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The Journal of Immunology, 1998, 161: 2079-2083.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Fc{gamma}RII-B1 Regulates the Presentation of B Cell Receptor-Bound Antigens1

Stacey A. Minskoff2, Karl Matter3 and Ira Mellman4

Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Fc{gamma} receptors (Fc{gamma}RII) on B lymphocytes negatively regulate B cell receptor (BCR)-dependent activation upon cross-linking of the two receptors. The mechanism reflects the ability of the Fc{gamma}RII cytoplasmic tail to recruit specific phosphatases that inactivate elements of the BCR-signaling cascade. We now show that cross-linking also blocks the processing and presentation of BCR-bound Ag. This occurs because the Fc{gamma}RII isoform typically expressed by B cells (Fc{gamma}RII-B1) is incompetent for endocytosis. When cross-linked, Fc{gamma}RII-B1 acts as a dominant negative inhibitor of BCR endocytosis. In contrast, cross-linking of endocytosis-competent Fc{gamma}RII isoforms did not inhibit endocytosis or processing of BCR-bound Ag. Thus, Fc{gamma}RII-B1 acts not only to prevent B cell activation under conditions of Ab excess, but also to prevent clonotypic T cell activation by inhibiting the ability of B cells to generate specific MHC class II-bound TCR ligands.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Murine B lymphocyte Fc{gamma}RII-B1 negatively regulates activation of B cells by multiple mechanisms to help maintain clonal specificity and proper feedback control of secreted Abs. First, Fc{gamma}RII-B1 mediates negative signal transduction events that counteract activation signals triggered by B cell Ag receptor (BCR)5 cross-linking (reviewed in 1 . Established effects resulting from cocross-linking of Fc{gamma}RII-B1 with the surface Ig (sIg) include inhibition of IP3 production (2), calcium influx (3, 4, 5, 6), blast formation (7), and proliferation (8). More recent studies have begun to reveal the mechanism of this Fc{gamma}RII-B1-mediated inhibition. Cocross-linking of Fc{gamma}RII-B1 with sIg results in phosphorylation of the tyrosine residue in the Fc{gamma}RII-B1 immunoreceptor tyrosine-based inhibitory motif (ITIM) (5), followed by recruitment of the protein tyrosine phosphatases SHP-1 and SHP-2 (9, 10) and the inositol phosphatase SHIP (10, 11, 12). Indeed, B cells from motheaten mice, which are defective in SHP-1 (13, 14, 15), exhibit a loss of Fc{gamma}RII-B1-mediated negative regulation (9, 16). Fc{gamma}RII-B1 cross-linking with sIg also results in reduced tyrosine phosphorylation of CD19 (17, 18), inhibition of the ras pathway (19, 20), and apoptosis (12, 21, 22). Furthermore, an increase in Ig production occurs in Fc{gamma}RII-B1 knockout mice (23), consistent with a decrease in the capacity for B cells to be negatively regulated in vivo.

Fc{gamma}RII-B1 also helps to maintain specificity of B cell activation. The BCR binds a specific Ag via sIg, which is then internalized by endocytosis for processing and ultimately for presentation to T helper cells. In contrast, Fc{gamma}RII-B1 binds any Ag, as long as it is contained within an IgG-immune complex. The Fc{gamma}RII-B1-bound Ags are not internalized. As shown in the murine A20 B cell lymphoma, the binding of immune complexes to endogenous Fc{gamma}RII-B1 fails to result in efficient Ag presentation, instead resulting in the formation of caps of immune complex and Fc{gamma}RII-B1 on the cell surface (3). In A20 cells transfected with the endocytosis-competent murine macrophage Fc{gamma}RII-B2, the Fc{gamma}RII-B2 isoform does internalize and efficiently present Ags bound in IgG-immune complexes (3). Although murine Fc{gamma}RII-B1 and -B2 are encoded by the same structural gene, the -B1 isoform results from an alternative mRNA-splicing event that places a unique 47-amino acid cytoplasmic tail insertion that lies upstream of the ITIM and inhibits endocytosis by preventing accumulation in clathrin-coated pits (3, 24, 25). Fc{gamma}RII-B1-mediated negative regulation of B lymphocyte activation is therefore dependent upon multiple sequences contained within the cytoplasmic tail domain.

