Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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(Journal of Leukocyte Biology. 2001;70:335-340.)
© 2001 by Society for Leukocyte Biology

Biliary glycoprotein (BGPa, CD66a, CEACAM1) mediates inhibitory signals

Tie Chen*, Wolfgang Zimmermann{dagger}, James Parker{ddagger}, Ines Chen{ddagger}, Akito Maeda§ and Silvia Bolland||

* Department of Microbiology and Immunology, Department of Medicine, and Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana;
{ddagger} Laboratory of Bacterial Pathogenesis and Immunology, and
|| Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York;
§ Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Japan; and
{dagger} Institute of Immunobiology, University of Freiburg, Freiburg, Germany

Correspondence: Tie Chen, Department of Microbiology, Immunology and Medicine, Walther Oncology Center, Indiana University School of Medicine, MS 252, 635 Barnhill Dr., Indianapolis, IN 46202-5120. E-mail: tiechen{at}iupui.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Biliary glycoprotein (BGP, CD66a, CEACAM1) is a member of the carcinoembryonic antigen family (CEA, CD66), a group of transmembrane proteins belonging to the immunoglobulin superfamily. The structural features surrounding the tyrosine residues in the cytoplasmic domain of BGP share similarity with the consensus sequence of the immunoreceptor tyrosine-based inhibition motif (ITIM), the docking site for SHIP, SHP-1, and SHP-2 molecules. Using the well-characterized inhibitory receptor, Fc{gamma}RIIB, we constructed a Fc{gamma}RIIB-BGPa chimeric molecule that contained the extracellular and transmembrane domain of Fc{gamma}RIIB and the cytoplasmic tail of BGPa and expressed it in DT40 B cells. Our results showed that Fc{gamma}RIIB-BGPa, just like the unmodified Fc{gamma}RIIB molecule, inhibited calcium influx in activated DT40 B cells. Substitution of tyrosine with phenylalanine (Y459F) in Fc{gamma}RIIB-BGPa completely abrogated its ability to inhibit calcium influx, indicating that the motif surrounding Y459 is ITIM. The presence of ITIM was also supported by showing that the Fc{gamma}RIIB-BGPa-mediated inhibitory effect was reduced in SHP-1and SHP-2 mutant DT40 B cells and further diminished in a SHP-1/-2 double-deficient mutant line. The results suggest that SHP-1 and SHP-2 are required for the Fc{gamma}RIIB-BGPa-mediated inhibitory signals.

Key Words: B-cell antigen receptor • FcRs • ITIM • SHIP


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Biliary glycoprotein (BGP, CD66a) is a cell-surface immunoglobulin-like protein and a member of the carcinoembryonic antigen (CEA) or (CD66) family. It was initially demonstrated by in vitro aggregation assays [1 ] that BGP is an intercellular adhesion molecule, which can function as a Ca++-independent [2 ] and -dependent [3 ] adhesin. BGP is expressed on epithelium, endothelium, and human neutrophils [4 , 5 ]. The presentation of Lex and sialyl Lex carbohydrate moieties by BGP on mature neutrophils may provide ligands for E-selectins on activated endothelium [6 ]. Recently, BGP was also implicated as the receptor for the opacity (Opa) proteins of Neisseria gonorroheae (GC) and Neisseria meningitides (MC) [7 8 9 ], the bacterial pathogens responsible for gonorrhea and meningococcal meningitis.

The sequence surrounding the two tyrosine residues in the cytoplasmic domain of BGP [10 ] has similarities to immunoreceptor tyrosine-based activation motif (ITAM) [11 ] or immunoreceptor tyrosine-based inhibition motif (ITIM) [12 ] (Fig. 1 ). Previous studies suggested that phosphorylation of one of the tyrosine residues in the cytoplasmic domain of BGP caused its association with protein tyrosine phosphatase SH2-domain-containing phosphotyrosine phosphatase (SHP)-1 and SHP-2 [12 , 13 ], which usually interact with ITIM [14 15 16 17 18 ] to promote inhibitory action.



