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Receptor IIB on Follicular Dendritic Cells Regulates the B Cell Recall Response1
Departments of
*
Microbiology and Immunology and
Anatomy, Division of Immunobiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298;
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10021; and
§
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB. This regulated expression of FcRIIB on
FDC and its relation to recall Ab responses were examined both in vitro
and in vivo. Trapping of IC in spleen and lymph nodes of
FcRII-/- mice was significantly reduced
compared with that in wild-type controls. Addition of ICs to cultures
of Ag-specific T and B cells elicited pronounced Ab responses only in
the presence of FDCs. However, FDCs derived from
FcRIIB-/- mice supported only low level Ab
production in this situation. Similarly, when
FcRIIB-/- mice were transplanted with
wild-type Ag-specific T and B cells and challenged with specific Ag,
the recall responses were significantly depressed compared with those
of controls with wild-type FDC. These results substantiate the
hypothesis that FcRIIB expression on FDCs in GCs is important for
FDCs to retain ICs and to mediate the conversion of ICs to a highly
immunogenic form and for the generation of strong recall
responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Dissection of this pathway in vitro yielded the finding that ICs are
poorly immunogenic when added to Ag-specific B and T cell cultures,
presumably due to the inhibitory role of FcRIIB expression on B
cells (12, 13, 14, 15, 16). This prompted the speculation that one
function of the FDC is to convert the poorly immunogenic ICs to a form
capable of stimulating potent B cell responses (17).
Complement and complement receptors appear to be important for trapping
of ICs by FDC (18, 19, 20), and several studies have suggested
that Fc receptors for IgG are also involved (21, 22, 23)
Mice express three FcRs for IgG: FcRI, FcRII, and FcRIII.
FcRI and FcRIII are associated with the common FcR -chain and
trigger cellular activation responses upon cross-linking, while
FcRIIB is a monomeric inhibitory receptor, modulating activation
responses when coligated to an immunoreceptor tyrosine-based activation
motif (ITAM)-containing receptor such as the B cell receptor (BCR)
complex. Myeloid cells express the low affinity FcRII and FcRIII
constitutively and may express the high affinity FcRI upon
activation. B cells exclusively express the low affinity inhibitory
FcRIIB receptor (24).
To begin testing the hypothesis that a major FDC accessory function is
to trap and convert ICs into a highly immunogenic form through FcRs, we
characterized the expression of these receptors on FDCs. The
consequence of this expression was investigated to determine whether
the presence of specific FcRs on FDCs is important for generating a B
cell recall response in vitro and in vivo. Of the three FcRs, we
found that FcRIIB is highly expressed on FDCs in secondary follicle
GCs. Because this expression pattern of FcRIIB correlated with the
appearance of the secondary response, we studied the functional
consequences of this expression. Addition of FDCs derived from
wild-type mice to cultures containing Ag-primed T and B cells and
Ag-containing ICs resulted in potent Ag-specific IgG responses. In
contrast, analogous cultures containing FDCs lacking FcRIIB (derived
from FcRIIB-/- mice)
or in which the anti-FcRIIB mAb 2.4G2 was present were markedly
depressed in their ability to augment Ag-specific IgG production. The
importance of FcRIIB expression on FDCs was evident in vivo as well.
ICs stimulated potent recall responses in vivo only when FcRIIB was
expressed on FDCs; reconstitution of
FcRIIB-/- mice with
Ag-primed T and B cells from wild-type mice resulted in animals that
responded poorly to IC stimulation. These results suggest that
FcRIIB expression on FDCs is important for an optimal B cell recall
response and provides an explanation for why ICs, despite their ability
to mediate feedback regulation of B cell activity, are potent
stimulators of the recall response in vivo.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Female C57BL or BALB/cByJ mice, 6–8 wk of age, were purchased
from The Jackson Laboratory (Bar Harbor, ME). FcRIIB knockout mice
(25) were housed in standard plastic shoebox cages with
filter tops. Food and water were supplied ad libitum, and the mice were
used between 8–20 wk of age.
Ags and immunization
Common FcR chain -/-,
FcRIIB-/-, and +/-
mice (8–10 wk old, maintained on a mixed C57BL/6 x 129
background) were immunized i.p. (100 µg/mouse) with
NP((4-hydroxy-3-nitrophenyl) acetyl)-chicken -globulin (CGG)
precipitated in alum for induction of primary responses. For passive
deposition of ICs, groups of mice were injected with rabbit
anti-HRP (Sigma, St. Louis, MO) antiserum containing 8 mg of Ig or
the same amount of normal rabbit serum. One day later, the mice were
injected with 11 µg of purified HRP (Sigma) i.p. in saline. The mice
were killed 1 day later, and their spleens were frozen and sectioned as
described below.
