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(Received for publication, June 8, 1995; and in revised form, August 1, 1995) From the
The type I interferon (IFN) receptor complex is assumed to be
composed of multiple protein subunits. Recently, two proteins have been
identified as potential receptor components, both of which share a high
degree of structural homology with the immunoglobulin superfamily. One
of these proteins, referred to as the human interferon
Ligand-receptor cross-linking experiments (1, 2) suggest that a functional type I interferon
(IFN) ( A second IFN receptor protein, P40,
identified by Novick et al.(8) , was purified as a
soluble protein from human urine by its ability to bind to an
IFN- Neither IFNAR nor FLP40 alone appears to
be able to act as a receptor capable of high affinity ligand binding.
Therefore, it seems likely that in the case of the type I IFN receptor
a ligand-induced association between two or more proteins would be
required to form a functional type I IFN receptor complex capable of
specific high affinity ligand binding. In this report we describe the
results of co-expressing IFNAR and FLP40 in a L929 murine cell line.
The co-expression of these two proteins in L929 cells results in the
formation of a high affinity ligand binding site for human type I IFNs
in a cell type initially lacking the ability to bind type I IFNs.
Two primers
(5`-GCGAGAGCTGCAAAGTTTAATT and 5`-AGAAAACATTGACAAACGAGAAA)
corresponding to the 5`- and 3`-untranslated region of P40 (8) were used to generate a full-length form of P40 cDNA
(FLP40) by reverse transcriptase-PCR. The PCR fragment was then cloned
into pTA vector (Invitrogen). Nucleotide sequence analysis of the
cloned cDNA showed two nucleotide changes when compared to the
published sequence (8) which resulted in an amino acid change
in the signal peptide region (Val L929 cells were transfected using
LipofectAMINE according to the protocol from the supplier (5 µg/ml
LipofectAMINE for 5 h in Opti-MEM I media) (Life Technologies, Inc.).
After transfection, cells were placed in selection media, and
individual clones were selected by limited dilution. The resultant cell
line expressing only IFNAR was referred to as L929R
Figure 1:
Detection of human IFNAR expression on
murine L929R
Next we generated L929 cell lines
expressing either FLP40 (L929R
Figure 2:
Northern blot analysis of FLP40 mRNA.
Murine L929 (lane 1), L929R
Figure 3:
IFN-
Both IFN-
Figure 4:
Binding of IFN-
To
investigate further the role of IFNAR in the formation of a ligand
binding complex, we performed studies using a polyclonal antiserum
directed against the extracellular region of IFNAR. This antiserum
reacts with IFNAR present on the surface of Daudi, L929R
Figure 5:
Inhibition of IFN-
The data presented here indicate that
IFNAR and FLP40 cooperate to form a high affinity ligand binding site
for type I IFNs. Previous examples of other cytokine receptors, such as
interleukin receptors, suggests this class of cell surface receptors
form multicomponent complexes(5, 6, 21) .
Such a receptor complex is thought to bring together proteins which act
to form a high affinity ligand binding complex. Once this occurs,
cytosolic protein kinases (e.g. Jak, Tyk2) are activated and
phosphorylate specific tyrosines located within the cytoplasmic
C-terminal region of the receptor(22, 23) . The
potential interaction between various proteins forming such a receptor
have been suggested in structural models for the type I IFN
receptor(24, 25) . In line with other known cytokine
families, it is likely that the human type I IFN receptor is comprised
of multiple protein subunits and that the interaction of these subunits
is a prerequisite for ligand binding or signaling. We have tested this
hypothesis by first demonstrating that murine cell lines L929R One final issue to be
addressed is that of biological response in our L929R Understanding the process by which these components interact with
each other will help to shed some light on the mechanism by which IFNAR
and FLP40 form a ligand binding site on L929R
Note Added in Proof-A paper appeared after
the submission of this Communication (29) in which a somewhat similar
result in murine NIH 3T3 cells was observed. In agreement with our
results, co-expression of IFNAR and FLP40 in murine NIH 3T3 cells
generated a high affinity ligand binding site.