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  		Figure 1. The possible ITAM or ITIM in the cytoplasmic domain of BGP. Similarity between the cytoplasmic sequence of BGPa and the consensus sequences for the immunoreceptor tyrosine-based inhibition motif (ITIM, V/IXXYXXL/V, where X represents any amino acid).

 
A class of molecules, which contain ITAM in their cytoplasmic domain, are responsible for cell activation [19 20 21 22 23 ]. These include B-cell antigen receptors (BCR), T-cell antigen receptors (TCR), and receptors for the Fc portion of immunoglobulin (Ig)G and IgE (FcRs). Inhibitory receptors, like the natural killer inhibitory receptor (KIR) [24 , 25 ], CD22 antigens [16 , 26 ], and the Fc{gamma}RIIB molecules [17 , 27 ] (Fig. 1) , are involved in the termination of the stimulatory signals by controlling the levels of activation responses. Inhibitory receptors that contain ITIMs (Fig. 1) have several common features. They are inactive until co-ligated to a stimulatory receptor, at which time they undergo tyrosine phosphorylation of the conserved, inhibitory motif in their cytoplasmic domains. This phosphorylation leads to the recruitment of signaling molecules such as the SH2-domain-containing inositol polyphosphate 5'-phosphatase (SHIP) and SHP-1 to inhibit calcium fluxes in the activated cells [17 , 27 , 28 ]. Inhibitory activity is seen only upon coligation to an ITAM-containing receptor [29 ].

A well-defined, inhibitory receptor is Fc{gamma}RIIB, which promotes negative signal transduction events that counteract the activation signals generated by BCR cross-linking. It is clear that the critical step to this inhibitory mechanism is phosphorylation of the tyrosine residues in its ITIM [17 ], which creates a docking site for the SH2 domains of SHP-1 and SHIP to terminate calcium influx [17 , 27 , 28 ] and cell proliferation [30 31 32 ].

The BGPa antigen has gained attention recently because it is a down-regulatory molecule that inhibits the growth of various tumors [33 34 35 36 37 ]. It is speculated that tumor-growth inhibition might be caused by inhibiting cell-activation processes such as cell proliferation through its potential ITIM. In the present study, a well-characterized system, namely the inhibition of activation signals by Fc{gamma}RIIB, was used to determine whether the cytoplasmic domain of BGPa contains ITIM to inhibit cell-activation effects.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Cell culture
The wild-type chicken B-cell line DT40, derived mutants (SHIP-/-, SHP-1-/-, SHP-2-/- and SHP-1-/-/SHP-2-/-) (8 30 37 38) and transfectants were maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum, 1% chicken serum, 50 µM 2-mercaptoethanol and 2 mM L-glutamine.

Generation of Fc{gamma}RIIB-BGPa chimera and mutants of tyrosine residues
Fc{gamma}RIIB constructs and BGPa cDNA have been described previously [17 , 39 , 40 ]. The two tyrosine residues, Y459 and Y486 (position 1 corresponds to the first amino acid of the mature protein after removal of the 34 amino acid leader peptide), in the wild-type (WT) cytoplasmic domain of BGPa were changed to phenylalanine residues by site-directed mutagenesis, giving rise to three different mutants: Y459F, Y486F, and Y459F/Y486F (Fig. 2 ). The sequence coding for the cytoplasmic domain of the Fc{gamma}RIIB construct was first removed by digestion with BstEII and EcoRI. Then, two primers (5'-CAT GGG TCA CCxC GGG CAA GCG ACC AGC GTG AT and 5'-CAT GGA ATT CxAT TAC TGC TTT TTT ACT TCT G; the underlined sequences are the restriction sites for BstEII and EcoRI) were used to amplify by polymerase chain reaction (PCR) the sequences of the entire cytoplasmic domain of BGPa and its tyrosine mutants using full-length BGP cDNA and the pGEX-3X plasmids (see above) as templates. The PCR products were cut with BstEII and EcoRI and subsequently ligated to the DNA sequence of the Fc{gamma}RIIB cDNA from which the cytoplasmic domain had been removed. The chimeric molecule was named Fc{gamma}RIIB-BGPa. The sequences and reading frames of Fc{gamma}RIIB-BGPa were confirmed by DNA sequencing using the following primer: 5'-CCA GAG GAA GTA GGT GAG TAC.