When OVA was used, wild-type C57 mice were primed by injecting 100–200 µg of OVA (Sigma catalogue no. A5503) precipitated with aluminum potassium sulfate (A7167, Sigma) in the nape of the neck as previously described (17, 26). Secondary immunizations were performed 2 wk later by injection into the front legs, hind feet, and i.p. (20 µg alum Ag/site).
Spleen sectioning and immunohistochemistry
Spleens were removed at various times after immunization and
embedded in Tissue-Tek OCT compound (Fisher Scientific, Bridgewater,
NJ) by flash-freezing in a 2-methylbutane bath cooled with liquid
N2. Frozen spleens were stored at -80°C until
sectioned. Six-micron-thick sections were cut on a cryostat microtome
and thaw-mounted onto 0.05% poly-L-lysine (Sigma)-coated
slides. Sections were allowed to air-dry, then were fixed in ice-cold
acetone for 10 min, air-dried, and stored at -80°C. The frozen
sections were thawed and rehydrated in PBS for 20 min. Endogenous
peroxidase activity was blocked by immersing the sections in 0.3%
(v/v) aqueous H2O2
solution. The sections were then blocked with 5% BSA and 0.1%
Tween-20 in PBS. They were labeled with mAbs 8C12-biotin (anti-CR1,
PharMingen, San Diego, CA), 2.4G2 (anti-FcRII/III, PharMingen),
and FDC-M1 or FDC-M2 (anti-follicular dendritic cell, gifts from
Dr. Marie Kosco-Vilbois, Serono Pharmaceutical Research Institute,
Plan-les-Ouates, Switzerland) Abs. Slides labeled with 2.4G2, FDC-M1,
and FDC-M2 were further developed using alkaline phosphatase
(AP)-conjugated F(ab')2 mouse anti-rat Ig
(Jackson ImmunoResearch Laboratories, West Grove, PA). All slides
labeled with biotinylated Abs were then labeled with streptavidin-AP
(Southern Biotechnology Associates, Birmingham, AL). Most slides were
then labeled with peanut agglutinin coupled to HRP (E-Y Laboratories,
San Mateo, CA) to identify GCs. Bound AP and HRP activities were
visualized using Napthol AS-MX/Fast Blue BB and 3-aminoethylcarbazole,
respectively.
FDC isolation
FDCs were isolated from the lymph nodes (popliteal, brachial, axillary, inguinal, periaortic, and mesenteric) using previously described procedures, except higher levels of irradiation were used (17). The high irradiation doses did not interfere with FDC functions; this may be due to a high level of thiol compounds in FDCs (27), which can protect against radiation injury. Three days after irradiation, the lymph nodes were removed from the mice and cut with 26.5-gauge sterile needles to facilitate enzymatic digestion. The cut nodes were incubated with 1 ml of 8 mg/ml collagenase D (lot FIA148, Roche, Indianapolis, IN) and 0.5 ml of 10 mg/ml DNase I (lot 32H9545, Sigma) in 1 ml of complete DMEM at 37°C. After 1-h incubation, cells were released from the stroma by gentle pipetting, and the media containing the free cells were collected. The isolated cells were then directly layered onto a continuous 50% Percoll gradient and centrifuged for 20 min at 700 x g. The low density (1.050–1.060 g/ml) FDC-enriched fraction was then removed and washed twice. Finally, the washed cells were incubated in petri dishes at 37°C for 1 h to remove adherent macrophages. The nonadherent cell suspension typically contained 30–50% FDCs as determined by flow cytometry using the FDC-specific mAb FDC-M1. The vast majority of the contaminating cells were medium to large lymphocytes.
FDC depletion
FDCs were depleted from enriched FDC preparations using
biotin-labeled FDC-specific mAb, FDC-M1 (26), as described
previously (28). In brief, FDC preparations were incubated
with rat anti-mouse FcR Ab (2.4G2) at 4°C for 30 min to block
nonspecific Fc binding of rat mAb. Biotinylated FDC-M1 was then added
and incubated with the cells for 30 min. After washing the cell
fraction three times, streptavidin-covalently coupled magnetic
Dynabeads (M-280, lot 3171, Dynal, Oslo, Norway) were added at a
concentration of 15 beads/target cell in a final volume of 500 µl.