Volume 270,
Number 44,
Issue of November 3, 1995 pp. 26033-26036
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
receptor
(IFNAR), has been shown to be involved in interferon signal
transduction, but it does not bind IFN with high affinity. A second
putative receptor protein, named FLP40, has been cloned from human
Daudi cells. Transfection of FLP40 into murine NIH 3T3 cells does not
result in high affinity IFN binding. In this study, we demonstrate that
when expressed in murine L929 cells neither IFNAR nor FLP40 by
themselves are capable of binding human IFN-8. Co-expression of
IFNAR and FLP40 results in cells capable of binding IFN-8 and
IFN-2. Scatchard analysis of binding demonstrated the presence of
high (K 350 pM) and low (K
4.0 nM) affinity binding
sites. Binding of radiolabeled IFN-
8 can be competed with either
unlabeled IFN-8 or a recombinant form of human interferon 
,
IFN-1b, but not with IFN-. Ligand binding of IFN-
8 can
be inhibited by antibodies directed against IFNAR providing further
support for a role for this protein in the formation of a ligand
binding site. This is the first demonstration indicating that two
previously identified IFN receptor proteins, which individually do not
bind type I IFN with high affinity, cooperate in the formation of a
type I IFN receptor ligand binding complex.
)receptor complex is comprised of multiple components
much like that of the previously described IFN-, interleukins, and
granulocyte-macrophage colony-stimulating factor receptor
families(3, 4, 5, 6) . However, the
identity and mechanism of interaction between proteins comprising the
human type I IFN receptor is unclear. Two proteins have recently been
identified as potential components of the human type I IFN receptor
complex(7, 8) . One, the human interferon
receptor (IFNAR) was identified by its ability to reconstitute an
antiviral response to IFN-8 in a murine cell
line(7, 9) . Monoclonal antibodies directed against
the extracellular region of IFNAR have been shown to block the
antiviral activity of a number of type I IFNs(10) . It appears,
however, that neither human IFNAR nor the purified extracellular domain
of IFNAR is able to mediate high affinity
binding(11, 12) . Although Daudi cells, from which
IFNAR was cloned, bind high levels of type I IFN at 20 °C, murine
cells expressing human IFNAR could only be demonstrated to bind ligand
at 37 °C in which binding values were expressed as cellular uptake
rather that direct receptor binding(7) . Indeed, it was later
shown that murine cells expressing IFNAR did not bind detectable levels
of type I IFN when ligand binding was measured under conditions which
minimized endocytosis(11) . Recent studies in which human IFNAR
was expressed in Xenopus laevis oocytes (13) confirmed the notion that IFNAR alone binds type I IFN
with very low affinity. Finally, it has been shown that IFNAR becomes
phosphorylated by IFN- and IFN- but not IFN- in a
ligand-dependent manner demonstrating again its involvement in type I
IFN signaling(14) .
2 affinity column. A variation of this protein also appears as
a membrane-bound form in Daudi cells where it contains a transmembane
and cytoplasmic domain(8) . We refer to the membrane-bound form
of this protein as full-length P40 (FLP40). Antibodies directed against
the soluble form of this protein block the antiviral activity of a
number of human type I IFNs on human WISH cells (8) . Although
P40 binds to immobilized IFN-2, it appears to do so with only low
affinity. This is implied by the observation that the membrane-bound
form of this protein when expressed on murine NIH 3T3 cells could only
be demonstrated to bind low levels of ligand after extensive
cross-linking(8) .
Cell Lines
Human Daudi cells and murine L929
cells were obtained from the American Type Tissue Culture (ATTC).
Murine L929 cells were maintained in Dulbecco's modified
Eagle's media and Daudi cells in RPMI 1640. Media in both cases
were supplemented with 10% fetal bovine serum, 2.0 mML-glutamine, 200 units/ml penicillin, and 60 µg/ml
streptomycin. Following transfection, murine cells were selected in
media supplemented with 1.5 mg/ml Geneticin (Life Technologies, Inc.)
or 0.6 mg/ml hygromycin.Plasmid Construction and Transfection
Protocol
IFNAR cDNA was kindly provided by Dr. Gilles
Uzé, Institut de Genetique Moleculaire, CNRS,
Montpellier, Cedex 1, France and cloned into a plasmid containing the
cytomegalovirus promoter, SV40 origin of replication (pbSER99), and a
neomycin gene for resistance to Geneticin (G418). FLP40 was cloned from
Daudi cell mRNA using the reverse transcriptase-polymerase chain
reaction (PCR). Single-strand cDNA was synthesized from mRNA isolated
from Daudi cell using Superscript II (BRL). to Phe), and one in the
intracellular region (Thr
to Ala). For expression in
mammalian cells, FLP40 cDNA was first cloned into an expression vector
(pbSER97) which contains the myeloproliferative sarcoma virus promoter,
a hygromycin resistance gene, and an SV40 origin of
replication(15) .
