By
§
§
From the * Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University,
Moriguchi 570, Japan; the Department of Molecular Embryology, Institute of Development, Aging
and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-77, Japan; and § Core Research for Evolution
Science and Technology, Japan Science and Technology Corporation, Japan
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Abstract |
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Paired immunoglobulin-like receptor B (PIR-B) (p91) molecule has been proposed to function as an inhibitory receptor in B cells and myeloid lineage cells. We demonstrate here that the cytoplasmic region of PIR-B is capable of inhibiting B cell activation. Mutational analysis of five cytoplasmic tyrosines indicate that tyrosine 771 in the motif VxYxxL plays the most crucial role in mediating the inhibitory signal. PIR-B-mediated inhibition was markedly reduced in the SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 double-deficient DT40 B cells, whereas this inhibition was unaffected in the inositol polyphosphate 5'-phosphatase SHIP-deficient cells. These data demonstrate that PIR-B can negatively regulate B cell receptor activation and that this PIR-B-mediated inhibition requires redundant functions of SHP-1 and SHP-2.
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Introduction |
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The ability of B cells to respond to antigen relies on signals transmitted through the B cell antigen receptor (BCR) complex. Activation of cytoplasmic protein tyrosine kinases is the earliest measurable biochemical response to BCR cross-linking. This initial event leads to the generation of secondary signals including Ras activation, phosphatidylinositol 3-kinase activation, turnover of phosphoinositides, and calcium mobilization. Both the strength and duration of the BCR-elicited signal are important in directing biological responses of B cells such as proliferation, differentiation, and apoptosis (for reviews see references 1). Thus, attenuation and termination of these activation signals are also critical components for B cell response.
B cell activation is inhibited by cross-linking FcRIIB
with the BCR (5, 6). The cytoplasmic domain of Fc
RIIB
contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), which is necessary for the inhibitory function of
the receptor (7, 8). Phosphorylation of the tyrosine in the
ITIM by an activated protein tyrosine kinase(s) is critical to
its inhibitory mechanism (7). Although the phosphorylated
Fc
RIIB ITIM associates with the SH2-containing protein
tyrosine phosphatase SHP-1 and the SH2-containing inositol polyphosphate 5'-phosphatase SHIP (9, 10), functional
evidence has shown that inhibition by Fc
RIIB primarily
involves SHIP (11). In B cells, in addition to Fc
RIIB, a recently cloned p91 (PIR-B) is suggested to function as
an inhibitory receptor. PIR-B, a member of the immunoglobulin superfamily, is a 91-kD transmembrane glycoprotein containing four potential ITIMs in its cytoplasmic region (14, 15).
A growing family of inhibitory receptors that can interrupt the activation process have generated interest in the
mechanism of inhibition and raised questions about the
similarity in this mechanism used by the different receptors.
To test whether PIR-B can deliver inhibitory signals in B
cells, and whether both PIR-B- and FcRIIB-mediated
inhibitory responses are dependent on the same signaling
molecule SHIP, we have constructed chimeric Fc
RIIB- PIR-B molecules with the cytoplasmic region of PIR-B
and assessed their ability to inhibit BCR signaling. We report
here that SHP-1 and SHP-2, but not SHIP, are required
for PIR-B-mediated inhibitory signal.
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Materials and Methods |
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Cells, Expression Construct, and Abs.
Various mutant DT40 cells, wild-type A20, and A20 IIA1.6 cells were maintained in RPMI 1640 supplemented with 10% FCS, penicillin, streptomycin, and glutamine. FcGeneration of SHIP-, SHP-1-, SHP-2-, and SHP-1/SHP-2-deficient DT40 Cells.