After a 30-min incubation at room temperature on a shaking platform,
FDCs bound to Dynabeads were separated by a Magnetic Particle
Concentrator (Dynal, Great Neck, NY). This step removes about 90% of
the FDCs, leaving an FDC-depleted fraction (28).
FACS analysis
FDCs were isolated from immunized C57 mice as described above. The FDC preparation was split into two aliquots and incubated with FITC-conjugated 2.4G2 Ab (PharMingen) for 30 min in the cold. The aliquots of FDCs were then incubated with biotinylated FDC-M1 or biotinylated isotype control IgG for 2 h in the cold. After washing twice, the cells were incubated with streptavidin-conjugated PE for 30 min in the cold. The labeled cells were observed using FACScan. Data for 10,000 cells from each aliquot were collected and analyzed.
Lymphocyte preparation
Memory lymphocytes were obtained from draining lymph nodes of OVA-immunized mice 1 mo or more after the final OVA challenge. The lymph nodes were bathed in complete DMEM with 10% FBS and ground between two sterile slides. This harsh treatment of the lymph nodes disrupts Ag-bearing FDCs and plasma cells (29). Consequently, very little Ab is produced when these cells are cultured in the absence of added Ag. After disrupting the lymph node and releasing the cells with the slides, the cell suspensions were filtered through nylon mesh to remove stromal tissue.
Cell cultures
Enriched FDC preparations (1 x 105 cells) were added to 3 x 105 B and T memory cells in 96-well tissue culture plates (catalogue no. 3595, Costar, Cambridge, MA) containing 200 µl of complete culture medium/well. The culture medium used in all studies consisted of DMEM supplemented with 10% FCS, 20 mM HEPES, 2 mM glutamine, 50 µg/ml gentamicin, and MEM-nonessential amino acids. The cell cultures were incubated at 37°C in a 5% CO2 incubator for 14 days, and medium was harvested on days 7 and 14.
Ab assay
Culture medium was collected from the lymphocyte cultures every 6–7 days and anti-OVA-specific IgG was measured by means of a solid phase ELISA as described previously (30). Murine IgG specifically bound to OVA was detected using biotinylated goat anti-mouse IgG (Southern Biotechnology Associates) and AP-labeled streptavidin (Kirkegaard & Perry, Gaithersburg, MD). The levels of anti-OVA in the cultures were determined from standard curves prepared using a standard serum in each ELISA assay. This standard anti-OVA serum was collected from hyperimmunized BALB/c mice, and the anti-OVA level in serum was determined using quantitative precipitin analysis (31).
In vivo IC trapping
The mice used in these studies were given water containing KI
(50 µg/ml) for 1 wk to saturate iodine in the thyroid gland. The
serum used to from IC was obtained from hyperimmunized mice (primed and
boosted twice) containing 1.5 mg/ml anti-OVA IgG. The iodinated
HSA-anti-HSA IC was injected s.c. into the feet on the right site
(2.5 µg/site). Fourteen days later spleen and draining and
nondraining popliteal lymph nodes were harvested. Macrophages trapped,
but rapidly degraded, IC made of
[125I]HSA-anti-HSA
(t1/2, 
30 min), and the
radiolabel was rapidly released in the urine. Autoradiography revealed
that after only a few days macrophages in the draining lymphoid tissue
had cleared the IC, and persisting radioactivity was exclusively
associated with intact HSA on FDCs (21, 32). The amount of
IC trapped and retained on FDCs for 2 wk after challenge was determined
by radioactivity retained in lymph nodes using a gamma counter. A small
amount of the iodinated HSA was saved and counted at the same time as
the lymph nodes and spleens to convert the counts to picograms of
retained Ag (21, 32).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB expression on FDCs and up-regulation in secondary
follicles
To determine which of the Fc receptors is expressed on FDCs,
mice lacking expression of FcRI and FcRIII due to the absence of
the common FcR -chain were exploited. In sections FDCs appear as
integral members of a sponge-like network known as the follicular
reticulum or FDC-reticulum. These FDC-reticula are formed by
interdigitating dendrites from a number of FDCs. Spaces within this
spongework of FDCs are filled with B cells and some T cells. This
microenvironment, located in the light zone of secondary follicles,
brings together Ag, FDCs, B cells, and Th cells. Spleen sections
obtained from immunized
-/- mice (that lack
FcRI and FcRIII due to the absence of the common FcR -chain)
were labeled with the anti-CR1 mAb 8C12 or the mAb 2.4G2, which
detects both FcRII and FcRIII. As shown in Fig. 1
, the follicular reticulum was easily
visualized by anti-CR1 (A) as previously reported
(33). In reactive follicles containing GCs (C, arrows)
FDCs could be visualized using the mAbs FDC-M2 (B) and
FDC-M1 (C). These same regions of the reactive follicles
labeled strongly with 2.4G2 (D), which in the
-/- background only
detected FcRIIB. Importantly, identical labeling results were
obtained using immunized wild-type mice (data not shown).
