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Secretion: Adhesion Is Mediated by Ig-Like Domain 11
*
Immunology Unit, Department of Cellular Biology and Pathology, Medical School, and Department of
Physiology, Faculty of Biology, University of Barcelona, and
Liver Unit, Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi ySunyer, Barcelona, Spain
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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secretion in human lymphocytes. Thus, CD84 is its own ligand
and acts as a costimulatory molecule. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several receptor-ligand interactions between members of this subfamily
have been described. The first interaction reported was between human
CD2 and CD58 (8). However, the ligand for rodent CD2 was
identified as CD48 (9). Although human CD48 is also a
ligand for human CD2, its affinity for CD2 is 
100-fold lower
(10). Later, CD48 was shown to be a high affinity ligand
for CD244 (11, 12). Recently, homophilic binding for CD150
has been reported (13, 14). The extracellular region of
CD150 has been identified as a receptor for measles virus
(15).
Another common feature of these receptors is that they induce cellular
activation. Although the function of CD84 is unknown, other members of
the subfamily such as CD2, CD244, and CD150 are known to activate
lymphocytes, suggesting that the CD84 molecule is also involved in
leukocyte activation. CD2 promotes cell adhesion, calcium flux,
tyrosine phosphorylation of intracellular substrates, proliferation,
cytokine production, and cytotoxicity (16). CD244 ligation
on human NK results in cell adhesion, increased cytotoxicity, and
cytokine secretion (17, 18). Anti-CD150 mAbs promote the
proliferation of activated human T cells (13) and induce
IFN- secretion (19, 20, 21). The cytoplasmic domains of
CD150 and CD244 are quite distinct from that of CD2. Whereas the CD2
cytoplasmic domain contains proline-rich sequences that may mediate
signal transduction, CD150 and CD244 contain unique tyrosine-based
motifs. The TxYxxV/I present in both receptors interacts with Src
homology 2 domain containing tyrosine phosphatase
(SHP)-23 and a novel
Src homology 2-domain-containing protein 1A (SH2D1A), also referred to
as signaling lymphocytic activation molecule-associated protein
(SAP). Mutations of the SH2D1A gene cause a primary
immunodeficiency called X-linked lymphoproliferative syndrome (XLP),
which is characterized by increased susceptibility to EBV infection
(22, 23, 24). The CD84 cytoplasmic region contains two
tyrosine motifs identical with those found in CD150 and CD244.
Recently, it has been shown that SHP-2 and SH2D1A (SAP) bind to the
phosphorylated CD84 cytoplasmic tail (25).
Here we show that CD84 is expressed on thymocytes and T cells, mainly CD45RO+, and we provide the first evidence that CD84 binds to itself and its ligation leads to T cell activation and cytokine secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell lines COS and NS1 (murine myeloma
cell line) were obtained from the American Type Culture Collection
(Manassas, VA). PBMCs were isolated by Ficoll density gradient
centrifugation from buffy coats of cells obtained from healthy donors.
Thymocytes and platelets were isolated as described previously
(26, 27). Thymi were obtained from three children (aged
3–7 yr) who underwent cardiac surgery. None of them presented a
history of immunological diseases. The protocol was approved by the
ethics committee of our institution. The following mAbs and reagents
were obtained from BD PharMingen (San Diego, CA): anti-human
IFN- (clone NIB42), anti-human biotinylated IFN- (clone
4SB3), anti-human CD3-allophycocyanin, CD19-FITC, CD2-PE,
CD58-PE, CD4-FITC, CD8-PerCP, biotin anti-mouse 
L chain,
IFN- standard, and murine CD62-P-Ig. Anti-human CD45RO- FITC was
obtained from Sigma (St. Louis, MO). The mAbs anti-human CD3 (clone
332A3) and CD48 (clone 156.4H9) were gifts from R. Vilella (Hospital
Clinic, Barcelona, Spain). Anti-human CD150 (clone IPO-3) was obtained
from Kamiya Biomedical (Seattle, WA), and anti-human 2B4-PE (clone
C1.7) was purchased from Immunotech (Marseilles, France). Human Ly-9
mAb (clone HLy-9.1.84) was produced in our laboratory, as was control
Ab, anti-CD62P (clone 2.3) IgG1 isotype. Streptavidin-PE was
obtained from Southern Biotechnology Associates (Birmingham, AL), and
biotinylated anti-human and goat F(ab')2
anti-mouse FITC were purchased from Caltag Laboratories
(Burlingame, CA). Human cells and tissues were obtained in accordance
with protocols approved by the ethics committee of the Hospital Clinic
of Barcelona (Barcelona, Spain).
