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RIIB1
Laboratoire d’Immunologie Cellulaire et Clinique, Institut National de la Santé et de la Recherche Médicale Unité 255, Institut Curie, Paris, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB are single-chain low-affinity receptors for IgG that bear
an immunoreceptor tyrosine-based inhibition motif in their
intracytoplasmic domain and that negatively regulate immunoreceptor
tyrosine-based activation motif-dependent cell activation. They are
widely expressed by cells of hematopoietic origin. We investigated here
whether FcRIIB could also negatively regulate protein tyrosine
kinase receptor (RTK)-dependent cell proliferation. As an experimental
model, we used growth factor-dependent mast cells that constitutively
express FcRIIB and c-kit, an RTK prototype. We
found that anti-c-kit Abs mimicked the effect of
stem cell factor and induced thymidine incorporation in
FcRIIB-/-, but not in wild-type (wt) mast cells unless
FcRIIB were blocked or anti-c-kit
F(ab')2 were used. When coaggregated with
c-kit by intact Abs in wt mast cells, FcRIIB
inhibited thymidine incorporation, as well as cell proliferation, and
inhibition was correlated with an arrest of cells in G1 during the cell
cycle. The coaggregation of c-kit with FcRIIB did not
affect ligand-induced c-kit phosphorylation and induced
the tyrosyl-phosphorylation of FcRIIB, which selectively recruited
the Src homology 2 domain-bearing inositol 5-phosphatase SHIP. Our
results indicate that IgG Abs to growth factors or growth factor
receptors may control RTK-dependent proliferation of a variety of cells
that express FcRIIB. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB (4, 5). FcRIIB are
widely expressed receptors for IgG Abs (6). When coaggregated with
ITAM-bearing receptors, they are tyrosyl-phosphorylated by specific Src
family kinases and recruit the Src homology 2 domain-bearing inositol
5-phosphatase SHIP (7, 8). SHIP blocks the intracellular propagation of
activation signals by preventing the membrane recruitment of Btk to
phosphatidylinositol (3, 4, 5)trisphosphate (PIP3) (9, 10).
In previous works, we extended FcRIIB-mediated negative regulation
to cell activation by all ITAM-bearing immunoreceptors (5). In the
present work, we investigated whether FcRIIB-mediated negative
regulation might also control RTK-dependent cell proliferation. To this
aim, we used mouse mast cells that coexpress FcRIIB and
c-kit, a typical RTK of the platelet-derived growth
factor-receptor family (11). Upon dimerization by stem cell
factor (SCF), c-kit autophosphorylates and triggers the
growth of hematopoietic progenitor cells, mast cells, basophils,
germinal cells, and melanocytic cells (12). We found that, when
coaggregated with c-kit, FcRIIB became
tyrosyl-phosphorylated, recruited SHIP, and abrogated
c-kit-dependent thymidine incorporation and cell
proliferation by arresting the cell cycle in G1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The rat mAbs anti-mouse FcRIIB 2.4G2 and anti-mouse
c-kit ACK2 were affinity purified from culture supernatants
on protein G-Sepharose (Pharmacia Fine Chemicals, Uppsala, Sweden).
ACK2 F(ab')2 fragments were obtained following pepsin
digestion for 2 h at 37°C (pH 3.0).
Cells
Bone marrow-derived mast cells (BMMC) were obtained by culturing mouse bone marrow cells in RPMI 1640 culture medium supplemented with 10% FCS, 100 IU/ml penicillin, 100 µg/ml streptomycin, and 20% WEHI-3B-conditioned medium. After 4 wk, cultures contained >90% mast cells. Culture reagents were from Life Technologies (Paisley, Scotland).
Immunofluorescence
BMMC were incubated at 0°C with 10 µg/ml rat mAb 2.4G2 or ACK2, or medium alone, washed, and stained with 50 µg/ml FITC-conjugated F(ab')2 fragments of mouse anti-rat Ig (MAR) (Jackson ImmunoResearch, West Grove, PA). Fluorescence was analyzed by flow cytometry using a FACScalibur (Becton Dickinson, Mountain View, CA).
Cell stimulation and thymidine incorporation
Aliquots of 3 x 104 BMMC, in RPMI 1640 containing 1% FCS and 0.5% BSA (Sigma, St. Louis, MO), were incubated with recombinant SCF (R&D Systems, Minneapolis, MN) or preformed immune complexes for 24 h at 37°C. [3H]thymidine (0.5 µCi/well) (Amersham, Les Ulis, France) was added, and radioactivity incorporated into cells was measured 4 h later.