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). Adjacent parallel sections were
labeled using 2.4G2 (Fig. 2A, red labeling), FDC-M1 (Fig. 2B, green labeling), and then both labels on the same
section (Fig. 2C). The overlapping of the green and red gave
the yellow FDC-reticulum shown in Fig. 2C. The double
labeling was further established by testing FDC in a single-cell
suspension (confirmed by microscopy) using immunized mice as donors and
staining using FDC-M1 and 2.4G2. Nearly 30% of the cells in the
FDC-enriched preparation labeled with FDC-M1 and FACS analysis revealed
that almost all these cells also labeled with 2.4G2.
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, Fig. 3 presents
representative results from a similar histological analysis of the
spleens of mice with a targeted inactivation of the FcRIIB gene.
While the A panels show that the primary follicular
reticulum as defined by 8C12 labeling is well developed in
FcRIIB-/- spleen,
2.4G2 labeling of the follicular reticulum (C panels) is
absent in GCs (arrows), and FDC-M1 labeling (B panels) is
reduced. Collectively, these data define the FcR on FDCs in GCs as
FcRIIB, consistent with previous suggestions (23, 34),
and indicate that the level of expression of this receptor is highly
induced on FDCs in this microenvironment.
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presents representative data from this
experiment. The primary follicular reticulum is easily visualized with
8C12 labeling (A), but reticular labeling in the primary
follicle is not observed using FDC-M1 or 2.4G2.
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RIIB reduces immune complex trapping in the
follicle
While passively formed ICs strongly label the splenic follicular
reticulum in wild-type mice (Fig. 5A), these same ICs give rise
to reduced labeling of this reticulum in
FcRIIB-/- mice (Fig. 5B). A semiquantitative analysis of IC deposition in these
splenic sections indicated that IC trapping was reduced severalfold in
the FcRIIB-/- mice.
These results were confirmed and extended using radiolabeled ICs to
quantitate the amount of IC trapping in both splenic and lymph node
(LN) follicles (Table I). Retained IC
persisted in the spleen and draining LNs, in contrast to nondraining
LNs. The amount of Ag retained in
FcRIIB-/- mice was
reduced to about 25% of normal in the spleen, which is compatible with
the histochemistry, and to 50% of normal in the draining LNs.
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RIIB in the conversion of IC into potent immunogens
To directly test the hypothesis that FDCs are able to convert a
poorly immunogenic IC into a highly immunogenic form, OVA-containing
ICs were added to OVA-primed T and B cells derived from normal mice,
and the level of secretion of OVA-specific IgG Ab was measured. In the
absence of FDCs only picogram levels of anti-OVA were induced at
any dose of IC used (Fig. 6A).
In contrast, addition of FDCs from normal mice to these cultures
elicited substantial levels of OVA-specific IgG over a wide dose range
of IC.
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was enriched but not pure,
depletion studies were conducted to exclude the possibility that the
adjuvant-like activity was mediated by other cells. The FDC-specific Ab
FDC-M1 was used to generate an FDC-depleted fraction. As shown in Fig. 7B, depletion of most FDCs
resulted in a 90% reduction of the stimulatory response observed,
confirming that FDCs in the in vitro culture of memory T and B cells
were responsible for the stimulatory effect of IC. Because the data
presented above show that expression of the FDC-M1 epitope and
FcRIIB on FDCs is highly correlated, FDCs expressing high levels of
FcRIIB would have been preferentially depleted in this
experiment.