CD84 Ab production
A panel of new anti-CD84 mAbs was generated by fusing
NS1 with spleen cells from BALB/c mice that had
been immunized twice with 300.19 cells stably transfected with the CD84
full-length DNA. Twelve mAbs reactive with CD84-transfected cells, but
not with untransfected cells, were produced. The mAbs were purified
with a protein A column (Bio-Rad, Hercules, CA), and we selected the
clones CD84.1.1 (IgG1-), CD84.1.21 (IgG2a-), CD84.1.7 (IgG1-),
and CD84.2.151 (IgG1-). Fab were obtained using the Immunopure Fab
and F(ab')2 kit (Pierce, Rockford, IL) following
the instructions of the manufacturer. Briefly, purified Abs (1 mg) were
diluted in digestion buffer containing 40 mg cysteine-HCl in 2 ml
ImmunoPure IG1 digestion buffer (10 times) and applied to an
immobilized ficin column. Fab were generated after 3–5 h of digestion
at 37°C. They were eluted and separated from undigested IgG and Fc
fragments using a protein A column. Their purity was assessed by
SDS-PAGE, and the absence of reactivity with the anti-human IgG was
shown by flow cytometry. Fab were used immediately after purification
or frozen at -80°C.
Construction of the CD84-Ig fusion protein
The CD84-Ig fusion protein containing the CD33 leader peptide and the Fc region of human IgG1 was obtained by inserting the human CD84 sequence corresponding to the two extracellular domains into the mammalian expression vector signal pIg-Tail (R&D Systems, Minneapolis, MN). The CD84 oligonucleotides used were: as a forward oligonucleotide, 5'-GAG CGG ATC CAA AAG ACT CAG AAA TCT TCA C-3'; and as a reverse oligonucleotide, 5'-CAC AGG ATC CAC TTA CCT GTA CGG AAG CCC ATT GCG ATG T-3'. Ly9-Ig was used as a control with the following oligonucleotides: 5'-AGG AAG ATC TAA AGG ACT CAG CCC CAA CAG TGG T-3' as a forward primer and 5'-AGG AAG ATC TAC TTA CCT GTT CTG GAG GCT CCT GGA TCT GTA C-3' as a reverse primer. The constructs were stably transfected in NS-1 cells by electroporation. Cells were cultured in INTEGRA CL 350 flasks (Integra Biosciences, Wallisellen, Switzerland), and the supernatants containing the fusion proteins were purified as described above for the anti-CD84 Abs.
Flow cytometry
Cells were stained with anti-human CD4-FITC, CD8-PerCP, and biotinylated anti-CD84 (clone CD84.1.1) for 30 min at 4°C. They were then washed with cold PBS and incubated with streptavidin-PE (1/400 final dilution) for 30 min at 4°C. Samples were washed and measured by FACS (FACSCalibur cytometer, BD Biosciences, San Jose, CA). Similarly, a triple staining was conducted with lymphocytes from peripheral blood using anti-human CD3-allophycocyanin, CD19-FITC, and biotinylated anti-CD84. To test CD84 expression on memory cells, lymphocytes were stained with CD3-allophycocyanin, CD45RO-FITC, and biotinylated anti-CD84. A parallel isotype control experiment was performed. When CD84-Ig fusion protein staining was assayed, cells were incubated with a biotinylated goat anti-human IgG as a second step at 4°C for 30 min. They were then washed, streptavidin-PE was added at a 1/400 final dilution, and incubation proceeded at 4°C for 30 min. Thereafter, they were washed and immediately analyzed by FACS. Ten thousand cells were counted for each sample.
COS transfection
COS-7 cells were transfected with human CD84, CD229 (Ly9), CD150 (signaling lymphocytic activation molecule), CD48, CD2, CD58, and CD244 (2B4) cDNAs using the LipofectAMINE Plus reagent (Life Technologies, Rockville, MD). After 48 h of incubation, cells were labeled with biotinylated mAbs against CD84 (CD84 1.1) or Ly-9 (HL9.1.84) or with PE-directed labeled Abs against CD150, CD48, CD2, CD58, or CD244 to detect the expression of the transfected molecules. CD84-Ig fusion protein binding assay was conducted as described above.