Assessment of cell viability
Aliquots of 5 x 105 cells were incubated for 10 min at 0°C with propidium iodide and FITC-conjugated annexin V, as recommended by the manufacturer (Immunotech, Marseille-Luminy, France). Fluorescence was analyzed by flow cytometry.
Cell proliferation assay
BMMC were incubated with or without 10 µg/ml 2.4G2 for 1 h at 37°C in culture medium supplemented with 2% WEHI-3B-conditioned medium. Cells were seeded at 3 x 105 cells/ml and cultured for 5 days with SCF or preformed immune complexes in the same medium. Trypan blue-excluding cells were enumerated at day 5.
Cell cycle analysis
BMMC were incubated with or without 10 µg/ml 2.4G2 for 1 h at 37°C in culture medium supplemented with 2% WEHI-3B-conditioned medium. Cells were resuspended at 1 x 106 cells/ml in the same medium, and incubated for 24 h with preformed immune complexes or SCF. Cells were treated with 75% ethanol for 2 h at 4°C, then with 50 µg/ml RNase (Boehringer Mannheim, Meylan, France), and nuclei were stained for 15 min with 100 µg/ml propidium iodide. Fluorescence was analyzed by flow cytometry. The percentages of cells in G0 + G1, S, and G2 + M were calculated using the Modfit program (Verity Software House, Topchan, ME).
Immunoprecipitation and Western blot analysis
BMMC were incubated for 1 h at 37°C with or without 10
µg/ml 2.4G2, washed, challenged for 5 min at 37°C with immune
complexes or SCF, and lysed in lysis buffer as described (8).
Postnuclear lysates were immunoprecipitated with protein G-Sepharose
coated with the anti-c-kit mAb 2B8 (PharMingen, San
Diego, CA) or with 2.4G2, electrophoresed, and transferred onto
Immobilon-P (Millipore, Bedford, MA). Membranes were saturated with
either 5% BSA (Sigma) or with 5% skimmed milk (Régilait,
Saint-Martin-Belle-Roche, France) diluted in buffer containing 150 mM
NaCl, 10 mM Tris, and 0.5% Tween 20 (Merk, Schuchardt, Germany) (pH
7.4). C-kit immunoprecipitates were blotted with horseradish
peroxidase (HRP)-conjugated anti-phosphotyrosine Abs (Chemicon,
Temecula, CA) and with rabbit anti-c-kit Abs (Upstate
Biotechnology, Lake Placid, NY), followed by HRP-conjugated goat
anti-rabbit Ig (GAR) (Santa Cruz Biotechnologies, Santa Cruz, CA).
FcRIIB immunoprecipitates were blotted with HRP-conjugated
anti-phosphotyrosine Abs and with FcRIIB-specific rabbit
polyclonal Abs raised against a synthetic peptide corresponding to the
19 C-terminal residues of FcRIIB (13), anti-SHP-1 (Transduction
Laboratories, Lexington, KY) and anti-SHIP Abs (Upstate
Biotechnology Inc.), followed by HRP-GAR or goat anti-mouse Ig Abs
(Santa Cruz Biotechnologies). Labeled Abs were detected using an
enhanced chemoluminescence kit (Amersham).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB-deficient, but not in wt mast cells
Growth factor-dependent BMMC were chosen as an experimental
model to investigate the possibility that FcRIIB might negatively
regulate proliferative signals delivered by c-kit. BMMC
constitutively express FcRIIB and traces of FcRIIIA (14). They
depend on either IL-3 or SCF for their survival and proliferation. BMMC
were generated from FcRIIB-deficient mice and from wt C57BL/6
control mice. The absence of FcRIIB in FcRIIB-/-
BMMC was checked by Western blot analysis of whole cell lysates with
FcRIIB-specific polyclonal anti-peptide Abs (6 , and data
not shown). When incubated for 24 h with SCF, wt and
FcRIIB-/- BMMC incorporated comparable amounts of
thymidine (Fig. 1
A). When
incubated with BMMC for 24 h, immune complexes made with IgG Abs
of the rat anti-mouse c-kit mAb ACK2 (15) and MAR
F(ab')2 induced no thymidine incorporation in wt BMMC.
Under the same conditions, the same complexes, however, induced a
dose-dependent thymidine incorporation in FcRIIB-/-
BMMC (Fig. 1B). Anti-c-kit Abs could therefore
mimic the effects of SCF in BMMC, provided these did not express
FcRIIB.