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RIIB, CR1/2, or a combination
of these receptors. To determine whether the FcRIIB on FDCs has the
ability to convert the IC to a potent immunogen in vitro, FDCs were
prepared from FcRIIB+/+ or
FcRIIB-/- mice and
added to cultures of OVA-primed T and B cells as before. Deficiency of
FcRIIB on the FDCs dramatically reduced the stimulatory effect of
these cells on IgG Ab production (Fig. 7A), establishing
that this receptor is important for enabling the FDCs to convert the IC
into a potent immunogen in vitro. However, the addition of FDC from the
FcRIIB-/- mice to the
memory cells plus OVA-anti-OVA increased anti-OVA production
from <10 ng/ml to >500 ng/ml, indicating that some adjuvant activity
persisted in the absence of FcRIIB. Because the development or
regulation of FDC activity may be perturbed in
FcRIIB-/- mice (see
below), analogous experiments were performed by blockingFcRIIB (with
soluble 2.4G2) in cultures containing FDCs derived from wild-type mice.
Results similar to those achieved with FDCs isolated from
FcRIIB-deficient mice were obtained (Fig. 7B).
These in vitro results suggested that FcRIIB mediate a specific
function on FDCs by enabling ICs to stimulate a B cell recall response
in vivo. To dissect the in vivo role of FcRIIB on FDCs, LN
lymphocytes were obtained from OVA-immune mice and were injected into
irradiated wild-type and
FcRIIB-/- mice.
Twenty-four hours after adoptive transfer, mice in both groups were
injected i.v. with preformed OVA-anti-OVA ICs. Preformed ICs were used
because there was no specific anti-OVA in the recipients to convert
OVA into ICs as there would be in typical recall responses. Two weeks
later the mice were bled, and the levels of serum anti-OVA IgG
generated during this recall response were determined. ICs generated a
potent serum recall response in wild-type recipients (Fig. 8), while the response in
FcRIIB-/- recipients
was significantly diminished. To determine whether an additional
immunization would overcome the reduced response of the wild-type
lymphocytes in
FcRIIB-/- mice, both
groups of mice were challenged with free OVA. Free OVA was used because
Ab from the previous immunization would form the IC in vivo. Two weeks
later, serum Ab levels were determined and compared. The specific
anti-OVA levels in wild-type mice increased to >2 mg/ml (a robust
response), while the response in
FcRIIB-/- mice
remained low (10% of that level; p < 0.01). These
in vivo results support the in vitro studies presented above and
suggest that FcRIIB functions specifically to enable the retained IC
to stimulate B cells in the secondary follicular reaction.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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R) (22, 23, 35). These
receptors are expressed on both B cells and FDCs; however, given our
results and those of others, their function on each cell type is
apparently quite different. Expression of CR1/2 on B cells is essential
for their stimulation as well as survival within the GC (36, 37). These receptors play a positive role in mediating B cell
stimulation through their interaction with the CD19 complex
(38) and by delivering a survival signal to B cells that
have entered the GC provided by a ligand present on the FDC, presumably
C3d (36, 39, 40). The expression of CR1/2 on FDCs may also
play a role in an immune response. For example, it is reported that
CR1/2 on FDC is important for a strong Ab response (41).
Nevertheless, transfer of CR1/2-expressing B cells into a
CR1/2-deficient mouse is sufficient to reconstitute a substantial
immune response and leads to the generation of memory cells (36, 37, 42).
FcRIIB expression on B cells can result in the generation of an
inhibitory signal, triggered by its coligation to the BCR by ICs
(12, 13, 14, 15, 16). Given the general inhibitory function of
FcRIIB on hemopoietic cells (12, 13, 14, 15, 16), it was unexpected
that the capacity of the FDCs to convert ICs into a form capable of
stimulating B cell activation was dramatically enhanced by FcRIIB
expression on FDC. Strikingly, our results indicate that FcRIIB
functions as a positive regulator of the adjuvant property of FDCs.
Interestingly, a balanced effect was obtained in
FcRIIB-/- mice, where
B cell activation and proliferation would not be down-regulated by
FcRIIB, but trapping of Ag by FDCs was substantially reduced (Fig. 5
and Table I). The net outcome of the opposing effects was minimal, as
the immune response in the
FcRIIB-/- mice was
essentially normal (25). This normal response stands in
marked contrast with the subnormal recall response obtained in the
present study when wild-type B memory cells bearing FcRIIB were used
in combination with FDC from FcRIIB knockout mice (Figs. 7A and 8). These observations suggest that FcRIIB-bearing
FDC are critical for recall responses derived from wild-type
FcRIIB-bearing B cells, and this concept is consistent with results
from models where the lack of FDC is associated with a lack of germinal
centers and the recall Igs IgG and IgA (43, 44, 45). FDC
deficiencies occur in animals lacking lymphotoxin or TNF, or receptors
for these cytokines (33, 43).