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  		Figure 2. Schematic representation of Fc{gamma}RIIB-BGPa chimeric molecules. Fc{gamma}RIIB-BGPa constructs (WT, Y459F, Y486F, and Y459-486F) contain the extracellular domain of Fc{gamma}RIIB and the cytoplasmic tail of BGPa. The Y459F and Y486F represent tyrosines (Y) at positions 459 and 486 of BGPa that have been altered to phenylalanines (F). The expression levels of different chimeric molecules in stable DT40 B-cell transfectants were determined by flow cytometry (right panel) with anti-Fc antibody 2.4G2. Untransfected DT40 B cells were used as negative control (filled-in curve).

 
Transfections
DNA (10 µg) of Fc{gamma}RIIB-BGPa construct and its mutants were co-transfected with 1 µg pBabe-puror vector [41 ] into DT40 cells by electroporation at 250 V and 960 µF in phosphate-buffered saline (PBS; 107 cells in 0.5 ml). Stable transfectants were selected in 0.5 µg/ml puromycin 24 h after electroporation. The presence of Fc{gamma}RIIB-BGPa was determined by flow cytometry analysis using FACScan (Becton Dickinson, Mountain View, CA) with fluorescein isothiocyanate (FITC)-conjugated 2.4G2 antibody (Pharmingen, San Diego, CA).

Calcium-ion measurements
DT40 cells (6x106) were suspended in 3 ml RPMI medium. Fura-2AM [6 µl of 1 µM; Molecular Probes, Eugene, OR; dissolved in dimethyl sulfoxide (DMSO)] was added to the suspension, which was then incubated in the dark at 37°C for 30 min with intermittent shaking. Cells were washed twice with Hank’s balanced salt solution (HBSS; Cellgro, Herndon, VA) and resuspended in 3 ml HBSS. Cell suspension (0.5 ml) was mixed with 1 ml PBS containing 1 mM CaCl2 and 1 mM MgCl2. For activation assays, the cell mixtures were incubated with anti-chicken BCR monoclonal antibody (M4 mAb, IgM) as described previously [28 , 38 ]. For the inhibition assay, Fc{gamma}RIIB-BGP was co-ligated to the endogenous chicken BCR by addition of rabbit anti-mouse IgM as secondary antibody at 10 µg/ml (Pierce, Rockford, IL). This secondary antibody specifically recognizes the Fc portion of M4 mAb, and its own Fc portion is bound by Fc{gamma}RIIB [31 ]. The secondary antibody was added 1 min prior to the addition of the anti-chicken BCR antibody, which was used to activate the cells. The cytosolic calcium concentration was determined with a fluorescence spectrophotometer (LB50B, Perkin Elmer, Foster City, CA) at an excitation wavelength of 340 and 360 nm and an emission wavelength of 510 nm. Calculation of the calcium concentration was performed using the FL WinLab software (Perkin Elmer). We usually test three (at least two) different transfectants of each mutant to ensure they behave equally.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fc{gamma}RIIB-BGPa chimera inhibits the calcium-ion influx
Our recent data have shown that BGPa does not contain a functional ITAM, in contrast with CGM1a [42 ]. Thus, the question arises as to whether the cytoplasmic domain of BGPa contains an ITIM. To examine this hypothesis, we constructed and expressed Fc{gamma}RIIB-BGPa chimeric molecules in DT40 B cells, because inhibition of activation signals by Fc{gamma}RIIB is a well- characterized system to examine or define ITIM-containing receptors [17 , 27 ]. A schematic representation of the constructs is shown in Figure 2 . Surface expression of Fc{gamma}RIIB-BGPa (WT) was determined by flow cytometry (FACScan) with the nti-Fc{gamma}RIIB antibody 2.4G2 (Fig. 3 , Flow Cytometry panel). The calcium flux assay was adopted to examine the inhibitory ability of the Fc{gamma}RIIB-BGPa chimera (Fig. 3A) . Co-ligation of BCR with Fc{gamma}RIIB-BGPa (WT) resulted in a strong inhibition of the calcium-ion flux, which mimics Fc{gamma}RIIB-mediated inhibition of activation signals [17 ].