Cross-blocking experiments
The mAb cross-blocking was performed as described previously (28). Briefly, stably transfected CD84–300.19 cells were first incubated with 10-fold saturating concentrations (determined after Ab titration and between 5 and 10 µg) of Fab of CD84 mAbs; then they were washed and stained with the CD84-Ig fusion protein at an optimal staining concentration. Thereafter, cells were incubated with a biotinylated anti-human Ab at 4°C for 30 min and then with streptavidin-PE (1/400 dilution). Samples were washed and measured by FACS. No cross-reactivity was detected between the Fab and the biotinylated secondary anti-human Ab. Fab irrelevant Ab and human Ly-9 Ig-fusion protein were used as controls.
Domain mapping of the ligand-binding region
The 300.19 cells were stably transfected with human CD84 cDNA human/mouse chimeras. Mouse CD84 extracellular domain had replaced the first or second Ig-like domains of human CD84. The plasmid H1-M2 (human CD84 first domain and murine CD84 second domain) was constructed by substitution of the murine CD84 leader peptide and first domain with a fragment encoding the human CD84 leader peptide and domain 1 flanked by SalI sites on the murine CD84 cDNA cloned in pCI Neo vector. The plasmid M1-H2 (murine CD84 first domain and human CD84 second domain) was generated by ligation on SalI sites of the fragment encoding the leader peptide and domain 1 of the murine CD84 with the human CD84 cDNA, lacking the leader peptide and domain 1, cloned in pCI Neo.
The CD84 mutant lacking the cytoplasmic tail was generated by PCR using CD84 cloned in PCI Neo as a template and the following oligonucleotides: 5'-CCC AAG CTT TTC CAC AGA AGG TTA GAC-3' as forward and 5'-TGA GGC AGC TCA TTG TCT TCT CTT-3' as reverse. It was cloned in pCI Neo vector. These transfectants were stained with CD84 mAbs and the CD84-Ig fusion protein as described above.
Cytokine assay
To analyze IFN- secretion, cells were activated as reported
previously (19). PBMCs were activated with a suboptimal
concentration of previously titrated soluble anti-CD3 (data not
shown) plus purified soluble CD84 mAb CD84.1.1, CD84.1.21,
anti-CD150 (IPO-3), or control IgG at various concentrations. For
CD84-Ig cytokine assays, an anti-human Fc Ig at 5 or 20 µg/ml was
bound to 96-well plates. After incubation overnight at 4°C, the
excess Ab was washed with sterile PBS, and the CD84-Ig or control-Ig
(20–50 µg/ml) was added. Fusion proteins were incubated for 4 h
at room temperature, and the plate was then washed to remove the
unbound material before adding the cells and anti-CD3 to various
concentrations. Supernatants were collected after 48 h of culture,
and IFN- levels were measured by sandwich ELISA. Primary and
biotinylated secondary anti-human IFN- Abs were used at the
concentrations recommended by the manufacturer. The values reported are
the mean of triplicate wells, and the SEM was <15%.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A new panel of anti-CD84 mAbs was generated by immunizing the
300.19 murine pre-B cell line transfected with human CD84 cDNA. In this
study we analyzed four CD84 mAbs reactive with CD84-transfected cells,
but not untransfected 300.19 cells. CD84 mAbs (clones CD84.1.1,
CD84.1.21, CD84.1.7, and CD84.2.151) similarly stained human cells and
transfectants (Table I
). All these Abs
had the same pattern of staining, although the intensity of
fluorescence was higher in the case of CD84.1.21. Cross-blocking
experiments showed that these mAbs recognized four epitopes; three of
them (CD84.1.1, CD84.1.7, and CD84.1.21) were overlapping (Table II).
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CD84 was expressed on almost all thymocytes (Fig. 1A). It appears early during T
cell differentiation, because
CD4-CD8- immature
thymocytes express this molecule. CD84 expression was higher on
CD4-CD8- immature
thymocytes than on double- or single-positive
CD4+ or CD8+ thymocytes, as
indicated by means of fluorescence. T lymphocytes were also positive
for CD84, but the expression was lower than on B cells (Fig. 1B and Table I
). On T cells, CD84 expression was higher on
the CD45ROhigh memory cells subset (Fig. 1C and Table I). Our results show that CD84 is expressed not
only on B cells, monocytes, and platelets, but also on thymocytes and T
cells, indicating a broader role for CD84 in leukocyte function.
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We studied the binding of CD84 to the described members of the CD2
subfamily. CD84-Ig binds to CD84-transfected cells, but no binding was
detected on COS cells transfected with CD229, CD150, CD48, CD244, CD58,
and CD2, showing that CD84 specifically binds to itself (Fig. 2). Our data indicate that CD84 is a self
ligand, which is consistent with a previous report on homophilic
binding for CD150 (14).