In this study, we were interested in further elucidating the role of Fc{gamma}RII-B1 in the regulation of B lymphocyte function. We find that the receptor, by virtue of its ability to block endocytosis when cross-linked to BCR, can act as a dominant-negative inhibitor of BCR-mediated Ag processing. Thus, by inhibiting Ag presentation, Fc{gamma}RII-B1 can inhibit Ab responses by indirectly inhibiting Ag-dependent T cell stimulation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Cell lines

The A20 murine B lymphoma cell line, which expresses endogenous Fc{gamma}RII-B1 and cell surface IgG, and the A6B9 cell line, which expresses stably transfected murine Fc{gamma}RII-B2 (3), were used for this study. A6B9 cells were derived from transfecting an Fc{gamma}RII-B1-negative A20 cell line, IIA1.6, that maintains the cell surface IgG. Fc{gamma}RII-B1 mutants containing a deletion or point mutation in the cytoplasmic tail were prepared by PCR mutagenesis (primers are available upon request) and transfected into IIA1.6 cells as previously described (3). The murine T cell hybridoma 2R.50, which recognizes peptides (specificity unknown) derived from F(ab')2 fragments of rabbit Ig in the context of I-Ad (26), was used in the Ag presentation assay.

Ag presentation assay

The Ag presentation assay used was based on a previously published assay (27). A20 or A6B9 cells suspended at 2 x 106 cells/ml in RPMI 1640 complete medium (10% FBS, 50 µM ß-mercaptoethanol (Sigma, St. Louis, MO), 1.0 mM sodium pyruvate (Life Technologies, Gaithersburg, MD), 0.1 mM nonessential amino acids (Life Technologies), and 4 mM glutamine (Life Technologies)) were incubated with various concentrations of Ag (F(ab')2 fragments of rabbit anti-mouse IgG (Cappel, Durham, NC)), either alone or in preformed soluble immune complexes with intact goat anti-rabbit IgG (Cappel) for 3 h at 37°C. Immune complexes were prepared by incubating intact goat anti-rabbit IgG with Ag in RPMI 1640 complete medium for 30 min at 37°C at a molar ratio of 2.5:1, respectively. Following the 3-h incubation of A20 and A6B9 cells with Ag, cells were fixed with 0.5% paraformaldehyde for 30 min at room temperature, washed, and resuspended with 2R.50 cells (2 x 106 cells/ml). After an 18-h incubation at 37°C, the supernatants were collected and assayed for IL-2 by ELISA (Endogen, Woburn, MA).

Endocytosis assays

The endocytosis assay used to analyze internalization of sIg- and Fc receptor-bound Ag was based on a previously published protocol (3) with the following changes included. A20 or A6B9 cells suspended at 1 x 107 cells/ml in RPMI 1640 complete medium plus 10 mM HEPES, pH 7.4, were incubated with horseradish peroxidase (HRP)-tagged F(ab')2 fragments of rabbit anti-mouse IgG (20 µg/ml, Zymed) either alone or in preformed immune complexes with intact goat anti-rabbit IgG (50 µg/ml, Cappel) for 15 min on ice and then for various times at 37°C. Ice-cold RPMI 1640 complete medium with HEPES was added to stop the reaction, followed by two washes with cold PBS. Each sample was then split into two equal volumes that were incubated in PBS plus or minus 0.5% Triton X-100 for 15 min on ice, and the cell-associated HRP activity was determined. The percentage of internalized HRP was calculated for each time point. Endocytosis of Fc receptor-bound immune complexes was assayed as previously described (3).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Fc{gamma}RII-B1 inhibits presentation of BCR-bound Ag

Specific Ag bound to the BCR is endocytosed, processed within vesicles of the endocytic pathway, and resulting peptide-MHC II complexes then routed back to the cell surface for presentation to helper T cells. B cell Fc{gamma}RII-B1, on the other hand, binds any Ag that is contained within IgG-immune complexes regardless of the Ag specificity of the BCR. Since Fc{gamma}RII-B1 is unable to mediate endocytosis, Ag bound in this way is not internalized and therefore is not presented to T cells (3). Since the presence of excess IgG Ab may cross-link Ag bound to the BCR to Fc{gamma}RII-B1, we asked if the formation of a cross-linked complex between BCR and Fc{gamma}RII-B1 might prevent processing and presentation of BCR-bound Ag.

