By
From the * Laboratory of Immunohistochemistry and Immunopathology (LIIPAT), The National
Hospital, University of Oslo, Rikshospitalet, N-0027 Oslo, Norway; the Department of Nephrology,
Leiden University Medical Center, 2300 RC Leiden, The Netherlands; the § Division of Immunology
and Pathology, The Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, United
Kingdom; and the
Department of Immunology and Medarex Europe, University Hospital Utrecht,
3584 CX Utrecht, The Netherlands
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Abstract |
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To localize the immunoglobulin (Ig)-binding regions of the human Fc receptor (Fc
RI, CD89)
and the bovine Fc
2 receptor (bFc
2R), chimeric receptors were generated by exchanging comparable regions between these two proteins. Fc
RI and bFc
2R are highly homologous and are
more closely related to each other than to other human and bovine FcRs. Nevertheless, they are
functionally distinct in that Fc
RI binds human IgA (hIgA) but not bovine IgG2 (bIgG2), whereas bFc
2R binds bIgG2 but not hIgA. Fc
RI and bFc
2R possess extracellular regions
consisting of two Ig-like domains, a membrane-distal extracellular domain (EC1), a membrane-proximal EC domain (EC2), a transmembrane region, and a short cytoplasmic tail. Chimeras constructed by exchanging complete domains between these two receptors were transfected to
COS-1 cells and assayed for their ability to bind hIgA- or bIgG2-coated beads. The results
showed that the Ig-binding site of both Fc
RI and bFc
2R is located within EC1. Supporting
this observation, monoclonal antibodies that blocked IgA binding to Fc
RI were found to recognize epitopes located in this domain. In terms of FcR-Ig interactions characterized thus far, this
location is unique and surprising because it has been shown previously that leukocyte Fc
Rs and
Fc
RI bind Ig via sites principally located in their EC2 domains.
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Introduction |
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Immunoglobulin (Ig) Fc receptors (FcRs) expressed on
phagocytic cells provide a crucial link between the humoral and cellular branches of the immune system. Ligation
of FcRs by antigen-bound Ig leads to cellular activation and
triggering of powerful effector mechanisms (1, 2). In humans
and other mammals, IgA predominates in mucosae and,
furthermore, comprises a substantial proportion of the circulating Ig pool. At mucosal surfaces IgA provides a first-line
protective function, termed immune exclusion, whereby it
inhibits microbial colonization on epithelial cells and penetration of harmful antigens. In addition, the protective function of IgA both in mucosa and in the circulation may be reinforced by interaction of IgA-complexed antigens with the
myeloid FcRI (CD89)(3, 4). Fc
RI is expressed on monocytes, macrophages, polymorphonuclear granulocytes, and
eosinophils, and its cross-linking triggers a variety of immunological effector functions, including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators and cytokines (3).
Among FcRs characterized until now, FcRI is most
closely related to the bovine Fc receptor for IgG2 (bFc
2R)1
expressed on monocytes and granulocytes. In fact, these two
FcRs are more closely related to each other than to any
known human or bovine FcRs (7). More recently, it has
been shown that Fc
RI and bFc
2R are members of a
new gene family that apparently evolved from a common
ancestral gene. Other human genes belonging to this family
include the natural killer cell inhibitory receptors (KIRs), the Ig-like transcripts (ILTs), the leukocyte and monocyte/
macrophage Ig-like receptors (LIRs, MIRs), LAIR-1, and
HM18 (8). These genes are located close to the Fc
RI
gene within the so-called leukocyte receptor complex on
chromosome 19q13.4 (13). Several murine members of
the same gene family, gp49B1 (a structural homologue of
human KIRs), and the paired Ig-like receptors A and B
(PIR-A and PIR-B), have also been described (16).
FcRI and bFc
2R are both transmembrane glycoproteins
composed of two extracellular (EC) Ig-like domains (EC1 and
EC2), a transmembrane region containing a charged arginine
residue, and a short cytoplasmic tail devoid of signaling motifs (7, 19). Signal transduction via Fc
RI is mediated via
the FcR
chain, which associates with Fc
RI through the
charged arginine residue within its transmembrane domain
but does not affect its affinity for IgA (20). Despite the
high level of amino acid identity (41%) within the EC and
transmembrane regions of Fc
RI and bFc
2R, these two
receptors are functionally quite distinct in that Fc
RI binds
IgA but not bIgG2, whereas bFc
2R binds bIgG2 but not
IgA. Therefore, to map the ligand-binding domains of
these two FcRs we utilized their high degree of identity and
exchanged homologous regions between them. Based on
knowledge of interactions between other two-domain
FcRs (Fc
RII, Fc
RIII, and Fc
RI) with their respective
ligands (IgG or IgE), we expected the Ig-binding sites to be
located within the membrane-proximal EC2 domain (24-
30). Surprisingly, however, our results demonstrated that
the ligand-binding region of both Fc
RI and bFc
2R is
located in their membrane-distal EC1 domain. In part, this
finding probably reflects the evolutionary development of
Fc
RI and bFc
2R from an ancestral gene distinct from
the putative Fc
R/Fc
R precursor.