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The anti-CD84 mAbs generated were used to perform competition
assays with CD84-Ig. CD84 Fab were obtained to avoid the bridge
formation due to the simultaneous interaction of CD84 mAb between the
fusion protein and the CD84 from the cell surface. The CD84.1.1 mAb
completely blocked binding of the fusion protein, whereas CD84.1.7 and
CD84.1.21 hindered it only partially, and CD84.2.151 did not affect it
(Fig. 3). The CD84-Ig fusion protein
binding is blocked by anti-CD84 mAbs, further demonstrating the
homophilic interaction of this molecule.
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To elucidate the ligand binding region, we mapped the domain
involved in CD84-CD84 binding using human/mouse chimeras containing the
first or second domain of the mouse CD84. CD84-Ig bound to the first
human CD84 extracellular domain, but failed to bind to the second
extracellular domain. The expressions of both chimeric receptors were
comparable, as revealed by fluorescence (Fig. 4). Moreover, the Abs that blocked
CD84-Ig binding recognized epitopes located in the first Ig-like
domain, whereas CD84.2.151, which did not compete for CD84-Ig binding,
recognized the second extracellular domain (Fig. 4).
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, CD84 mutant was expressed on the cell surface (A), and it
was able to bind to CD84-Ig similarly to wild-type CD84
(B).
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As shown in Fig. 6A,
CD84-Ig bound to platelets, whereas no binding was detected with the
control-Ig protein. This binding was completely blocked by mAb
CD84.1.1, but not by mAb CD84.2.151. No binding of CD84-Ig to
lymphocytes could be observed (data not shown). Note that platelets
expressed higher CD84 levels (mean log fluorescence, 415) than T and B
lymphocytes (mean log fluorescence intensities of 138 and 179; Figs. 1 and 6B and Table I). These data show that CD84-Ig binds to
normal cells with high levels of CD84 surface expression.
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production
The ligation of CD84 with anti-CD84 mAbs enhanced IFN-
secretion induced by suboptimal concentrations of anti-CD3 after
48 h of culture (Fig. 7A). IFN- secretion levels
were dose-dependent and equivalent to the levels induced by an
anti-CD150 mAb, which was used as a positive control. CD84 mAb by
itself did not enhance cytokine secretion, indicating that CD84 acts as
a costimulatory molecule. Ligation of CD84 with Abs that recognized
first (clone CD84.1.1) and second (clone CD84.2.151) extracellular
domains induced similar effects on IFN- induction after TCR
triggering. The CD84 Abs generated (clones CD84. 1.1, CD84.1.21,
CD84.1.7, and CD84.2.151) are able to induce IFN- secretion.
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secretion induced by soluble CD84-Ig were
difficult to evaluate due to the Fc fragment of the fusion protein as
well as the ability of these molecules to interact with themselves, we
cross-linked CD84-Ig to an anti-human Fc Ab previously bound to the
plate. In this fashion, CD84-Ig, bound to the anti-human Fc Ab by
its Fc fragment exposed the CD84 domains to the cell more efficiently.
As shown in Fig. 7B, CD84-Ig consistently induces (2- to
3-fold) IFN- secretion at several anti-CD3 suboptimal
concentrations. IL-4 secretion was not detected under the same
conditions (data not shown). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD84-Ig binding to CD84-transfected cells was inhibited in the presence of specific mAbs against CD84. Epitope-mapping studies performed with these CD84 mAbs demonstrated that mAbs with epitopes wholly within domain 1 blocked CD84-mediated binding. This result is consistent with our data obtained using CD84 human/mouse chimeras, which showed that CD84-Ig binds to domain 1. The CD84-CD84 homophilic interaction is species-restricted, because human CD84 does not bind to murine CD84, although murine CD84 can bind to itself (data not shown), indicating that the homophilic interaction of this molecule occurs in different species. It has been determined that the domains involved in adhesion between CD2 and human CD58 and mouse CD48, and between 2B4 and CD48 are the N-terminal Ig V domains (1). These observations suggest that CD84 expressed on the surface of adjacent cells establishes head-to-head contacts. These data also agree with the finding that soluble CD2 crystals are dominated by homophilic head-to-head dimers and that these crystal contacts mimic the topology of the natural ligand interaction CD2-CD58 (30).
Because the cytoplasmic region of platelet endothelial cell adhesion molecule-1 (CD31), another homophilic binding receptor of the Ig superfamily, has been shown to be critical for its binding (31), we tested the interaction of CD84-Ig with cells transfected with a CD84 mutant that lacks the cytoplasmic domain. Our results show that the cytoplasmic domain does not control its homophilic ligand-binding property, because CD84-Ig binding is not affected in the CD84 mutant.