, and
L929 cells expressing FLP40 were referred to as L929R
. For
co-expression of both IFNAR and FLP40, murine L929 cells expressing
IFNAR (L929R cells) were transfected with pbSER97
containing the FLP40 coding sequence and selected in media containing
both Geneticin and hygromycin. The resultant cell line containing both
IFNAR and FLP40 was referred to as L929R.
Northern Blot Analysis
Total RNA (10 µg)
isolated from stable transformants was electrophoresed through a
formaldehyde-containing agarose gel and transferred to nylon membrane.
The membrane was hybridized with a specific P-labeled
full-length RNA probe (Riboprobe) for FLP40 using conditions described
previously (15) and exposed to x-ray film.
Ligand Binding Assay
A phosphorylatable form of
human recombinant IFN-8 and IFN-2 were obtained from Pestka
Biomedical (16) . All ligands were phosphorylated (specific
activities of 60-61.2 µCi/µg) following previously
described procedures(16) . Phosphorylated ligands retained full
activity after radiolabeling as judged by their ability to generate an
antiviral effect on human WISH cells using a cytopathic
effect-antiviral assay (not shown). Direct binding assays on Daudi
(10
cells/ml) and murine L929 (10
cells/ml)
were performed at 20 °C for 90 min. After ligand binding, Daudi
cells were collected by centrifugation through a cushion of silicone
oil prior to determination of bound radioactivity. Binding assays using
adherent mouse L929 cells were performed on 35-mm dishes in which cells
were grown to near confluency. After ligand binding, cells were washed
in cold media as described above and solubilized in 2.0% sodium dodecyl
sulfate (SDS) prior to scintillation counting. Nonspecific binding was
determined by incubation with 100-fold excess unlabeled ligand.
Recombinant human IFN-8 was kindly provided by Ciba-Geigy AG,
Basel, and recombinant human IFN-1b was purified as described
previously(17) . Binding data were analyzed according to
Scatchard(18) . For neutralization studies using polyclonal
antibodies directed against IFNAR, cells were preincubated with
preimmune or immune sera (1:100 dilution) for 60 min at 4 °C prior
to addition of ligand.IFNAR Antibody Production
A soluble form of IFNAR
was expressed in baculovirus and purified, and the resultant material
was used to generate both monoclonal and polyclonal antibodies. The
production of monoclonal antibodies recognizing the native form of
IFNAR has been described previously(12) . The monoclonal
antibody 4B1 was iodinated using the IODOBEADS following procedures
described by the manufacturer (Pierce). The polyclonal antiserum used
in these studies was developed in rabbits.
Selection of Murine Cells Expressing Type I IFN
Receptor Proteins
Mouse L929 cells (L929) have previously been
shown not to be able to bind or produce an antiviral response to human
type I IFNs at concentrations which induce such responses in human
cells(7, 11, 19) . Therefore, this cell line
was chosen for transfection studies in which the function of individual
human type I IFN receptor subunits could be examined. As a first step
in studying the role of IFNAR and FLP40 in ligand binding, stable L929
cell lines expressing only IFNAR (L929R) were generated.
The surface expression of IFNAR on L929R cells was
confirmed by making use of a monoclonal antibody (4B1) which is
specific for human IFNAR (12, 14) . Iodinated 4B1 was
used in direct binding studies to demonstrate the presence of IFNAR on
the surface of L929R cells (Fig. 1, A and B). Scatchard analysis of binding curves revealed that binding
of 4B1 detected 17,000 ± 2000 antibody sites/cell (mean ±
S.E., n = 2) on L929R cells. Scatchard
analysis of binding curves was also performed on L929R cells (Fig. 1C) and showed that binding of 4B1
(detected (10,234 ± 3,000 antibody sites/cell, mean ±
S.E., n = 2). Therefore, L929R
and
L929R cells express similar amounts of IFNAR on their cell
surface. The expression of IFNAR on these cells was also confirmed by
fluorescent-activated cell sorting (FACS) analysis using the monoclonal
antibody 4B1 (not shown).
and L929R cells using the
anti-human IFNAR monoclonal antibody, 4B1. A, binding of
increasing concentrations of 4B1 to L929R
. Specific binding (open circles), nonspecific binding in the presence of
100-fold excess unlabeled monoclonal antibody (closed
circles), and binding of I-4B1 to parental L929
cells (squares) is shown. Data represent mean values of n = 2, and variation between replicates was less than 15%. B, Scatchard analysis of
I-4B1 binding to
L929R
(17,000 ± 2000 antibody sites/cell, mean
± S.E., n = 2) C, Scatchard analysis of I-4B1 binding to L929R
cells (10,234
± 3,000 antibody sites/cell, mean ± S.E., n = 2).