In this regard, and in contrast to its function on B cells, FcRIIB
expressed on FDCs may play a role, allowing more efficient trapping and
retention of IgG containing ICs in follicles than could be achieved
with CRs alone. Indeed, Fig. 5 and Table I show that IC trapping in
follicles is reduced in
FcRIIB-/- mice.
Although additional experiments will be required to test this idea,
several of our observations argue against this simple interpretation.
First, histological analysis of the splenic follicular reticulum in
FcRIIB-deficient mice showed that FDC-M1 expression was
significantly reduced (Fig. 3), indicating that the absence of
FcRIIB precludes as yet undefined steps in either FDC maturation or
activation. Second, the in vitro adjuvant effect of purified FDCs from
normal mice on T cell-dependent B cell activation by ICs is readily
blocked by soluble 2.4G2, a treatment that represses the inhibitory
function of FcRIIB on B cells (14, 15, 16). Finally, FDCs
from FcRIIB-deficient mice are unable to augment potent IC-mediated
B cell recall responses in vitro in a complement-deficient system, even
when high levels of cognate Ag containing ICs are added to the cultures
(Fig. 7). It should also be noted that the level of FcRIIB on FDCs
appears to be related to activity in the germinal center, and the
possibility of passive acquisition of FcRIIB by FDC has not been
ruled out.
The molecular mechanisms used by FDCs to amplify IC B cell
immunogenicity, and the role of FcRIIB in this process remain to be
established. One potential mechanism by which the interaction of an IC
with FcRIIB on the FDC may convert it to an immunogenic form may be
through competition for binding to FcRIIB on the B cell. By blocking
the ability of the IC to bind to FcRIIB on the B cell, the retained
Ag would be capable of stimulating the BCR in the absence of an
inhibitory signal (46). Alternatively, FcRIIB on the
FDC may function as a signaling molecule, inhibiting a FDC function
that prevents B cell stimulation, class switching, or Ab production.
This model would suggest that when stimulated B cells interact with
FDCs in the absence of ICs they receive survival signals (28, 36), but not differentiation signals (47). However,
after the GC becomes well developed, the induction and engagement of
FcRIIB on FDCs allow them to participate in the regulation of B cell
isotype class switching and differentiation to Ab-forming cells. It is
intriguing to speculate that FcRIIB engagement on FDCs induces the
generation of IC-containing iccosomes that, once internalized by
follicular B cells, would provide the intracellular levels of cognate
Ag necessary for MHC class II-mediated presentation and receipt of T
cell help.
The selective and up-regulated expression of FcRIIB on FDCs in
reactive follicles containing GCs further supports the idea that ICs
play an essential role in the B cell recall response (2, 17). During this phase of the secondary immune response it is
critical that B cells are appropriately activated, and Ab-forming cells
and memory cells are formed. After a productive secondary response it
may be important to down-regulate FcRIIB expression on FDCs and
thereby facilitate termination of the GC reaction by allowing more IC
to bind to the B cell FcRIIB and trigger inhibition. The results
presented here support a context regulation model of the secondary
response in which FcRIIB expression on FDCs influences whether an IC
is stimulatory or inhibitory to a B cell.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. John G. Tew, Department of Microbiology/Immunology, P.O. Box 980678, MCV Station, Richmond, VA 23298-0678.
3 Abbreviations used in this paper: IC, immune complex; GC, germinal center; CGG, chicken -globulin; AP, alkaline phosphatase; FDC, follicular dendritic cells; FcRIIB, Fc receptor IIB; CR2, complement receptor II; CR2L, ligand for complement receptor II; BCR, B cell receptor; HSA, human serum albumin; LN, lymph node.