We utilized A20 cells, which express endogenous Fc{gamma}RII-B1 and cell surface IgG in the BCR. F(ab')2 fragments of rabbit anti-mouse IgG were used as the Ag, since the antigenic epitope of the A20 surface IgG is unknown. A20 cells were incubated with various concentrations of Ag, either alone or in preformed soluble immune complexes with intact goat anti-rabbit IgG, and then assayed for their ability to present peptide to 2R.50 cells. As shown in Figure 1GoA, presentation increased with increasing concentrations of Ag to a higher degree when rabbit F(ab')2 fragments were added alone compared with presentation of Ag that was added to cells in the form of immune complexes. This was consistent with the F(ab')2 fragments added alone being bound and internalized by the BCR whereas preformed complexes of rabbit F(ab')2 and goat-anti-rabbit IgG would be bound to Fc{gamma}RII-B1, with or without also binding to the BCR.



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  		FIGURE 1. Fc{gamma}RII-B1 inhibits presentation of immune complex Ag. A20 (A) and A6B9 (B) cells were assayed for their ability to present Ag to 2R.50 cells. A20 and A6B9 cells were incubated with Ag (F(ab')2 fragments of rabbit anti-mouse IgG) either alone or in immune complexes with intact goat anti-rabbit IgG before incubation with 2R.50 cells. The supernatants were collected and assayed for IL-2 by ELISA. The concentration of Ag with or without immune complex IgG is shown on the x-axis. The samples were assayed in duplicate, and the range is shown. Samples in which 2R.50 cells were omitted or in which goat anti-rabbit IgG alone was added to A20 and A6B9 cells did not contain any IL-2 in the supernatant (data not shown).

 
Results from the A20 cells were next compared with results obtained with A6B9 cells, an Fc{gamma}RII-negative A20 cell derivative expressing transfected Fc{gamma}RII-B2. The Fc{gamma}RII-B2 isoform is endocytosis positive, and we have previously shown that nonspecific Ags in IgG-immune complexes can be internalized in A6B9 cells and can be presented to T cells (3). In the present study, A6B9 cells were assayed for presentation of F(ab')2 fragments of rabbit anti-mouse IgG added to cells either alone or in immune complexes, as above. In contrast to A20 cells, A6B9 cells demonstrated enhanced presentation with increasing concentrations of Ag at a similar rate, whether or not rabbit F(ab')2 fragments were added to cells in association with the immune complex Ab (Fig. 1GoB). These results show that Fc{gamma}RII-B1 inhibited presentation of a BCR-specific immune complex Ag, whereas Fc{gamma}RII-B2 did not.

To ensure that inhibition of presentation of the BCR-specific immune complex Ag in A20 cells was indeed due to the Fc receptor, A20 and A6B9 cells were incubated with Ag, either alone or in the form of immune complexes, in the presence of the anti-Fc receptor Ab 2.4G2. Under the conditions used, the 2.4G2 Ab blocks immune complex binding to both Fc{gamma}RII-B1 and Fc{gamma}RII-B2. In A20 cells, inhibition of Ag presentation in the presence of 2.4G2 occurred to the same extent (shown as percent inhibition in the parentheses) whether or not Ag was added to cells alone or in immune complexes (Fig. 2Go). Since 2.4G2 cross-reacts with the rabbit anti-mouse IgG F(ab')2 fragments, this result was not surprising: addition of both 2.4G2 and the F(ab')2 would effectively form an immune complex that could bind directly to Fc{gamma}RII-B1 or cross-link the BCR to Fc{gamma}RII-B1 on these cells. Furthermore, we observed that 2.4G2 inhibits endocytosis but not the binding of the F(ab')2 fragments in cells expressing either Fc{gamma}RII-B1 or -B2 (data not shown), which would result in decreased Ag presentation.