) or both IFNAR and FLP40
(L929R). L929R
cells were produced by
transfecting into L929R
cells a plasmid containing a gene
encoding FLP40 as described under ``Experimental
Procedures.'' FLP40 mRNA in L929R and L929R cells was confirmed by demonstrating the presence of a 1.5-kb
band corresponding to the expected size of FLP40 mRNA (Fig. 2)(8) . As expected, the 4.3-kb band, presumed to
represent a soluble truncated receptor(8) , was visible only in
blots using Daudi cell mRNA (8) and was not detected in cells
transfected with a plasmid containing only the cDNA encoding FLP40. In
all L929R
cell lines tested (8 individual clones), it
appeared that co-expression of IFNAR and FLP40 resulted in an apparent
increase in the amount of FLP40 mRNA. A second faint variable band of
3.0 kb was sometimes observed in L919R
cells. However, the
presence or absence of this band did not correlate with ligand binding.
The monoclonal antibody 4B1 was used to confirm that the expression of
IFNAR in L929R
cells was similar to that observed in
L929R
cells (Fig. 1).
(lane 2),
L929R (lane 3), L929R
(lane
4), and Daudi (lane 5) cells were probed for the presence
of FLP40 mRNA. Total RNA (10 µg) from each cell line was
electrophoresed through a formaldehyde-containing agarose gel,
transferred to a Nylon membrane, and hybridized to a P-labeled full-length FLP40 RNA probe (Riboprobe). A
1.5-kb band, corresponding to the expected size of FLP40, was observed
only in cell lines transfected with a plasmid containing a gene
encoding this protein (lanes 3 and 4) and Daudi cells (lane 5). A 4.3-kb band was also detected in Daudi cells as
described previously(8) . Occasionally, a second 3.0-kb
unidentified band was observed in L929R
cells (lane
3), the presence of which had no effect on ligand binding. No
FLP40 mRNA was detected in either the parental L929 or
L929R
cells (lanes 1 and 2).
Hybridization with a P-labeled actin probe revealed equal
RNA loading between lanes (not shown). The 28 S and 18 S ribosomal RNA
is indicated.
Human Type I IFN Binding to Murine
Cells
L929R and L929R cells were
evaluated for their ability to bind IFN by measuring the binding of
increasing concentrations (25-750 pM) of phosphorylated
IFN-8 and IFN-2 in the presence or absence of 100-fold excess
unlabeled ligand (Fig. 3, A and B). We could
not demonstrate ligand binding to either L929R or
L929R cells. The lack of ligand binding to L929R cells confirms previous results in which the binding of type I
IFNs could not be detected in L929 cells expressing IFNAR(11) .
Next, we determined the ability of L929R cells, which
express both IFNAR and FLP40, to bind labeled ligands. Both IFN-
8
and IFN-2 specifically bound to L929R cells (Fig. 3, A and B). Saturation ligand binding
could be demonstrated, and Scatchard analysis of the binding data
demonstrated the presence of 31,000 ± 5,000 high affinity and
125,640 ± 20,000 low affinity sites/cell (mean ± S.E., n = 2). The K
of IFN-8
binding for the high affinity site was 350 pM ± 80
pM (mean ± S.E., n = 2) whereas the K of binding to the low affinity site was 4.5
nM ± 1.0 nM (mean ± S.E., n = 2). The affinity of ligand binding to L929R cells was similar to that observed on Daudi cells(20) .
8 and -2 binding to L929,
L929R, L929R, and L929R cells.
Cell lines were grown to near confluency in 35-mm dishes, and
phosphorylated ligand (25-750 pM) was allowed bind to
cells for 90 min at 20 °C. Cells were then washed and solubilized,
and radioactivity was determined by scintillation counting. Nonspecific
binding was determined in the presence of a 100-fold excess of
unlabeled IFN. A, binding of IFN-
8 was observed in
L929R (open circles), but not in L929R
(triangles), or L929R (large
circles) cells. Nonspecific binding to L929R cells (filled circles) was determined in the presence of a 100-fold
excess of unlabeled IFN-
8. Inset, Scatchard analysis of
IFN-8 binding revealed 31,000 ± 5,000 high affinity and
125,640 ± 20,000 low affinity sites/cell (mean ± S.E., n = 2). The K of
IFN-
8 binding for the high affinity site was 350 pM ± 80 pM (mean ± S.E., n =
2) whereas the K of binding to the low
affinity site was 4.5 nM ± 1.0 nM (mean
± S.E., n = 2). B, binding of
IFN-
2 was observed in L929R (open circles),
but not in L929R
(triangles) or L929R (large circles) cells. Nonspecific binding to
L929R cells (filled circles) was determined in
the presence of a 100-fold excess of unlabeled
IFN-
8.