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RIIB inhibits
c-kit-mediated thymidine incorporation in wt mast cells
Based on the above results, we investigated the possibility
that the inability of anti-c-kit Abs to trigger
thymidine incorporation in wt BMMC could result from an interaction of
their Fc portion with FcRIIB. To analyze the interactions of
anti-c-kit Abs with c-kit and FcRIIB on wt
mast cells, BMMC were generated from BALB/c mice and used for
subsequent experiments. These BMMC expressed c-kit, as
assessed with ACK2, and FcR, as assessed with the rat anti-mouse
FcRIIB/IIIA mAb 2.4G2 (16) (Fig. 2A). BALB/c BMMC incorporated
thymidine when incubated for 24 h with SCF, but also when
incubated with ACK2 F(ab')2 fragments complexed with MAR
F(ab')2 fragments (Fig. 2B). Together with data
shown in Fig. 1
, this result indicates that, although ACK2 blocks the
binding of SCF to c-kit and was thus described as an
antagonistic Ab (15), it could function as an agonistic Ab when
deprived of its Fc portion or when added to mast cells lacking
FcRIIB. This suggested that the coaggregation of c-kit
with FcRIIB, via the Fab and Fc portions of
anti-c-kit Abs, respectively, could inhibit
c-kit-mediated BMMC proliferation.
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RIIB were rendered inaccessible, or
not, using 2.4G2, which blocks the binding site of FcRIIB (16). When
incubated with BMMC for 24 h, ACK2-biotin-anti-biotin
complexes induced no significant thymidine incorporation. However, if
BMMC were preincubated with 2.4G2, ACK2-biotin-anti-biotin
complexes induced a dose-dependent thymidine incorporation (Fig. 2C). Cell viability was comparable in cells treated with
ACK2-biotin-anti-biotin, whether they had been preincubated with
2.4G2 or not, and in cells treated with SCF (Fig. 2D),
excluding that cell death might explain the lack of thymidine
incorporation by cells not incubated with 2.4G2. When coengaged with
c-kit by the same Ab, FcRIIB can therefore inhibit
anti-c-kit-induced thymidine incorporation without
killing BMMC.
The coaggregation of c-kit with FcRIIB induces
the phosphorylation of FcRIIB and the subsequent recruitment of
SHIP, and does not prevent the inducible phosphorylation of
c-kit
To analyze the contribution of FcRIIB in inhibition,
BMMC were preincubated with or without 2.4G2 before they were
stimulated with ACK2-biotin-anti-biotin complexes for 5 min.
FcRIIB and c-kit were immunoprecipitated, and their
tyrosyl-phosphorylation was assessed by Western blot analysis. When
coaggregated with c-kit, FcRIIB became phosphorylated,
and SHIP, but not SHP-1, coprecipitated with FcRIIB. FcRIIB
phosphorylation and SHIP coprecipitation were both prevented if BMMC
were incubated with 2.4G2 before stimulation with
ACK2-biotin-anti-biotin (Fig. 3A).
ACK2-biotin-anti-biotin complexes also induced the
tyrosyl-phosphorylation of c-kit. Phosphorylation was of a
comparable magnitude when c-kit was aggregated by
ACK2-biotin-anti-biotin in BMMC that had been preincubated with
2.4G2 and when c-kit was coaggregated with FcRIIB by
ACK2-biotin-anti-biotin in BMMC that had not been preincubated with
2.4G2 (Fig. 3B). The coaggregation of c-kit with
FcRIIB by anti-c-kit Abs, therefore, did not prevent
c-kit phosphorylation.