Chicken spleen cDNA library (Clontech, Palo Alto, CA) was screened by murine SHP-1 cDNA (provided by Dr. J.N. Ihle, St. Jude Children's Research Hospital, Memphis, TN) (19). Using the isolated chicken SHP-1 cDNA, the chicken genomic DNA library (Clontech) was screened to obtain genomic clones. After subcloning, the neo- or his-targeting constructs were made by replacing the genomic fragment containing exons corresponding to SHP-1 amino acid residues 420-520 with neo or his cassette. These constructs were sequentially transfected into wild-type DT40 cells by electroporation to obtain null mutants. Selection for drug-resistant clones was carried out by using G418 (2 mg/ml) and histidinol (1 mg/ml). Based on a previously published sequence of chicken SHP-2 (20), chicken SHP-2 cDNA and genomic clones were obtained by the PCR method. The targeting vectors, pSHP-2-bsr, pSHP-2-hisD, and pSHP-2-hygro were constructed by replacing the genomic fragment-containing exons that correspond to SHP-2 amino acid residues 472-533 with bsr, hisD, or hygro cassette. The targeting vector pSHP-2-bsr was linearized and introduced into wild-type DT40 cells. Selection was done in the presence of 50 µg/ml blasticidin S. Clones were screened by Southern blot analysis. pSHP-2-hisD was transfected into the bsr-targeted clone and selected with both blasticidin S (50 µg/ml) and histidinol (1 mg/ml). For the generation of SHP-1/ SHP-2 double-deficient DT40 cells, the targeting vectors pSHP-2-bsr and pSHP-2-hygro were sequentially transfected into SHP-1-deficient cells (11). Clones were selected in the presence of 50 µg/ml blasticidin S and 1.6 mg/ml hygromycin. The procedures to establish SHIP-deficient DT40 cells were described in reference 11. Evidence for null mutants of these knock-out DT40 cells were demonstrated by Western blotting analysis (see Fig. 5 A) as well as Northern blotting analysis (data not shown).
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Immunoprecipitation and Western Blotting Analysis.
IIA1.6 transformants and wild-type A20 cells (2 × 107) in 1 ml of RPMI 1640 medium were incubated for 3 min at 37°C with intact (50 µg) or F(ab')2 fragment (25 µg) of rabbit anti-mouse IgG. Cells were solubilized in lysis buffer (1% NP-40, 150 mM NaCl, 20 mM Tris, pH 7.5, 1 mM EDTA, 10% glycerol) containing 50 mM NaF, 10 µM molybdate, 2 mM sodium vanadate supplemented with protease inhibitors as previously described (17). Precleared lysates were sequentially incubated with 2.4G2 and anti-rat IgG-agarose. Immunoprecipitates were separated by SDS-PAGE gel, transferred to nitrocellulose membrane, and detected by appropriate Abs and ECL system (Amersham Corp., Arlington Heights, IL).Calcium measurements.
Cells (5 × 106) were suspended in PBS containing 20 mM Hepes (pH 7.2), 5 mM glucose, 0.025% BSA, and 1 mM CaCl2, and loaded with 3 µM Fura-2/AM at 37°C for 45 min. Cells were washed twice, and adjusted to 106 cells/ml. Continuous monitoring of fluorescence from the cell suspension was performed using Hitachi F-2000 fluorescence spectrophotometer (Hitachi Limited, Tokyo, Japan) at an excitation wavelength of 340 nm and an emission wavelength of 510 nm. Calibration and calculation of calcium levels were done as previously described (21). IIA1.6 cells expressing FcNuclear Factor in Activated T Cell Luciferase Assays.
24 h after transfection with 20 µg of nuclear factor in activated T cell (NF-AT) (Renilla luciferase control reporter vector) luciferase reporter gene and 2 µg of pRL-CMV (Promega, Madison, WI), 2 × 105 transfected cells were aliquoted into a 96-well plate and cultured in a final volume of 100 µl of RPMI 1640 medium. Cells were stimulated as previously described (11). After 5 h of stimulation, cells were lysed and luciferase activity was measured with the Dual-luciferase reporter assay system (Promega).Flow Cytometric Analysis for Surface Expression of FcRIIB-PIR-B.
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Results and Discussion |
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To test whether the cytoplasmic domain
of PIR-B may inhibit BCR activation, a chimeric molecule with the cytoplasmic domain of PIR-B and the extracellular domain of FcRIIB was constructed (Fig. 1). This
molecule was transfected into the Fc
RIIB-negative mutant of the mouse A20 B cell lymphoma IIA1.6 (22) to obtain stable transformants. Expression level of this chimeric
receptor was assessed by flow cytometry analysis using anti-
mouse Fc
RIIB mAb, 2.4G2 (Fig. 2 A). IIA1.6 cells expressing the Fc
RIIB-PIR-B receptor was stimulated by
BCR cross-linking alone (Fig. 2 A, solid line) or coligation
of BCR and the Fc
RIIB-PIR-B (Fig. 2 A, dashed line).
Coligation of Fc
RIIB-PIR-B to the BCR resulted in an
inhibition of intracellular free calcium. Incubation with EGTA further decreased Ca2+ mobilization upon co-cross-linking of BCR with Fc
RIIB-PIR-B, indicating that the
Fc
RIIB-PIR-B acts at least on calcium release from intracellular stores. Consistent with these results, transcriptional activation of the NF-AT luciferase reporter was inhibited
by coligation of the BCR to this chimeric molecule (Fig. 2 B).