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Materials and Methods |
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Cell Culture.
COS-1 cells were maintained in DMEM (BioWhittaker) supplemented with 10% FCS, 1 mM L-glutamine, and 50 µg/ml gentamycin (Life Technologies, UK). The murine IIA1.6 B cell line that coexpresses FccDNAs and Construction of Chimeric FcRs.
cDNAs encoding the complete Fc
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Transfections.
COS-1 cells were transiently transfected with 2 µg chimeric FcR cDNA constructs by means of Fugene 6 transfection reagent (Boehringer Mannheim, Germany) according to the manufacturer's instructions. In some experiments, 1 µg pCMV-GFP was cotransfected together with the FcR constructs. Cells were incubated at 37°C in a humidified CO2 atmosphere for 48 h before harvesting.Ig-binding Assays.
Uncoated magnetic M-450 Dynabeads (Dynal, Norway) were coated, according to the manufacturer's instructions, with either human serum IgA (hIgA) or bovine IgG2 (bIgG2), which were purified as previously described (7, 32). Due to low transfection efficiency of some DNA constructs (see Results), transfected COS-1 cells were first enriched for those becoming positive for gene expression by cotransfection of the FcR and pCMV-GFP constructs. Experiments showed that most fluorescent (GFP+) cells had also taken up both plasmids, thus expressing the chimeric FcR together with GFP (see Results). Therefore, binding assays were performed as follows: 5 × 104 GFP+ COS-1 cells (which had also been cotransfected with an FcR construct) were purified in a FACSVantage® cell sorter (Becton Dickinson) and mixed with Ig-coated Dynabeads in a final volume of 50 µl per well in V-bottomed microtiter plates. After a 15-min incubation at room temperature, the plate was spun at 50 g for 1 min and incubated for an additional 45 min at room temperature. Cells and beads were resuspended and examined for the presence of rosettes, using a combination of light and fluorescent microscopy, in a Nikon Eclipse E800 microscope. Rosettes were defined as GFP+ cells binding four or more Ig-coated beads and at least 200 GFP+ COS-1 cells were counted for each determination. For blocking studies, cells were incubated with either mAb My43 (50 µl culture supernatant) or CC-G24 (50 µl ascites fluid diluted 1:4) for 30 min at room temperature before the addition of Ig-coated beads.Production and Purification of Recombinant Soluble FcRI.
Monoclonal Antibodies.
The previously described FcFACS® Analysis.
Cells (5 × 105) were washed twice with FACS buffer (PBS/0.5% BSA/0.02% azide) and incubated with either Fc ![]() |
Results |
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To map the ligand-binding domains of FcRI
and bFc
2R, we generated five chimeric receptors as follows: hEC-bFc
2R, consisting of the two EC domains of
Fc
RI fused to the transmembrane/cytoplasmic (TM/C)
domain of bFc
2R; bEC-Fc
RI, the two bovine EC
domains fused to the TM/C domain of Fc
RI; hEC1-bFc
2R, the EC1 domain of Fc
RI fused to the EC2
TM/C region of bFc
2R; bEC1-Fc
RI, the EC1 domain
of bFc
2R joined to the EC2 TM/C region of Fc
RI;
and bEC1(1-50)-Fc
RI, the first 50 amino acids of bFc
2R
fused at isoleucine 50 to Fc
RI (Fig. 1). Together with
wild-type Fc
RI and bFc
2R cDNAs, individual chimeric
FcR constructs were transfected to COS-1 cells, and their
cell surface expression was assessed by FACS® analysis and
by a specific binding assay using Ig-coated beads (see Materials and Methods). Initial experiments revealed the transfection efficiency of individual constructs to be quite variable. The most efficient construct directed expression of
Fc
RI on the surface of ~30% of COS-1 cells, whereas
the least efficient (bEC1-Fc
RI) was expressed by only 3%
of the transfectants (Fig. 2 A). Therefore, we developed a
method to selectively enrich for transiently transfected cells
by cotransfecting a plasmid that directed expression of GFP
(visualized by green fluorescence) together with the chimeric FcR constructs. Most GFP+ COS-1 cells cotransfected with Fc
RI were recognized by mAb A62 (Fig. 2 B),
and formed rosettes with hIgA-coated beads (Fig. 2 C). By
this procedure we obtained an approximately twofold enrichment of chimeric FcR-expressing cells, which in the
case of Fc
RI resulted in >60% of cells being reactive with
Fc
RI mAb and further able to form rosettes with hIgA
coated beads (Fig. 2, B and C). It should be noted that
GFP
COS-1 almost never formed rosettes, most likely
because transfectants expressing Fc
RI alone accounted for
only ~1% of the total cells (Fig. 2 B). We, furthermore,
demonstrated the specificity of our binding assay by using
blocking mAbs specific for Fc
RI or bFc
2R to inhibit
rosette formation (Fig. 3). The finding that the inhibition obtained with My43 was only partial (~50%) was most
likely explained by the use of culture supernatant other
than a higher concentration of purified antibody which was
not available.