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RIIB inhibits
mast cell proliferation and arrests the cell cycle in G1
Finally, we examined the consequences of aggregating
c-kit and of coaggregating c-kit with FcRIIB
on the actual proliferation of BMMC and on their progression through
the cell cycle. To examine the effects of coaggregating
c-kit with FcRIIB on mast cell proliferation, BMMC that
had been preincubated with 2.4G2 or not were cultured for 5 days with
SCF or with ACK2-biotin-anti-biotin complexes in the presence of a
limiting concentration of WEHI-3B-conditioned medium that was
determined to be sufficient to support the survival of BMMC, but not
their proliferation, and the number of viable cells at the end of the
culture was enumerated. BMMC proliferated when cultured in the
presence, but not in the absence of SCF. ACK2-biotin-anti-biotin
complexes also induced cells whose FcRIIB were blocked by 2.4G2 to
proliferate, but not cells whose FcRIIB were accessible (Fig. 4). To analyze the effects of
coaggregating c-kit with FcRIIB on the cell cycle, BMMC
were incubated for 24 h in the same medium and with the same
ligands, and the content of DNA was analyzed by flow cytometry,
following labeling of nuclei with propidium iodide. Five percent
nonstimulated cells and 32% cells incubated with SCF were found to be
cycling (cells in S + G2 M). Likewise, ACK2-biotin-anti-biotin
complexes induced a dose-dependent increase in the percentage of
cycling cells that had been preincubated with 2.4G2. The percentage of
cycling cells was reduced if they had not been preincubated with 2.4G2
(Fig. 5A). Thymidine
incorporation, measured in the same cells, during the same experiment,
under the same conditions as in Fig. 2, paralleled the percentage of
cycling cells (Fig. 5B). The coaggregation of
c-kit with FcRIIB therefore inhibits mast cell
proliferation as well as thymidine incorporation, and inhibition
correlates with a blockade of the G1-S transition, during the cell
cycle.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB has long been known to negatively regulate B cell
activation (4, 17). Because this regulation is mediated by IgG Abs,
i.e., the end product of Ag-driven B cell activation and
differentiation, it was understood as a B cell-specific negative
feedback mechanism of the Ab response. We demonstrated in previous
works that FcRIIB can inhibit not only BCR-dependent B cell
activation, but also TCR-dependent T cell activation and Fc
RI- or
FcRIIA-dependent mast cell activation, and using ITAM-bearing
chimeric molecules, we showed that FcRIIB-dependent negative
regulation could be extended to cell activation induced by all
ITAM-bearing receptors (5). We demonstrate here that negative
regulation exerted by FcRIIB can be further extended to RTK-mediated
cell proliferation. This is the first demonstration that a receptor
other than an ITAM-bearing receptor, i.e., RTK, can be controlled by
FcRIIB. By contrast with ITAM-bearing receptors, RTKs do not need to
recruit intracellular protein tyrosine kinases to deliver positive
signals, and they use different transduction pathways. The
tyrosyl-phosphorylation of FcRIIB, which is mandatory for inhibition
of cell activation (8, 18), was shown to depend on specific Src family
protein kinases recruited by ITAM-bearing receptors (8). Therefore, the
fact that signal transduction by RTKs may be negatively regulated by
FcRIIB was not predictable.
Although under the control of distinct mechanisms, cell activation and
cell proliferation are often linked, particularly in lymphocytes.
Indeed, BCR and TCR are constitutively and inducibly associated with
coreceptors whose coengagement is required to trigger productive
signals leading to both cell activation and proliferation. FcRIIB
were reported to inhibit B cell activation and proliferation assessed
by thymidine incorporation and the induction of c-myc
transcripts (19, 20). As long as FcRIIB had not been shown to
inhibit specific mechanisms that control cell proliferation,
FcRIIB-dependent inhibition of B cell proliferation could be
understood as the mere consequence of an upstream inhibition of
signaling via the BCR complex. The issue was further complicated by the
recent finding that FcRIIB could kill B cells by inducing apoptosis
via an ITIM-independent mechanism (21). In mast cells, activation
signals and proliferation signals are delivered by separate receptors.
We provide evidence here that FcRIIB can inhibit proliferative
responses of mast cells that are under the contol of receptors that
induce cell proliferation without triggering cell activation.
As it was previously demonstrated for FcRIIB-dependent inhibiton of
mast cell activation by FcRI (14), inhibition of cell proliferation
required the coaggregation of c-kit with FcRIIB by the
same extracellular ligand. This was achieved in wt BMMC by intact
anti-c-kit IgG Abs that could bind simultaneously to
c-kit by their Fab portions and to FcRIIB by their Fc
portion. Inhibition was indeed not seen in FcRIIB-/-
BMMC or in wt BMMC whose FcRIIB were rendered unaccessible for
anti-c-kit Abs. Inhibition was not seen either when the
Fc portion of anti-c-kit Abs was removed. Negative
regulation of c-kit-mediated cell proliferation by FcRIIB
demonstrated here in an experimental model may conceivably be induced
by anti-SCF or anti-c-kit autoantibodies in vivo.
This finding calls for assessing the existence and the potential role
of such Abs in normal or pathological conditions. Inhibition could
possibly also be induced by IgG Abs to any cell surface molecule borne
by cells that express membrane SCF with which mast cells were shown to
interact through cell-cell contact (22). Killer cell inhibitory
receptors, which inhibit Ab-dependent cell mediated cytotoxicity in NK
cells when binding to MHC class I molecules on target cells while the
Fc portion of IgG Abs bind to FcRIIIA, provide evidence that an
efficient Ab-mediated coaggregation of ITIM-bearing receptors with
ITAM-bearing receptors can occur during cell-cell interactions (23).
FcRIIB-dependent inhibition affected not only thymidine
incorporation, measured 24 h following stimulation, but also the
number of viable cells recovered after a 5-day culture with
anti-c-kit Abs. Inhibition of thymidine uptake, however,
was not due to a decreased cell viability as previously reported in B
cells (21), and inhibition of cell proliferation was correlated with a
blockade of the progression of BMMC through the cell cycle at the G1
stage. The mechanism of this arrest in G1 is not known.