Thus, the cytoplasmic domain of PIR-B can deliver a signal that inhibits BCR-mediated function in IIA1.6 B cells.
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The presence of ITIM-related sequences in the
PIR-B cytoplasmic domain (Fig. 1) suggests that the PIR-B
may become tyrosine phosphorylated, resulting in its association with SH2-containing signaling molecules such as
SHP-1, SHP-2, and/or SHIP. Using IIA1.6 cells transfected
with FcRIIB-PIR-B, the status of tyrosine phosphorylation of Fc
RIIB-PIR-B was determined by immunoprecipitation followed by Western blotting with antiphosphotyrosine mAb 4G10. As shown in Fig. 3 A, the chimeric receptor was slightly tyrosine phosphorylated upon BCR
cross-linking alone and this phosphorylation was markedly augmented by coligation of BCR and Fc
RIIB-PIR-B.
The Fc
RIIB-PIR-B phosphorylation was due to tyrosine
residues located in the cytoplasmic domain of PIR-B, since
Fc
RIIB-PIR-B(Y/F) (Fig. 1) did not undergo tyrosine
phosphorylation upon coligation of BCR and Fc
RIIB-
PIR-B(Y/F) (data not shown). After co-cross-linking of
BCR with Fc
RIIB-PIR-B, the chimeric molecule was
immunoprecipitated followed by Western blotting with
anti-SHP-1 or anti-SHP-2 Ab (Fig. 3 B, middle and right),
demonstrating that SHP-1 and SHP-2 are recruited to Fc
RIIB-PIR-B. In contrast, recruitment of SHIP to Fc
RIIB-PIR-B could not be detected (Fig. 3 B, left, lanes 1-3).
As a positive control, recruitment of SHIP to phosphorylated Fc
RIIB molecule was clearly observed under the
same experimental conditions (Fig. 3 B, left, lanes 4-6).
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The cytoplasmic tail of PIR-B contains
four copies (residues 688-693, 717-722, 769-774, and
799-804) of potential ITIMs (14, 15, 23). The inhibition
assay described above allowed us to assess the structural importance of each phosphotyrosine for the inhibitory signal.
Various tyrosine mutants were made (Fig. 1) and transfected into IIA1.6 cells to obtain stable transformants. IIA1.6 cells expressing comparable levels of chimeric receptors (Fig. 4 A) were stimulated by BCR alone or coligation of BCR and the chimeric mutants. FcRIIB-PIR-B(Y/F) almost reverted the inhibitory effect of PIR-B.
This result demonstrates that phosphorylation of cytoplasmic tyrosines of PIR-B plays an important role in the inhibitory signal and that the residual inhibition may be independent of tyrosine phosphorylation on PIR-B (Fig. 4 B).
Similar to Fc
RIIB-PIR-B(Y/F), inhibition of the BCR-induced calcium mobilization was almost abrogated by
coligating of BCR and Fc
RIIB-PIR-B(Y771, 801F). Analysis of the single tyrosine mutants, Fc
RIIB-PIR-B(Y771F) and Fc
RIIB-PIR-B(Y801F), indicates that these tyrosines
have different degrees of importance in the inhibitory signal
mediated by Fc
RIIB-PIR-B. Fc
RIIB-PIR-B(Y801F) inhibited calcium mobilization to a lesser degree than did
wild-type chimeric receptor, whereas the Fc
RIIB-PIR-B(Y771F) mutant inhibited it to a much lesser degree than
wild-type Fc
RIIB-PIR-B (Fig. 4, A and B). Thus, these data indicate that both tyrosines contribute to the inhibitory effect and that tyrosine 771 plays a more critical role in
inhibiting the BCR-induced calcium mobilization.
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To test directly the role of SHIP,
SHP-1, and SHP-2 in the inhibitory signal delivered by
PIR-B cytoplasmic tail, B cell lines deficient in SHIP,
SHP-1, or SHP-2 individually and in a combination of
SHP-1 and SHP-2 were established using a chicken DT40
B cell line as a consequence of homologous recombination
(Fig. 5 A). A detailed analysis of BCR signal transduction
in these mutants will be presented elsewhere. FcRIIB-
PIR-B chimeric molecule was transfected into DT40 wild-type and mutant cells, and compared for its ability to mediate the inhibitory signaling response. In contrast to IIA1.6
B cells, a more residual inhibition by Fc
RIIB-PIR-B(Y/F) was observed in DT40 cells (Fig. 5, B and C). Various genetic background DT40 cells expressing similar levels of Fc
RIIB-
PIR-B were stimulated with BCR cross-linking alone (Fig.