Received for publication October 12, 1999. Accepted for publication March 31, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB1. Science 268:293.RIIB modulates B-cell receptor signalling [published erratum appears in Nature 1994 May 26;369(6478):340]. Nature 368:70.[Medline]
RII-deficient mice. Nature 379:346.[Medline]
and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells. J Exp. Med. 186:1997.-chain does not alter maturation of the B cell response. J. Immunol. 159:2116. and lymphotoxin . J. Virol. 72:9514.RIIB-induced B cell apoptosis. Immunity 10:753.[Medline]
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 D. B. Lowe, M. H. Shearer, C. A. Jumper, R. K. Bright, and R. C. Kennedy Fc{gamma} Receptors Play a Dominant Role in Protective Tumor Immunity against a Virus-Encoded Tumor-Specific Antigen in a Murine Model of Experimental Pulmonary Metastases J. Virol., February 1, 2007; 81(3): 1313 - 1318. [Abstract] [Full Text] [PDF]
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Z. S. M. Rahman, B. Alabyev, and T. Manser Fc{gamma}RIIB Regulates Autoreactive Primary Antibody-Forming Cell, but Not Germinal Center B Cell, Activity J. Immunol., January 15, 2007; 178(2): 897 - 907. [Abstract] [Full Text] [PDF]
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Y. Nishikawa, M. Hikida, M. Magari, N. Kanayama, M. Mori, H. Kitamura, T. Kurosaki, and H. Ohmori Establishment of Lymphotoxin beta Receptor Signaling-Dependent Cell Lines with Follicular Dendritic Cell Phenotypes from Mouse Lymph Nodes J. Immunol., October 15, 2006; 177(8): 5204 - 5214. [Abstract] [Full Text] [PDF]
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M. A. Brockman, A. Verschoor, J. Zhu, M. C. Carroll, and D. M. Knipe Optimal Long-Term Humoral Responses to Replication-Defective Herpes Simplex Virus Require CD21/CD35 Complement Receptor Expression on Stromal Cells J. Virol., July 15, 2006; 80(14): 7111 - 7117. [Abstract] [Full Text] [PDF]
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 T R D J Radstake, K C A M Nabbe, M H Wenink, M F Roelofs, A Oosterlaar, A W T van Lieshout, P Barrera, P L E M van Lent, and W B van den Berg Dendritic cells from patients with rheumatoid arthritis lack the interleukin 13 mediated increase of Fc{gamma}RII expression, which has clear functional consequences Ann Rheum Dis, December 1, 2005; 64(12): 1737 - 1743. [Abstract] [Full Text] [PDF]
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Z. S. M. Rahman and T. Manser Failed Up-Regulation of the Inhibitory IgG Fc Receptor Fc{gamma}RIIB on Germinal Center B Cells in Autoimmune-Prone Mice Is Not Associated with Deletion Polymorphisms in the Promoter Region of the Fc{gamma}RIIB Gene J. Immunol., August 1, 2005; 175(3): 1440 - 1449. [Abstract] [Full Text] [PDF]
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Y. Aydar, S. Sukumar, A. K. Szakal, and J. G. Tew The Influence of Immune Complex-Bearing Follicular Dendritic Cells on the IgM Response, Ig Class Switching, and Production of High Affinity IgG J. Immunol., May 1, 2005; 174(9): 5358 - 5366. [Abstract] [Full Text] [PDF]
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 L. J. Brady Antibody-Mediated Immunomodulation: a Strategy To Improve Host Responses against Microbial Antigens Infect. Immun., February 1, 2005; 73(2): 671 - 678. [Full Text] [PDF]
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R. Sacedon, B. Diez, V. Nunez, C. Hernandez-Lopez, C. Gutierrez-Frias, T. Cejalvo, S. V. Outram, T. Crompton, A. G. Zapata, A. Vicente, et al. Sonic Hedgehog Is Produced by Follicular Dendritic Cells and Protects Germinal Center B Cells from Apoptosis J. Immunol., February 1, 2005; 174(3): 1456 - 1461. [Abstract] [Full Text] [PDF]
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T R D J Radstake, A B Blom, A W Sloetjes, E O F van Gorselen, G J Pesman, L Engelen, R Torensma, W B van den Berg, C G Figdor, P L E M van Lent, et al. Increased Fc{gamma}RII expression and aberrant tumour necrosis factor {alpha} production by mature dendritic cells from patients with active rheumatoid arthritis Ann Rheum Dis, December 1, 2004; 63(12): 1556 - 1563. [Abstract] [Full Text] [PDF]