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  		Figure 3. BCR-mediated calcium flux is inhibited by Fc{gamma}RIIB-BGPa chimeric molecules in DT40 B cells. Intracellular calcium flux was triggered by BCR cross-linking through addition of anti-BCR antibodies (solid line). Inhibition of this flux was induced by co-ligation of BCR and Fc{gamma}RIIB-BGPa by adding rabbit anti-mouse IgM secondary antibody 1 min prior to the addition of the anti-BCR antibody (dashed line). Arrows indicate the time points where the antibodies were added. A, B, C, and D represent the Fc{gamma}RIIB-BGPa (WT) and its mutants Y459F, Y486F, and Y459-486F, respectively. The expression levels of different chimeric molecules in stable DT40 B-cell transfectants were determined by flow cytometry (right panel) with the anti-Fc antibody 2.4G2. Untransfected DT40 B cells were used as negative control (filled-in curve).

 
Mutation of tyrosine residue Y459 in Fc{gamma}RIIB-BGPa abolishes its inhibitory capability
The cytoplasmic domain of BGPa contains two putative ITIMs (Fig. 1) . To test whether any of the tyrosine residues in these potential ITIMs were required for inhibition of the calcium flux, three different tyrosine mutants, Fc{gamma}RIIB-BGPa (Y459F), Fc{gamma}RIIB-BGPa (Y486F), and Fc{gamma}RIIB-BGPa (Y459F/Y486F; Fig. 2 ), were constructed and transfected into DT40 B cells. Stable transfectants that expressed similar levels of chimeric molecules were selected to perform calcium flux experiments (Fig. 3 , Flow Cytometry panel). Single mutation Y459F (Fig. 3B) and double mutation Y459/486F (Fig. 3D) completely abolished the ability of Fc{gamma}RIIB-BGPa to inhibit the calcium flux. Conversely, mutant Y486F was still able to inhibit the calcium flux (Fig. 3C) . This mutation analysis of the cytoplasmic tyrosines indicates that the motif surrounding tyrosine Y459 is a functional ITIM.

SHP-1 and SHP-2 but not SHIP are involved in the inhibitory effects of Fc{gamma}RIIB-BGPa
After co-ligation of BCR and Fc{gamma}RIIB, phosphorylated tyrosine residues within the ITIM most likely bind SHIP, SHP-1, or SHP-2 to deliver inhibitory signals [14 15 16 17 18 ]. If the cytoplasmic domain of BGPa indeed contains an ITIM, its ability to inhibit calcium flux should be impaired in mutant cells deficient in SHIP, SHP-1, or SHP-2. To determine this, SHIP-, SHP-1-, SHP-2-, and SHP-1/SHP-2-mutated DT40 B cells [16 ] were transfected with Fc{gamma}RIIB-BGPa (WT). Compared with WT DT40 cells, inhibition of calcium flux by Fc{gamma}RIIB-BGPa (WT) was reduced in SHP-1 and SHP-2 mutants (Fig. 4C and D ). Furthermore, the Fc{gamma}RIIB-BGPa-mediated inhibition was perturbed severely in SHP-1/SHP-2 double-deficient cells (Fig. 4E) , suggesting that SHP-1 and SHP-2 are needed for the Fc{gamma}RIIB-BGPa-mediated inhibitory signal. Because Fc{gamma}RIIB-BGPa is able to inhibit BCR signaling in SHIP-deficient cells (Fig. 4B) , SHIP probably does not participate in the inhibitory response. These data further demonstrate that BGPa contains an ITIM.