5, solid line) or coligation of BCR and the Fc
RIIB-PIR-B
(dashed line). As shown in Fig. 5 B, Fc
RIIB-PIR-B-mediated inhibition of calcium mobilization was unperturbed in
SHIP-deficient DT40 cells, but was substantially reduced
in SHP-1/SHP-2 double-deficient cells. The reduction of the chimeric receptor-mediated inhibition was also observed
by loss of either SHP-1 or SHP-2 alone. However, this reduction was less than that in double-deficient cells. These
results demonstrate that redundant functions of SHP-1 and
SHP-2 are required for the Fc
RIIB-PIR-B-mediated inhibitory signal.
Signals from the BCR and coreceptors such as CD19,
CD22, and FcRIIB (24, 25) are integrated inside the cell,
allowing the B cell to mount a response appropriate to the
source of the antigen and the lymphocyte environment. In
this study, we provide evidence that the cytoplasmic region
of PIR-B is capable of inhibiting B cell activation by a
phosphotyrosine-dependent manner in IIA1.6 and DT40 B
cells. Coligation of BCR and Fc
RIIB-PIR-B induced tyrosine phosphorylation of the cytoplasmic domain of PIR-B
and this phosphorylation was abrogated by the Fc
RIIB-
PIR-B(Y/F) mutant. Moreover, this mutant markedly reduced the inhibitory effects on BCR signaling, suggesting that
the SH2-containing proteins are involved in PIR-B-mediated inhibitory signals.
The finding that the residual inhibition by FcRIIB-
PIR-B still occurs in SHP-1 and SHP-2 double-deficient
DT40 cells, implicates that, in addition to SHP-1 and
SHP-2, another SH2-containing protein(s) may participate
in this inhibitory signal to some extent. Nevertheless, the
substantial reduction of the inhibition by loss of SHP-1 and SHP-2 clearly indicates that the redundant functions of
these SH2-containing phosphatases are required for PIR-B-mediated inhibition. Supporting this conclusion, both
SHP-1 and SHP-2 were recruited to the phosphorylated
Fc
RIIB-PIR-B. In contrast to requirement of SHIP for
an inhibitory response by Fc
RIIB, our biochemical and
functional data demonstrate that SHIP is dispensable for the PIR-B-mediated inhibitory response.
Mutational analysis of five cytoplasmic tyrosines indicates that tyrosine 771 in the motif VTYAQL plays the most crucial role in mediating the inhibitory signal and that tyrosine 801 in the motif SVYATL also contributes. The more functional importance of tyrosine 771 may reflect the fact that the motif surrounding tyrosine 771 matches better with the consensus I/VxYxxL sequence than that of tyrosine 801 (26). Binding of SH2 domains of SHP-1 and SHP-2 to tyrosine phosphorylated PIR-B would serve to relocate SHP-1 and SHP-2 to membrane (11), where they may gain access to potential substrates. Simultaneously, these phosphatases may be converted to an open conformation by binding to phosphorylated PIR-B, thereby leading to an increase of their enzymatic activity (27).
The ligand of PIR-B is still unknown. Significant homology of PIR-B to recently isolated LIR-1 (28), together with the evidence that LIR-1 is able to bind to the MHC class I molecule, suggests that PIR-B may be a receptor for MHC class I or class I-related molecules. Thus, similar to inhibition of NK cytotoxicity by interaction between class I molecules on target cells and KIRs on NK cells (29), cell-cell interactions may bring PIR-B into the close proximity of antigen-bound BCR, resulting in attenuation of BCR signaling. Alternatively, interaction of PIR-B with a putative ligand may remove it from the vicinity of BCR in order to release the B cells from the negative regulatory effects. Identification of the ligand for PIR-B as well as substrates for SHP-1 and SHP-2 will further clarify biological roles of PIR-B in the immune response and its mechanism of inhibition.
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Footnotes |
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Address correspondence to Tomohiro Kurosaki, Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570, Japan. Phone: 81-6-993-9445; Fax: 81-6-994-6099; E-mail: kurosaki{at}mxr.meshnet.or.jp
Received for publication 8 December 1997.
We would like to acknowledge Dr. J.N. Ihle for providing us with the mouse SHP-1 cDNA.This work was supported by grants to T. Kurosaki from the Ministry of Education, Science, Sports, and Culture of Japan, the Science Research Promotion Fund of the Japan Private School Promotion Foundation, and the Sumitomo Foundation, and a grant to T. Takai from CREST.
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