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  		FIGURE 2. Ag presentation in the presence of anti-Fc receptor blocking Ab. A20 and A6B9 cells were assayed for their ability to present Ag in the presence of anti-Fc receptor Ab (2.4G2) to 2R.50 cells. A20 and A6B9 cells were incubated with Ag (F(ab')2 fragments of rabbit anti-mouse IgG) (100 µg/ml) either alone or in immune complexes with intact goat anti-mouse IgG in the absence or presence (+) of 2.4G2 (100 µg/ml) before incubation with 2R.50 cells. The supernatants were collected and assayed for IL-2 by ELISA. The numbers above the bars represent the percent inhibition of IL-2 release from samples incubated with Ag in the presence of 2.4G2.

 
More informative, therefore, were experiments with A6B9 cells expressing the internalization-competent Fc{gamma}RII-B2 isoform. Also as shown in Figure 2Go, A6B9-mediated presentation of Ag added to cells in the presence of 2.4G2 was inhibited more when the Ag was contained within immune complexes (84% inhibition) than when Ag was added alone (38% inhibition). Therefore, in A6B9 cells, presentation of immune complex Ag was clearly dependent upon both the BCR and Fc{gamma}RII-B2. However, when immune complexes were given, presentation via Fc{gamma}RII-B2 appeared to occur preferentially over presentation via the BCR, despite the fact that the immune complex contained an Ag that could bind to BCR. Taken together, these results show that the inhibition of immune complex Ag presentation observed in A20 cells (compared with Ag added to cells alone) was indeed due to the Fc receptor, Fc{gamma}RII-B1.

Fc{gamma}RII-B1 inhibits endocytosis of a BCR-specific immune complex Ag

To test whether the observed Fc{gamma}RII-B1-mediated inhibition of presentation of a BCR-specific immune complex Ag was due to the endocytosis-negative phenotype of this Fc receptor isoform, A20 and A6B9 cells were examined for their ability to endocytose HRP-tagged Ag added to cells either alone or in immune complexes. HRP-tagged Ag was incubated with cells continuously to mimic conditions of the Ag presentation assay, and internalization of Ag as measured by HRP activity was monitored over time. As shown in Figure 3Go, A20 cells showed decreased endocytosis of immune complex Ag compared with internalization of Ag added to cells alone (Fig. 3GoA), whereas A6B9 cells demonstrated similar rates of endocytosis with either form of Ag (Fig. 3GoB). These results are presumably due to the endocytic competence of the particular cell surface Fc receptor, Fc{gamma}RII-B1 being internalization-negative while Fc{gamma}RII-B2 is internalization-positive. Therefore, we can conclude that inhibition of presentation of the BCR-specific immune complex Ag in A20 cells was mediated by Fc{gamma}RII-B1 at the level of endocytosis.



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  		FIGURE 3. Fc{gamma}RII-B1 inhibits endocytosis of immune complex Ag. A20 (A) and A6B9 (B) cells were assayed for their ability to endocytose HRP-labeled Ag (F(ab')2 fragments of rabbit anti-mouse IgG) (20 µg/ml), either alone or in immune complexes with intact goat anti-rabbit IgG. The percent HRP internalized for each time point is shown. The results represent an average of two separate experiments, and the range for each time point is shown.

 
The Fc{gamma}RII-B1-unique cytoplasmic tail insertion inhibits endocytosis by preventing accumulation in clathrin-coated pits (3, 24, 25). To determine whether or not the entire insertion sequence was required for inhibition of endocytosis, Fc{gamma}RII-B1 deletion mutants were assayed for internalization competence. Fc{gamma}RII-B1 missing amino acid residues in the amino-terminal half of the cytoplasmic tail insertion (B1 (CT{Delta}7-31)) endocytosed bound immune complexes at a similar rate as the -B2 isoform (Fig. 4Go). In contrast, endocytosis of Fc{gamma}RII-B1 with amino acid residues in the carboxyl-terminal half of the insertion omitted (B1 (CT{Delta}33-54)) occurred at the same low level as that of intact Fc{gamma}RII-B1 (Fig. 4Go). Therefore, the amino-terminal half of the murine Fc{gamma}RII-B1 cytoplasmic tail insertion contains sequences needed to inhibit endocytosis and the observed down-regulation of presentation of a BCR-specific immune complex Ag.