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FcRI does not bind bIgG2, and bFc
2R does not bind
hIgA (reference 7 and this paper); accordingly, we neither
observed rosettes when hIgA-coated beads were mixed
with bFc
2R transfectants, nor when bIgG2-coated beads
were mixed with Fc
RI transfectants (Fig. 4). Binding
studies with COS-1 cells enriched for FcR expression as
described above, showed not unexpectedly that wild-type
Fc
RI and bFc
R2 transfectants produced the highest levels of rosette formation with hIgA- and bIgG2-coated
beads, respectively (Fig. 4). Transfectants expressing chimeras coding for the entire EC portions of the receptors
(hEC-bFc
2R and bEC-Fc
RI) bound their respective
Ig-coated beads efficiently, although at a slightly lower
level than their wild-type counterparts (Fig. 4). The fact that the hEC1-bFc
2R chimera retained IgA-binding capacity demonstrated that the binding site of Fc
RI lies
within the membrane-distal EC1 domain. Furthermore,
because this chimera did not form rosettes with bIgG2-coated beads, our finding further suggested that the binding
site for bIgG2 in bFc
2R was not located within the EC2 domain of this receptor. Conversely, the bEC1-Fc
RI chimera did form rosettes with bIgG2-coated beads, but not
with beads coated with hIgA.
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Altogether these results showed that, in common with
FcRI, the ligand-binding site of bFc
2R appeared to
lie within the EC1 domain. It should be noted, however,
that the level of binding obtained with the two EC1 chimeras (hEC1-bFc
2R and bEC1-Fc
RI) was reduced
when compared with the wild-type receptors, and the EC
chimeras (hEC-bFc
2R and bEC-Fc
RI) (Fig. 4). Futhermore, to better localize the Ig-binding sites of these two
receptors, a further chimera was constructed in which the
first 50 amino acids of the EC1 domain were from bFc
2R,
while the remaining EC1 (49 amino acids) and the rest of
the receptor were from Fc
RI [bEC1(1-50)-Fc
RI]. Although this chimera was expressed at the cell surface and
could be recognized by the majority of Fc
RI mAb, it
bound neither hIgA- nor bIgG2-coated beads.
To confirm that the IgA-binding site of FcRI lies within the EC1
domain, we mapped the specific epitopes for a number of blocking and nonblocking mAbs. Of the previously described Fc
RI mAbs, only My43 (murine IgM) was able to
block the binding of hIgA to Fc
RI (33). Four others (A3,
A59, A62, and A77, all murine IgG1) did not inhibit binding (34). We also included a number of new Fc
RI mAbs
(2E6, 2D11, 7G4, 2H8, and 7D7, all murine IgG1), raised
against a soluble form of Fc
RI. These mAbs were shown to
be specific for Fc
RI by reaction with IIA1.6 cells expressing this receptor (Fig. 5 A). They were next assayed for ability to block binding of heat-aggregated hIgA to Fc
RI:
mAbs 2E6, 2D11, 7G4, and 2H8 produced such inhibition
while 7D7 did not (Fig. 5 B). Accordingly, we presumed
that the blocking mAbs would prove to be EC1-specific,
whereas the nonblocking ones would be EC2 specific.