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E. C. Whipple, R. S. Shanahan, A. H. Ditto, R. P. Taylor, and M. A. Lindorfer Analyses of the In Vivo Trafficking of Stoichiometric Doses of an Anti-Complement Receptor 1/2 Monoclonal Antibody Infused Intravenously in Mice J. Immunol., August 15, 2004; 173(4): 2297 - 2306. [Abstract] [Full Text] [PDF]
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N. Mohamed, J. Li, C. S. Ferreira, S. F. Little, A. M. Friedlander, G. L. Spitalny, and L. S. Casey Enhancement of Anthrax Lethal Toxin Cytotoxicity: a Subset of Monoclonal Antibodies against Protective Antigen Increases Lethal Toxin-Mediated Killing of Murine Macrophages Infect. Immun., June 1, 2004; 72(6): 3276 - 3283. [Abstract] [Full Text] [PDF]
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K. Su, J. Wu, J. C. Edberg, X. Li, P. Ferguson, G. S. Cooper, C. D. Langefeld, and R. P. Kimberly A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing Fc{gamma}RIIb Alters Receptor Expression and Associates with Autoimmunity. I. Regulatory FCGR2B Polymorphisms and Their Association with Systemic Lupus Erythematosus J. Immunol., June 1, 2004; 172(11): 7186 - 7191. [Abstract] [Full Text] [PDF]
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K. Su, X. Li, J. C. Edberg, J. Wu, P. Ferguson, and R. P. Kimberly A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing Fc{gamma}RIIb Alters Receptor Expression and Associates with Autoimmunity. II. Differential Binding of GATA4 and Yin-Yang1 Transcription Factors and Correlated Receptor Expression and Function J. Immunol., June 1, 2004; 172(11): 7192 - 7199. [Abstract] [Full Text] [PDF]
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 S. Han, E. Marinova, and B. Zheng Rectification of age-related impairment in Ig gene hypermutation during a memory response Int. Immunol., April 1, 2004; 16(4): 525 - 532. [Abstract] [Full Text] [PDF]
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T. Manser Textbook Germinal Centers? J. Immunol., March 15, 2004; 172(6): 3369 - 3375. [Abstract] [Full Text] [PDF]
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Y. Aydar, P. Balogh, J. G. Tew, and A. K. Szakal Altered Regulation of Fc{gamma}RII on Aged Follicular Dendritic Cells Correlates with Immunoreceptor Tyrosine-Based Inhibition Motif Signaling in B Cells and Reduced Germinal Center Formation J. Immunol., December 1, 2003; 171(11): 5975 - 5987. [Abstract] [Full Text] [PDF]
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 Z. SM. Rahman, S. P. Rao, S. L. Kalled, and T. Manser Normal Induction but Attenuated Progression of Germinal Center Responses in BAFF and BAFF-R Signaling-Deficient Mice J. Exp. Med., October 20, 2003; 198(8): 1157 - 1169. [Abstract] [Full Text] [PDF]
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R. A. Barrington, O. Pozdnyakova, M. R. Zafari, C. D. Benjamin, and M. C. Carroll B Lymphocyte Memory: Role of Stromal Cell Complement and Fc{gamma}RIIB Receptors J. Exp. Med., November 4, 2002; 196(9): 1189 - 1200. [Abstract] [Full Text] [PDF]
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S. P. Rao, K. A. Vora, and T. Manser Differential Expression of the Inhibitory IgG Fc Receptor Fc{gamma}RIIB on Germinal Center Cells: Implications for Selection of High-Affinity B Cells J. Immunol., August 15, 2002; 169(4): 1859 - 1868. [Abstract] [Full Text] [PDF]
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B. A. Smith-Franklin, B. F. Keele, J. G. Tew, S. Gartner, A. K. Szakal, J. D. Estes, T. C. Thacker, and G. F. Burton Follicular Dendritic Cells and the Persistence of HIV Infectivity: The Role of Antibodies and Fc{gamma} Receptors J. Immunol., March 1, 2002; 168(5): 2408 - 2414. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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V. M. Lentz and T. Manser Cutting Edge: Germinal Centers Can Be Induced in the Absence of T Cells J. Immunol., July 1, 2001; 167(1): 15 - 20. [Abstract] [Full Text] [PDF]
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T. A. Gondre-Lewis, A. E. Moquin, and J. R. Drake Prolonged Antigen Persistence Within Nonterminal Late Endocytic Compartments of Antigen-Specific B Lymphocytes J. Immunol., June 1, 2001; 166(11): 6657 - 6664. [Abstract] [Full Text] [PDF]
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