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  		FIGURE 4. The amino-terminal half of the Fc{gamma}RII-B1 insertion inhibits endocytosis. Cells expressing Fc{gamma}RII-B1 mutants were assayed for their ability to endocytose Fc receptor-bound HRP:anti-HRP IgG immune complexes (A). The wild-type and mutant Fc{gamma}RII-B1 cytoplasmic tail insertion sequences are shown in (B), and the mutants are labeled with the first cytoplasmic tail (CT) amino acid residue as number one. B1 (CT{Delta}7-31) cells express Fc{gamma}RII-B1 with cytoplasmic tail amino acid residues 7-31 deleted, and B1 (CT{Delta}33-54) cells express Fc{gamma}RII-B1 with cytoplasmic tail amino acid residues 33-54 deleted. B1 (CTY28A) cells express Fc{gamma}RII-B1 with sole tyrosine residue in the amino-terminal half of the cytoplasmic tail insertion changed to alanine. For the endocytosis assay, cells (1 x 107 cells/ml) were incubated with immune complexes (20 µg/ml) for 2 h on ice, washed, and then incubated for the indicated time period at 37°C. The percent HRP internalized for each time point is shown. The results represent an average of two separate experiments, and the range for each time point is shown.

 
Finally, since tyrosine phosphorylation has been implicated in Fc{gamma}RII function, we asked whether the single tyrosine reside found in the receptor’s amino-terminal half of the cytoplasmic tail insertion might play a role in regulating endocytosis in Fc{gamma}RII-B1. As shown in Figure 4Go, this proved not to be the case. This result demonstrates that the ability of the Fc{gamma}RII-B1 insertion to block endocytosis was not dependent on the presence of a phosphorylation site within the cytoplasmic tail insertion.

In this study, we observed that A20 cell Fc{gamma}RII-B1 inhibited presentation of a sIg-specific, immune complex Ag to T cells. Moreover, this Fc{gamma}RII-B1-mediated inhibition occurred at the level of immune complex endocytosis and, hence, was dependent upon the cytoplasmic tail insertion. Therefore, Fc{gamma}RII-B1 not only inhibits B cell activation, it inhibits activation of T cells as well. In addition, it is possible that the relative affinity of an immune complex with a BCR-specific Ag for either the sIg or Fc{gamma}RII-B1 helps to determine the outcome of a particular immune response, positive or negative.

The mechanism by which the Fc{gamma}RII-B1 cytoplasmic tail insertion inhibits endocytosis is not completely understood. Previous work suggests that Fc{gamma}RII-B1 associates with the cytoskeleton (25), and perhaps this association is responsible for preventing accumulation in clathrin-coated pits (3, 24, 25). We determined that the amino-terminal half of the Fc{gamma}RII-B1 insertion contains sequences required to inhibit endocytosis. The human Fc{gamma}RII-B1 isoform, which also mediates negative signaling in B cells but not endocytosis (28, 29), contains a cytoplasmic tail insertion that is highly homologous in sequence and length (19 amino acid residues) to the amino-terminal half of the murine B1 isoform, suggesting a conservation of function. With the absence of the cytoplasmic tail insertion sequence, murine Fc{gamma}RII-B2 mediates efficient endocytosis in A6B9 cells (Fig. 4Go; 3 . As observed with Fc{gamma}RII-B2-transfected MDCK cells (30, 31), Fc{gamma}RII-B2-mediated endocytosis in A6B9 cells requires a di-leucine motif in the ITIM (data not shown). Furthermore, the -B2 isoform can mediate negative signaling upon cocross-linking with the sIg in A6B9 cells (3). It is possible that the amino-terminal half of the Fc{gamma}RII-B1 insertion alters the conformation of the cytoplasmic tail domain such that the di-leucine motif is not available to mediate endocytosis but the ITIM still functions in negative signal transduction. Fc{gamma}RII-B1 thus functions in a multifaceted manner to maintain a tight control on B cell activation and to maintain the Ag specificity of the humoral immune response.


