization
regimen (Fig.
7), the primary and
secondary immune responses of BCMA-deficient mice are comparable
to
those of the wild-type mice across the various time points
examined,
although there seems to be a slightly higher antigen-specific
IgM titer
in the mutant animals within the first week of the primary
and
secondary challenge (Fig.
7A). The antigen-specific IgG titer
is,
however, comparable between the wild-type and mutant mice
(Fig.
7B).
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FIG. 7.
Primary and secondary immune responses of BCMA-deficient
mice to a high dose of T-cell-dependent antigen. Wild-type (open
circles) and mutant (filled circles) mice were immunized with 200 µg
of the alum-precipitated T-cell-dependent antigen NP-CG for the primary
(10) response and reboosted at day 45 with 5 µg of the
antigen for the secondary (20) immune response. Sera were
collected from the mice at various time points after primary and
secondary immunizations and quantified for the presence of NP-specific
antibodies of the IgM and IgG1 classes. The immune sera were diluted as
indicated. The value for each mouse was plotted. Preimmune sera were
negative for the antigen-specific antibodies and are not shown.
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Similarly, in the low-dose immunization regimen (Fig.
8), BCMA
/ and wild-type
mice do not differ significantly in their primary
and secondary immune
responses with the exception that there is
again a slightly higher IgM
titer immediately following a reboost.
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FIG. 8.
Primary and secondary immune responses of BCMA-deficient
mice to a low dose of T-cell-dependent antigen. Wild-type (open
circles) and mutant (filled circles) mice were immunized with 5 µg of
alum-precipitated NP-CG and reboosted at day 45 with the same amount of
the antigen. The ELISA was performed as for Fig. 7.
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Overall, the serological data indicate that BCMA
/ mice
are able to mount normal humoral immune responses to T-cell-independent
and T-cell-dependent antigens. Indeed, consistent with the serological
data on the basal and antigen-specific antibody titers, our flow
cytometry analysis indicates that plasma cells, as identified
by their
expression of the Syndecan-1 marker, are found in equivalent
proportions in wild-type and BCMA
/ mice (Fig.
9).
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FIG. 9.
Distribution of Syndecan-1-expressing B cells in
BCMA/ mice, determined by flow cytometry analyses of
Syndecan-1-expressing B cells found in the spleens of naive mice (A)
and wild-type and BCMA/ mice 10 days post-NP-CG
challenge (B). Numbers indicate percentages of total B cells present.
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BCMA-deficient mice have normal splenic architecture.
The
various immune system cells are organized into discrete zones in the
peripheral lymphoid organs (5), and certain members of the
TNF/TNF receptor family, such as TNF receptor I, have been shown to be
essential for this partitioning process (7). In addition,
treatment of mice with a soluble form of BCMA can lead to disrupted
splenic architecture (36). We thus examined whether the
disruption of BCMA would affect the morphology of the splenic architecture by staining cryosections with fluorescence-labeled antibodies that recognize B and T cells. The primary follicle comprising the B- and T-cell zones appears to be normal, as judged by
the anti-IgM and anti-CD3 staining that recognize separately B and T
cells (Fig. 10A and B). In addition,
the IgMhigh marginal zone B cells are present, as revealed
by anti-IgM and anti-IgD staining (Fig. 10C), consistent with the flow
cytometry data in Fig. 2C indicating the presence of this B-cell
subpopulation. During an ongoing immune response, germinal centers
comprising antigen-specific B cells are formed, and these structures
are readily identified with peanut agglutinin staining. As shown in Fig. 10D, germinal centers are observed in both wild-type and mutant mice following immunizations with NP-CG. Thus, in summary, no obvious
differences were observed in the splenic architecture of
BCMA/ mice.
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FIG. 10.
Structures of primary follicles and germinal centers in
spleens of BCMA-deficient mice. Cryosections of spleens from wild-type
and mutant mice were stained with the indicated antibodies conjugated
to FITC (green) or Texas red (red). Anti-IgM and anti-IgD stain B
cells, anti-CD3 stains T cells, and peanut agglutinin (PNA) stains
germinal center B cells.
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Expression of TACI in BCMA-deficient mice.
The lack of an
obvious phenotype in BCMA/ mice could be due to the
presence of TACI, the other TNF receptor family member that also binds
BAFF and APRIL (8, 18, 32, 33, 35, 36). It is also
possible that the inactivation of BCMA could lead to an up-regulation
of TACI, which could in turn compensate for BCMA deficiency. To examine
if this is the case, we perform semiquantitative RT-PCR of TACI
expression using splenocytes obtained from BCMA/ mice.
As seen in Fig. 11, the expression of
TACI is up-regulated in the absence of BCMA.
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FIG. 11.