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To test this hypothesis, we screened the reactivity of all
mAbs against the panel of chimeric FcR expressed in
COS-1 cells by FACS® analysis. Indeed, all mAbs capable
of blocking the binding of heat-aggregated hIgA to FcRI
(Fig. 5 B), mapped to the EC1 domain (Fig. 5 C). Also, all
nonblocking mAbs were directed against the EC2 domain,
except for mAb A3 that apparently recognized an epitope depending on parts of both domains. Unfortunately, because only one mAb against bFc
2R was available, a similar detailed study could not be performed for this receptor.
We showed that mAb CC-G24 only recognized wild-type
bFc
2R and the bEC-Fc
RI chimera (Fig. 5 C). Thus,
like mAb A3, it is most likely directed against a conformational epitope depending on both EC1 and EC2.
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Discussion |
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By means of a panel of chimeric FcRs, we identified
conclusively for the first time the ligand-binding sites of
FcRI and bFc
2R. Surprisingly, these sites were found to
be located in the EC1 domains. Fc
RI and bFc
2R are
highly homologous both at the protein and nucleotide
level (41 and 56% identity, respectively), but show much
less homology with other human and bovine FcRs (7). This suggests that Fc
RI and bFc
2R evolved from a
common ancestral gene (also shared by KIR, ILT, MIR,
LIR, LAIR-1, HM18, PIR, and gp49B1 genes) and not
shared by other human or bovine FcRs (7). Mapping of the
bFc
2R gene to bovine chromosome 18, which corresponds to human chromosome 19, further supports this notion (35).
Our finding that the Ig-binding sites of both FcRI and
bFc
2R are located within their EC1 domains, was based
on the fact that rosetting with Ig-coated beads was only
seen for the corresponding Fc
RI or bFc
2R EC1 chimera. In both cases, however, a reduction in binding activity was seen compared with that obtained for the wild-type
receptors and for the comparable EC chimeras (Fig. 4). Although these differences in part may be attributed to the
expression levels of individual constructs (especially for the
bEC1-Fc
RI chimera, see above), it is also possible that
the EC2 domains and membrane-proximal regions of
the receptors contribute either directly (by forming "secondary" contact sites) or indirectly (by preserving three-
dimensional structure) to the affinity and stability of the
ligand interactions. This would be analogous to the activity
of other two-domain FcRs, namely Fc
RII, Fc
RIII, and
Fc
RI in which the ligand-binding sites are located in
the membrane-proximal EC2 domains, whereas structures
within the EC1 domains contribute to the binding process
(29, 30).
It should also be noted that the region of hIgA interacting with FcRI has recently been mapped to the C
2/
C
3 boundary (36). This is in contrast to the region of human IgG responsible for interaction with Fc
Rs, which is
proposed to lie much closer to the hinge (30). Therefore,
in terms of the evolution of Ig/FcR interactions, it should
be interesting to map the region of bIgG2 that binds to
bFc
2R. Because recombinant bIgG2 is available, experiments can readily be designed to determine whether this region lies close to the hinge region as in human IgG or in
a position analogous to that of hIgA (37).
To substantiate our observation that hIgA binds to the
EC1 domain of FcRI, we mapped the epitopes for a
panel of blocking and nonblocking Fc
RI mAbs that
bound equally to the EC parts of wild-type Fc
RI and the
hEC-Fc
2R chimera. The nonblocking mAbs (A59, A62,
A77, and 7D7) were shown to react with the membrane-proximal EC2 domain because they bound only to wild-type Fc
RI and the hEC-bFc
2R, bEC1-Fc
RI, and
bEC1(1-50)-Fc
RI chimeras. The only exception was the
nonblocking mAb A3 that bound only to wild-type Fc
RI
and the hEC-bFc
2R and bEC1(1-50)-Fc
RI chimeras,
suggesting that its epitope is conformational and depends
on regions of both EC1 and EC2 (similar to the bFc
2R mAb CC-G24; see Results section). In contrast, all blocking mAbs (My43, 2E6, 2D11, 7G4, and 2H8) were shown
to react with the EC1 domain of Fc
RI because their
binding activity was retained with the hEC1-bFc
2R chimera. The epitopes recognized by My43 and 2D11 were
further localized to the region of EC1 directly adjacent to
EC2, because they were shown to bind the bEC1(1-50)-Fc
RI chimera. 2E6 and 2H8 on the other hand, bound
only weakly to this chimera, whereas 7G4 did not bind at
all. Similar mapping studies with blocking mAbs have previously been used to localize the IgG-binding sites of
Fc
RII and Fc
RIII to their EC2 domains (25, 27).