   Acknowledgments
 
We thank Dr. Richard Mitchell for providing the 2R.50 cells and Dr. Deborah Lazzarino for many helpful discussions.


   Footnotes
 
1 S.A.M. was supported by a postdoctoral training award from the American Cancer Society. Back

2 Current address: Department of Biology, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 Back

3 Current address: Department of Cell Biology, University of Geneva, Sciences III, 30, quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland. Back

4 Address correspondence and reprint requests to Dr. Ira S. Mellman, Department of Cell Biology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208002, New Haven, CT 06520. E-mail address: Back

5 Abbreviations used in this paper: BCR, B cell Ag receptor; sIg, surface Ig; ITIM, immunoreceptor tyrosine-based inhibitory motif; HRP, horseradish peroxidase. Back

Received for publication February 4, 1998. Accepted for publication June 23, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Ravetch, J. V.. 1997. Fc receptors. Curr. Opin. Immunol. 9:121.[Medline]
  2. Bijsterbosch, M. K., G. G. B. Klaus. 1985. Crosslinking of surface immunoglobulin and Fc receptors on B lymphocytes inhibits stimulation of inositol phospholipid breakdown via the antigen receptors. J. Exp. Med. 162:1825.[Abstract/Free Full Text]
  3. Amigorena, S., C. Bonnerot, J. R. Drake, D. Choquet, W. Hunziker, J. G. Guillet, P. Webster, C. Sautes, I. Mellman, W. H. Fridman. 1992. Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256:1808.[Abstract/Free Full Text]
  4. Choquet, D., M. Partiseti, S. Amigorena, C. Bonnerot, W. H. Fridman, H. Korn. 1993. Cross-linking of IgG receptors inhibits membrane immunoglobulin-stimulated calcium influx in B lymphocytes. J. Cell Biol. 121:355.[Abstract/Free Full Text]
  5. Muta, T., T. Kurosaki, Z. Misulovin, M. Sanchez, M. C. Nussenzweig, J. V. Ravetch. 1994. A 13-amino acid motif in the cytoplasmic domain of Fc{gamma}RIIB modulates B-cell receptor signalling. Nature 368:70.[Medline]
  6. Diegel, M. L., B. M. Rankin, J. B. Bolen, P. M. Dubois, P. A. Kiener. 1994. Cross-linking of Fc gamma receptor to surface immunoglobulin on B cells provides an inhibitory signal that closes the plasma membrane calcium channel. J. Biol. Chem. 269:11409.[Abstract/Free Full Text]
  7. Phillips, N. E., D. C. Parker. 1984. Cross-linking of B lymphocyte Fc{gamma} receptors and membrane immunoglobulin inhibits anti-immunoglobulin-induced blastogenesis. J. Immunol. 132:627.[Abstract]
  8. Phillips, N. E., D. C. Parker. 1983. Fc-dependent inhibition of mouse B cell activation by whole anti-µ antibodies. J. Immunol. 130:(2):602.[Abstract]
  9. D’Ambrosio, D., K. L. Hippen, S. A. Minskoff, I. Mellman, G. Pani, K. A. Siminovitch, J. C. Cambier. 1995. Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc{gamma}RIIB1. Science 268:293.[Abstract/Free Full Text]
  10. D’Ambrosio, D., D. C. Fong, J. C. Cambier. 1996. The SHIP phosphatase becomes associated with Fc{gamma}RIIB1 and is tyrosine phosphorylated during "negative" signaling. Immunol. Lett. 54:77.[Medline]
  11. Ono, M., S. Bolland, P. Tempst, J. V. Ravetch. 1996. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FC-gamma-RIIB. Nature 383:263.[Medline]
  12. Ono, M., H. Okada, S. Bolland, S. Yanagi, T. Kurosaki, J. V. Ravetch. 1997. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 90:293.[Medline]
  13. Tsui, H. W., K. A. Siminovitch, L. de Souza, F. W. Tsui. 1993. Motheaten and viable motheaten mice have mutations in the hematopoietic cell phosphatase gene. Nat. Genet. 4:124.[Medline]
  14. Shultz, L. D., P. A. Schweitzer, T. V. Rajan, T. Yi, J. N. Ihle, R. J. Matthews, M. L. Thomas, D. R. Beier. 1993. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73:1445.[Medline]