Recently, it was reported that one of the members of the CD2 subset, CD150, binds to itself (14). Although CD150 self-associates with very low affinity, its functional significance has not been ruled out. Moreover, it has been reported that soluble and membrane-bound CD150 enhance B cell proliferation and Ig synthesis (32). We cannot rule out additional counter-receptors for CD84 and CD150 among emerging members of the CD2 subfamily.
CD84-CD84 interaction takes place in normal cells. Because platelets are known to express higher levels of CD84 than lymphocytes, we tested the interaction of the fusion protein with these cells. CD84-Ig bound to platelets, and this binding was specifically blocked by CD84 mAb recognizing domain 1, but not domain 2. This demonstrates that the binding was specific and involved the first extracellular domain of the molecule, as we previously showed with CD84 chimeras. The fact that we did not observe CD84-CD84 binding on lymphocytes may have various explanations. One is that the concentration of monomeric CD84-Ig available for binding to CD84 is far lower than the total concentration of fusion protein that minimizes binding to the cell receptor on the cell surface. A high density on the cell surface may be needed to detect binding. Another explanation is that most homophilic adhesion receptors interact with low affinities (14).
Ligation of CD84 with specific mAbs, such as CD2, CD150, and CD244
mAbs, modulates T cell activation (19, 20, 21, 33). The mAbs
against CD84 increased IFN- secretion through the TCR, similarly to
CD150. All Abs against CD84 used had a functional effect. Thus, the
induction of IFN- was epitope independent. Moreover, CD84-CD84Ig
interaction enhances IFN- levels, showing that this homophilic
interaction has functional significance. CD150 engagement enhances the
Th1 cytokine production profile, and it can reverse the Th2 phenotype
to Th1 (19). This suggests that during immune reactions
CD150 triggering may also participate in directing expanding T cells
toward a Th0/Th1 pathway. Interestingly, IL-4 secretion was not
enhanced after CD84 triggering with either mAb or fusion protein. On
this basis, we speculate that CD84 behaves similarly to CD150. In
addition, altered CD150 expression has been described in autoimmune
diseases such as rheumatoid arthritis (34) and multiple
sclerosis (35), in which dysregulation of IFN- occurs.
Similarly, CD84 expression may be affected. To date, the importance of
CD84 signaling in T lymphocytes is derived from the observation that
SH2D1A, a protein responsible for the XLP, binds to the cytoplasmic
region of CD84 (25). XLP disease is characterized by three
major phenotypes: fatal mononucleosis, B cell lymphomas, and
dysgammaglobulinemia (36, 37, 38). SH2D1A protein binds to at
least three other leukocyte cell surface receptors of the CD2 subset
(CD150, CD244, and CD229), and its association prevents recruitment of
the tyrosine phosphatase SHP-2 to their cytoplasmic tails, although the
functional consequences of this event are still unclear (22, 24, 25). Comparative studies with normal lymphocytes and lymphocytes
from XLP patients have revealed the functional requirements for
SH2D1A-CD244-mediated activation of human NK cells function. CD244
fails to induce cytotoxicity in SAP-deficient cells from XLP patients,
which may contribute to the pathogenesis and progression of the disease
(39). In contrast, an inhibitory function of CD244 has
been implicated in the inability of NK to kill EBV-infected cells in
XLP patients (40). It appears, therefore, that CD84
signaling may also be involved in the molecular pathogenesis of XLP.
Defects in IFN- production after CD84 triggering in SH2D1A-deficient
cells may impair viral clearance, as occurs with EBV infection in XLP
patients; this has also been proposed for CD150 (41). This
suggests that the complex phenotype of XLP could be due to a
combination of altered signaling pathways initiated by these four cell
surface receptors (42). Further biochemical and functional
characterization of these receptors is essential to our understanding
of the molecular basis of the disease.
Because CD84 is expressed on thymocytes, various subsets of T and B lymphocytes, monocytes, and platelets, the CD84-CD84 interaction extends the range of possible cellular interactions regulated by the homophilic binding of CD84.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Pablo Engel, Unidad de Inmunología, Departamento Biología Celular, Facultad de Medicina, C/Casanova 143, Barcelona E-08036, Spain. E-mail address: engel{at}medicina.ub.es
3 Abbreviations used in this paper: SHP, Src homology 2 domain-containing protein tyrosine phosphatase; SH2D1A, Src homology 2 domain-containing protein 1A; SAP, signaling lymphocytic activation molecule-associated protein; XLP, X-linked lymphoproliferative disease.
Received for publication April 2, 2001. Accepted for publication July 19, 2001.
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