8 and IFN-1b were able to compete binding of
radiolabeled IFN-8 (150 pM) to L929R cells (Fig. 4). Unlabeled IFN-
8 exhibited an IC of
500 pM, while unlabeled IFN-
1b competed for the binding
of radiolabeled IFN-8 with an IC of 50 pM. A
similar result was observed using Daudi cells (not shown).
8 to L929R cells in the presence of unlabeled IFN-
8 or human
IFN-1b. Radiolabeled IFN-8 (150 pM) was allowed to
bind to L929R cells in the presence of increasing
concentrations of unlabeled IFN-
8 (circles) or
IFN-1b (squares). IFN-1b appears to compete for the
binding of radiolabeled IFN-8 more efficiently than does
IFN-8 itself.
and L929R cells as judged by FACS analysis (not
shown). Preincubation of cells with this antiserum inhibited IFN-
8
binding to both Daudi and L929R cells by 80-90% (Fig. 5A). A dose-response curve demonstrating the
antibody induced inhibition of IFN-
8 binding to L929R cells is shown in Fig. 5B. The blocking of ligand
binding by the anti-IFNAR antibody supports the suggestion that IFNAR
interacts with an additional component(s) which together form a
receptor complex that can bind with high affinity either IFN-
8,
IFN-2, or IFN-1b.
8 binding to Daudi
and L929R cells using a polyclonal antibody recognizing
IFNAR. A, IFN-
8 (250 pM) binding to
10 L929R cells/ml and 10
Daudi
cells/ml was performed in the presence of a polyclonal antiserum (1:100
dilution, solid bars) directed against IFNAR. The antiserum
inhibited the binding of phosphorylated IFN-8 to L929R cells (L929R
) and Daudi cells. Values shown are the
mean for three experimental points ± S.E. Preimmune serum (1:100
dilution, open bars) did not inhibit ligand binding to Daudi
or L929R
cells. Percent of control binding of IFN-
8
is equal to the amount of IFN-8 bound in the absence of antisera. B, dose-response curve for the antibody induced inhibition of
IFN-8 (250 pM) binding to L929R cells. Data
represent the mean of two experimental points (S.E. ± 10%).
Antisera concentration is represented as the log of the
dilution.
and L929R, which stably express either IFNAR or
FLP40, respectively, do not specifically bind IFN-8 or IFN-2
at levels detectable by saturation binding. However, when we attempted
to establish ligand binding by producing an additional cell line,
L929R, expressing both IFNAR and FLP40, we observed
specific binding of IFN-
8 and IFN-2 to this cell. There are
several findings that suggest the possibility that other proteins may
be involved in the specific binding of some type I IFNs. First, our
finding that IFN-1b appears to be more efficient in competition
binding than IFN-8 (Fig. 4). Second, the recent
description(26, 27) and our finding (28) of a
IFN--specific IFNAR-associated surface protein. It appears likely
that although IFNAR does not bind ligand with high affinity, it is
capable of interacting with other receptor components. Such an
interaction between IFNAR and ligand is further suggested by the
observation that IFNAR can become phosphorylated in a ligand-dependent
manner by both IFN- and IFN-. cells. To address this, we are currently investigating the
functional response of L929R
cells to various human type I
IFNs in order to correlate ligand binding with biological activity.
cells. Such
studies can serve as a starting point for identifying the protein
components of the human type I IFN receptor. Studying the mechanism in
which receptor proteins assemble to form a multicomponent type I IFN
receptor complex in different cells will yield valuable insights into
early events of type I IFN signaling in addition to helping define
tissue-specific IFN responses.
)1b, human interferon in which cysteine 17
has been replaced with a serine; IFNAR, human interferon
receptor; FLP40, full-length P40; FACS, fluorescence activated cell
sorter; PCR, polymerase chain reaction; kb, kilobase(s).
We thank Dr. Trey White for performing polymerase
chain reaction (PCR) and Joanne Cordova for help in preparing the
manuscript.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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