Cyclin-dependent kinases that control the cell cycle are not specific
of any given growth factor receptor (24), and most RTKs use similar
transduction pathways to trigger the proliferation of a variety of cell
types (1). Negative regulation described here is therefore likely to be
restricted neither to mast cells nor to c-kit, and one
anticipates that FcRIIB can control cell proliferation that depends
on other growth factors that bind to RTKs. These include:
platelet-derived growth factor receptors, CSF receptors, epithelial
growth factor receptors, fibroblast growth factor receptors, nerve
growth factor receptors, vascular endothelial growth factor receptors,
insulin-like growth factor receptors, and insulin receptors. It follows
that major effector molecules of the immune system, IgG Abs, may
control the proliferation of a large number of cells within and outside
the immune system.
The coaggregation of c-kit with FcRIIB did not affect
c-kit phosphorylation, and it was correlated with the
tyrosyl-phosphorylation of FcRIIB and the subsequent recruitment of
SHIP. FcRIIB phosphorylation was likely to be mediated by
c-kit itself, when brought in proximity of the activated
kinase domain of c-kit, or by protein tyrosine kinases
recruited by c-kit. When tyrosyl-phosphorylated, FcRIIB
selectively recruited SHIP, as previously observed following their
coaggregation with FcRI (8). SHIP not being a protein tyrosine
phosphatase, it did not affect the phosphorylation of c-kit,
but it could block downstream signals that lead to proliferation.
Signaling by c-kit was previously reported to be negatively
regulated by the protein tyrosine phosphatase SHP-1, which was found
not to dephosphorylate c-kit but unknown downstream
substrates (25). The main substrate of SHIP is PIP3, which derives from
the phosphorylation of phosphatidylinositol (4, 5)bisphosphate by
phosphatidylinositol 3-kinase (PI3K). PIP3 enables the membrane
recruitment of Btk, which was shown to be sufficient to induce an
influx of extracellular Ca2+ (9). PI3K is activated upon
ligand-induced RTK dimerization (26). Supporting the role of SHIP in
inhibition of cell proliferation, progenitors of hematopoietic cells
from SHIP-deficient mice were reported to be hyperresponsive to several
growth factors, including SCF (27). Since SHIP-dependent
FcRIIB-mediated inhibition affects signaling events that stand
downstream to receptor phosphorylation (8, 9, 10), one can hypothesize
that it might also affect the proliferation of growth
factor-independent transformed cells that bear an oncogenic RTK. In
transformed human (28), mouse (29), and rat (30) mastocytoma cells, a
point mutation in the kinase domain leads to the constitutive
activation of c-kit and renders it oncogenic (31). IgG Abs
to growth factors or growth factor receptors might therefore provide
specific therapeutic tools that could potentially control the
proliferation of FcRIIB-expressing malignant cells.
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Acknowledgments |
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RIIB-deficient mice, Dr. Catherine Sautès (Institut Curie,
Paris, France) for FcRIIB-specific anti-peptide Abs, and Dr.
Michel Arock (Université Paris V, Paris, France) for his help in
generating BMMC. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Marc Daëron, Laboratoire d’Immunologie Cellulaire et Clinique, Institut National de la Santé et de la Recherche Médicale Unité 255, Institut Curie, 26 rue d’Ulm, 75005 Paris, France. E-mail address:
3 Abbreviations used in this paper: RTK, receptor tyrosine kinase; BCR, B cell receptor; BMMC, bone marrow-derived mast cells; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibition motif; MAR, mouse anti-rat Ig; PIP3, phosphatidylinositol (3, 4, 5)trisphosphate; SCF, stem cell factor; SHIP, Src homology 2 domain-containing inositol phosphate 5-phosphatase; wt, wild type.
Received for publication December 9, 1998. Accepted for publication January 20, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity 3:635.[Medline]
RIIB1. J. Immunol. 157:189.[Abstract]
RIIB. Nature 383:263.[Medline]
RI-associated lyn-dependent phosphorylation of FcRIIB during negative regulation of mast cell activation. J. Immunol. 160:1647. receptors (IgG-binding factors) are generated by cleavage of membrane FcRII. Eur. J. Immunol. 21:231.[Medline]
RIIB modulates B-cell receptor signalling. Nature 368:70.[Medline]
receptor effects on induction of c-myc mRNA expression in mouse B lymphocytes by anti-immunoglobulin. Mol. Immunol. 24:1199.[Medline]
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