  15. Kozlowski, M., I. Mlinaric-Rascan, G. S. Feng, R. Shen, T. Pawson, K. A. Siminovitch. 1993. Expression and catalytic activity of the tyrosine phosphatase PTP1C is severly impaired in motheaten and viable motheaten mice. J. Exp. Med. 178:2157.[Abstract/Free Full Text]
  16. Pani, G., M. Kozlowski, J. C. Cambier, G. B. Mills, K. A. Siminovitch. 1995. Identification of the tyrosine phosphatase PTP1C as a B cell antigen receptor-associated protein involved in the regulation of B cell signaling. J. Exp. Med. 181:2077.[Abstract/Free Full Text]
  17. Hippen, K. L., A. M. Buhl, D. D’Ambrosio, K. Nakamura, C. Persin, J. C. Cambier. 1997. FcgRIIB1 inhibition of BCR-mediated phosphoinositide hydrolysis and Ca2+ mobilization is integrated by CD19 dephosphorylation. Immunity 7:49.[Medline]
  18. Kiener, P. A., M. N. Lioubin, L. R. Rohrschneider, J. A. Ledbetter, S. G. Nadler, M. L. Diegel.. 1997. Co-ligation of the antigen and Fc receptors gives rise to the selective modulation of intracellular signaling in B cells: regulation of the association of phosphatidylinositol 3-kinase and inositol 5'-phosphatase with the antigen receptor complex. J. Biol. Chem. 272:3838.[Abstract/Free Full Text]
  19. Tridandapani, S., G. W. Chacko, J. R. Van Brocklyn, K. M. Coggeshall. 1997. Negative signaling in B cells causes reduced Ras activity by reducing Shc-Grb2 interactions. J. Immunol. 158:1125.[Abstract]
  20. Tridandapani, S., T. Kelley, D. Cooney, M. Pradhan, and K. M. Coggeshall. Negative signaling in B cells: SHIP Grbs Shc. Immunol. Today 18:424.
  21. Ashman, R. F., D. Peckham, L. Stunz. 1996. Fc receptor off-signal in the B cell involves apoptosis. J. Immunol. 157:5.[Abstract]
  22. Yamashita, Y., K. Miyake, Y. Miura, Y. Kaneko, H. Yagita, T. Suda, S. Nagata, J. Nomura, N. Sakaguchi, M. Kimoto. 1996. Activation mediated by RP105 but not CD40 makes normal B cells susceptible to anti-IgM-induced apoptosis: a role for Fc receptor coligation. J. Exp. Med. 184:113.[Abstract/Free Full Text]
  23. Takai, T., M. Ono, M. Hikida, H. Ohmori, J. V. Ravetch. 1996. Augmented humoral and anaphylactic responses in Fc{gamma}RII-deficient mice. Nature 379:346.[Medline]
  24. Miettinen, H. M., J. K. Rose, I. Mellman. 1989. Fc receptor isoforms exhibit distinct abilities for coated pit localization as a result of cytoplasmic domain heterogeneity. Cell 58:317.[Medline]
  25. Miettinen, H. M., K. Matter, W. Hunziker, J. K. Rose, I. Mellman. 1992. Fc receptor endocytosis is controlled by a cytoplasmic domain determinant that actively prevents coated pit localization. J. Cell. Biol. 116:875.[Abstract/Free Full Text]
  26. Tony, H. P., D. C. Parker. 1985. Major histocompatibility complex-restricted, polyclonal B cell responses resulting from helper T cell recognition of anti-immunoglobulin by small B lymphocytes. J. Exp. Med. 161:223.[Abstract/Free Full Text]
  27. Barnes, K. A., R. N. Mitchell. 1995. Detection of functional class II-associated antigen: role of a low density endosomal compartment in antigen processing. J. Exp. Med. 181:1715.[Abstract/Free Full Text]
  28. Budde, P., N. Bewarder, V. Weinrich, O. Schulzeck, J. Frey. 1994. Tyrosine-containing sequence motifs of the human immunoglobulin G receptors FcRIIb1 and FcRIIb2 essential for endocytosis and regulation of calcium flux in B cells. J. Biol. Chem. 269:30636.[Abstract/Free Full Text]
  29. Van Den Herik-Oudijk, I. E., N. A. C. Westerdaal, N. V. Henriquez, P. J. A. Capel, J. G. J. Van De Winkel. 1994. Functional analysis of human FcgRII (CD32) isoforms expressed in B lymphocytes. J. Immunol. 152:574.[Abstract]
  30. Matter, K., E. M. Yamamoto, I. Mellman. 1994. Structural requirements and sequence motifs for polarized sorting and endocytosis of LDL and Fc receptors in MDCK cells. J. Cell. Biol. 126:991.[Abstract/Free Full Text]
  31. Hunziker, W., C. Fumey. 1994. A di-leucine motif mediates endocytosis and basolateral sorting of macrophage IgG Fc receptors in MDCK cells. EMBO J. 13:2963.[Medline]