Semiquantitative RT-PCR of TACI expression in
BCMA/ mice. Total RNA was extracted from
splenocytes of wild-type and BCMA/ mice, and the
reverse-transcribed cDNA was subjected to PCR for the numbers of cycles
indicated. GADPH was amplified as a control for the amount of template
present in the reaction.
|
|
| |
DISCUSSION |
BCMA was first identified as the product of a gene that was fused
to the interleukin-2 gene by a t(4;16)(q26;p13) translocation in a
malignant T-cell lymphoma (13). Subsequently, BCMA was shown to be expressed exclusively in B lymphocytes and in particular at
the mature B to plasma cell stage of differentiation (6, 14). The latter observation raises the interesting possibility that BCMA might play an important role in B-cell activation and terminal differentiation. Indeed, the physiological relevance of BCMA
became apparent when it was shown to be the receptor for the TNF family
members APRIL and BAFF (8, 18, 22, 27). Both APRIL and
BAFF enhance cell survival and induce the proliferation of B cells as
well as stimulate their antibody secretion (19, 23, 36).
Given the potency of APRIL and BAFF, one would expect that the
inactivation of BCMA would affect B-cell development and/or activation
in vivo.
We have inactivated BCMA in the mouse germ line. BCMA-deficient mice
have no drastic phenotype in terms of B-cell differentiation and
activation and can respond to both T-cell-independent and T-cell-dependent antigens. This seems to contrast with experiments wherein the administration of soluble BCMA to mice led to a drastic reduction in the peripheral B-cell population (27) and
impaired immune responses in vivo (36). However, this
apparent discrepancy can be explained by the fact that TACI, another
member of the TNF receptor family, also binds APRIL and BAFF (8,
18, 32, 33, 35, 36). Thus, in BCMA/ mice, the
two TNF family cytokines could still bind TACI, and that presumably is
sufficient to elicit a biological response. On the other hand, the
administration of soluble BCMA to mice would block the binding of both
BAFF and APRIL to BCMA and TACI. This would mimic a double BCMA-TACI
gene knockout in mice, which presumably resulted in a more pronounced
phenotype. Our data showing the up-regulation of TACI in the absence of
BCMA (Fig. 11) could also explain why BCMA/ mice have
no obvious phenotype, as the increased TACI expression may compensate
for the lack of BCMA. Indeed, the slightly higher antigen-specific
immunoglobulin titers in BCMA/ mice in the first week
of the immune response (Fig. 6 to 8) may be due to the up-regulation of
TACI expression.
Using soluble BAFF as a staining reagent, several groups had initially
showed that the BAFF receptor was constitutively expressed on B cells
(19, 23). We now know that such a staining will identify
cells that express BCMA and/or TACI. However, BCMA is reported to be
expressed at the mature B to plasma cell stage of differentiation
(6, 14, 17). Thus, it appears that TACI may be the more
widely expressed receptor and may play a more important role than BCMA
in vivo. It will be interesting to determine if a single inactivation
of TACI is sufficient or whether a double TACI-BCMA knockout is
required to produce a phenotype in the mouse. As a corollary, it
remains to be determined if TACI-transgenic mice would have equivalent
or a more pronounced phenotype compared to BCMA-transgenic mice.
It is still not clear why a dual ligand-two receptor system exists for
BAFF-APRIL and BCMA-TACI. One scenario would be that one of the
receptors might act as a negative regulator to repress the activation
process. This would be analogous to the CD28-CTLA-4 system
(2), whereby the constitutively expressed CD28 provides the costimulatory signal whereas the inducibly expressed CTLA-4 provides the inhibitory signal upon binding the B7.1 and B7.2 molecules. Our current data suggest that TACI alone is sufficient to
provide the activation signal, as BCMA-deficient mice can mount a
normal immune response. On the other hand, BCMA does not appear to
provide a negative signal as the immune responses of mutant mice are
not exaggerated but are comparable to those of wild-type controls.
Thus, BCMA may be redundant in the presence of TACI.
| |
ACKNOWLEDGMENTS |
We thank Esther Wong for blastocyst injection, the IMCB In Vivo
Model Unit for the care and maintenance of mice, and Guo-ke, Li Jie,
and Bor-Luen Tang for their kind assistance with histology and confocal microscopy.
This work is supported by grants from The National Science and
Technology Board (NSTB) of Singapore.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Institute of
Molecular and Cell Biology, 30 Medical Dr., Singapore 117609, Republic of Singapore. Phone: (65) 874 3784. Fax: (65) 779 1117. E-mail: mcblamkp{at}imcb.nus.edu.sg.
| |
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Molecular and Cellular Biology, June 2001, p. 4067-4074, Vol. 21, No. 12
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.12.4067-4074.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