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  		Figure 4. Fc{gamma}RIIB-BGPa-mediated inhibitory response in SHIP, SHP-1, SHP-2 and SHP-1/SHP-2 mutated DT40 B cells. The inhibitory response was measured as described in Fig. 3 . A, B, C, D and E represented Fc{gamma}RIIB-BGPa (WT) expressed in wild-type DT40 and, SHIP-/-, SHP-1-/-, SHP-2-/- and SHP-1-/-/SHP-2-/- DT40 B cells, respectively. Shown in the right panel are expression levels of Fc{gamma}RIIB-BGPa of the various transfectants determined by flow cytometry using the anti-Fc antibody 2.4G2.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The stimulation of immune receptors such as the BCR, TCR, and FcR results in the activation by phosphorylation of tyrosine residues in their ITAMs, which become docking sites for high-affinity binding of protein tyrosine kinases (PYK) of the Src and Syk family [43 44 45 ]. Recruitments of the substrates such as phospolipase C-{gamma} (PLC{gamma}) and inositol-1,4,5 trisphosphate (IP3) by these kinases lead to stimulation of calcium mobilization from intracellular stores [46 47 48 49 ]. This calcium-ion flux reflects early activation of PYK, activated by binding the phosphorylated tyrsosine residues. Thus, detection of calcium-ion flux is used widely, because it is a convenient and reliable method to examine ITAM-mediated activation.

Co-ligation of BCR and Fc{gamma}RIIB inhibits B-cell activation, intracellular calcium-ion flux [17 , 27 , 28 ], and cell proliferation [30 31 32 ]. This inhibition is a result of the formation of ternary complexes among BCR, antibodies, and Fc{gamma}RIIB. The site of Fc{gamma}RIIB responsible for the inhibition of proliferation and calcium flux was localized to a 13 amino acid sequence motif (ITIM) in its cytoplasmic domain. The essential role of tyrosine residue Y309 of Fc{gamma}RIIB was demonstrated by the abrogation of the inhibitory effect in the Y309F mutant. It should be noted here that most FcRs promote ITAM-triggered activation of effector cells. In contrast, Fc{gamma}RIIB, which bears an ITIM, triggers inhibitory effects in ITAM-stimulated cells.

In this study, by constructing a Fc{gamma}RIIB-BGPa-chimeric molecule that contains the extracellular domain of Fc{gamma}RIIB and the cytoplasmic domain of BGPa, we showed that Fc{gamma}RIIB-BGPa virtually mimics the intact Fc{gamma}RIIB molecule in calcium-flux experiments [17 , 27 , 28 ]. This demonstrates that the motif surrounding Y459 is an ITIM (Fig. 1) . The existence of ITIM is supported further by the fact that the Fc{gamma}RIIB-BGPa-mediated inhibitory effect is reduced in SHP-1 and SHP-2 mutants and substantially decreased in the mutant cell line deficient in SHP-1 and SHP-2. However, Fc{gamma}RIIB-BGPa reduces calcium flux in the SHIP mutant cell line, suggesting that SHIP does not interact with the BGPa ITIM. These results are consistent with previous studies showing that BGPa is associated with SHP-1 and SHP-2 [12 , 13 ].

SHP-1 functions as a negative regulator in many signaling cascades, with profound effects on cellular proliferation. For example, the SHP-1 mutant, motheaten mice exhibit a range of autoimmune and inflammatory disorders [50 , 51 ]. The concentration of SHP-1 is reduced to 5% of that of normal B and T cells in certain phenotypes of Burkitt lymphomas [52 ], indicating that modulation of expression levels of SHP-1 may be involved in tumor development.

There is increasing evidence that BGPa functions as a tumor suppressor that inhibits the growth of various tumors [33 34 35 36 37 ]. Furthermore, a result from Izzi and colleagues [53 ] shows that a single point mutation Y488F in mouse BGPa (equivalent to Y459 in mature human BGPa) was sufficient to abolish the in vivo inhibition of tumor cell growth. These data suggest that the ITIM in the cytoplasmic domain of BGPa is responsible for the tumor cell-growth inhibition, possibly by controlling cell proliferation.


   ACKNOWLEDGEMENTS
 
This work was supported by PHS grants AI 47736 to T. C. and AI 26558 to Emil C. Gotschlich. We thank Dr. M. Kuroki for generously providing the cDNA of BGPa. We are indebted to Dr. Gotschlich for insightful scientific advice.

Received February 2, 2001; revised April 4, 2001; accepted April 5, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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