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Fc{gamma}RIIb Balances Efficient Pathogen Clearance and the Cytokine-mediated Consequences of Sepsis
J. Exp. Med., March 1, 2004; 199(5): 717 - 723.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
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J. Biol. Chem., May 2, 2003; 278(19): 17430 - 17437.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
F. Borrego, J. Kabat, T. B. Sanni, and J. E. Coligan
NK Cell CD94/NKG2A Inhibitory Receptors Are Internalized and Recycle Independently of Inhibitory Signaling Processes
J. Immunol., December 1, 2002; 169(11): 6102 - 6111.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. K. Reitan and K. Hannestad
Immunoglobulin heavy chain constant regions regulate immunity and tolerance to idiotypes of antibody variable regions
PNAS, May 28, 2002; 99(11): 7588 - 7593.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
J. Prechl, D. C. Baiu, A. Horvath, and A. Erdei
Modeling the presentation of C3d-coated antigen by B lymphocytes: enhancement by CR1/2-BCR co-ligation is selective for the co-ligating antigen
Int. Immunol., March 1, 2002; 14(3): 241 - 247.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
H. Phee, W. Rodgers, and K. M. Coggeshall
Visualization of Negative Signaling in B Cells by Quantitative Confocal Microscopy
Mol. Cell. Biol., December 15, 2001; 21(24): 8615 - 8625.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
M. B. Callanan, P. Le Baccon, P. Mossuz, S. Duley, C. Bastard, R. Hamoudi, M. J. Dyer, G. Klobeck, R. Rimokh, J. J. Sotto, et al.
The IgG Fc receptor, Fcgamma RIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma
PNAS, January 4, 2000; 97(1): 309 - 314.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. J. J. van Neerven, T. Wikborg, G. Lund, B. Jacobsen, A. Brinch-Nielsen, J. Arnved, and H. Ipsen
Blocking Antibodies Induced by Specific Allergy Vaccination Prevent the Activation of CD4+ T Cells by Inhibiting Serum-IgE-Facilitated Allergen Presentation
J. Immunol., September 1, 1999; 163(5): 2944 - 2952.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Wernersson, M. C. I. Karlsson, J. Dahlstrom, R. Mattsson, J. S. Verbeek, and B. Heyman
IgG-Mediated Enhancement of Antibody Responses Is Low in Fc Receptor {gamma} Chain-Deficient Mice and Increased in Fc{gamma}RII-Deficient Mice
J. Immunol., July 15, 1999; 163(2): 618 - 622.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
N. M. Wagle, A. E. Faassen, J. H. Kim, and S. K. Pierce
Regulation of B Cell Receptor-Mediated MHC Class II Antigen Processing by Fc{gamma}RIIB1
J. Immunol., March 1, 1999; 162(5): 2732 - 2740.
[Abstract] [Full Text] [PDF]

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