A number of FcRI mRNAs have been isolated and
shown to encode splice variants of the receptor (38).
One such report described cell surface expression of an Fc
RI
variant that lacked the complete EC2 domain, and suggested the EC1 domain to be involved in hIgA binding
(40). However, in contrast to our results, mAb My43 was
proposed to react with EC2, and mAb A59 with EC1. We
believe that observation to be spurious either due to incorrect cell surface expression of the splice variant and/or aberrant receptor structure caused by lack of the complete
EC2 domain. This possibility was supported by our attempts
to express various Fc
RI splice variants in COS cells with
no success (38). Additionally, chimeras constructed between
Fc
RI and Fc
RII were not expressed efficiently (Morton, H.C., and J.G.J. van de Winkel, unpublished observations),
possibly reflecting a degree of structural incompatibility between these two FcRs. In fact, our unsuccessful experience
with those approaches led us to construct chimeras between Fc
RI and bFc
2R as reported here, because their
levels of homology (and hence presumably their overall
structure) are more similar than for other FcRs. Thus swapping of highly homologous regions should have minimal affect on the overall structural integrity of the resultant chimeras. Therefore, we feel that the present approach is more
physiological than previous attempts to this end.
The surprising difference seen between the ligand-binding sites of FcRI and bFc
2R versus those of other leukocyte Fc
Rs and Fc
RI may have interesting implications in
terms of Ig interactions. As mentioned above, this disparity
could simply reflect the proposed evolution of Fc
RI and
bFc
2R from an ancestral gene distinct from that giving
rise to other Fc
Rs and Fc
RI. This notion is supported by
the observation that residues within the membrane-distal domain of two KIR proteins determine their ability to bind
to their respective ligands, the two groups of HLA-C allotypes (42). Moreover, due to their high levels of homology, the three-dimensional structure of Fc
RI and
bFc
2R might more closely resemble that of the KIR proteins than that of more distantly related FcRs (43). Indeed,
more detailed mutational analysis, directed by modeling studies using the recently published three dimensional
structure of the p58 KIR as a template for the protein
backbones of Fc
RI and bFc
2R, are currently underway
in our laboratory to further localize the Ig-binding sites
within these two receptors.
An alternative evolutionary explanation possibly applicable at least for FcRI might be that its ligand-binding site
developed to ensure interaction with all molecular forms of
IgA: monomeric IgA, dimeric IgA (including J chain), and
secretory IgA (including J chain and secretory component).
Fc
RI is reported to bind all these ligand variants (44, 45).
Therefore, because the site of interaction with Fc
RI at the
C
2/C
3 boundary appears to be accessible to the receptor
in all these forms of IgA, Fc
RI could have evolved to accomplish this interaction via its EC1 domain to avoid potential problems of steric hindrance of a more membrane-proximal binding site in relation to large IgA polymers.
In conclusion, we have shown that the closely related
FcRI and bFc
2R bind their ligands via sites located in
their membrane-proximal EC1 domains. The difference in
the Ig-binding sites of these two receptors versus other leukocyte Fc
Rs and Fc
RI, may reflect the proposed divergent evolutionary pathway from a distinct genetic precursor, or (at least in the case of Fc
RI) a specific adaptation for efficient interaction with large molecular forms of IgA.
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Footnotes |
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Address correspondence to H. Craig Morton, LIIPAT, Rikshospitalet, N-0027, Oslo, Norway. Phone: 47-22-86-86-31; Fax: 47-22-11-22-61; E-mail: craig.morton{at}labmed.uio.no
Received for publication 24 December 1998 and in revised form 29 March 1999.
Note added in proof. A recent report by Wines et al. (J. Immunol. 1999. 162:2146-2153) likewise identified the EC1 domain of FcWe would like to thank Drs. Li Shen for My43, Max Cooper for A62, and Charles Maliszewski and Immunex for FcRI cDNAs. We also gratefully acknowledge the technical staff of LIIPAT, specifically Bjørg Simonsen, Marie Johannesen, and Inger Johanne Ryen, for expert laboratory assistance. We further thank
Gøril Olsen for help with cell sorting, and Dr. Finn-Eirik Johansen (LIIPAT) for helpful discussions and
provision of the pCMV-GFP plasmid.
Abbreviations used in this paper b, bovine; EC, extracellular; GAM, goat anti-mouse; GFP, green fluorescent protein; KIR, natural killer cell inhibitory receptor; TM/C, transmembrane/cytoplasmic.
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