The Pre-B Cell Receptor Signaling for Apoptosis Is Negatively Regulated by FcγRIIB

Abstract

Many studies have shown that FcγRIIB is a negative regulator of B cell receptor signaling, and even though FcγRIIB is expressed through all developmental stages of the B cell lineage, its involvement in pre-B cell receptor (pre-BCR) signaling has not been examined. To investigate FcγRIIB function at the pre-B cell stage, we have established pre-BCR positive pre-B cell lines from normal mice and FcγRIIB-deficient mice, named PreBR and Fcγ−/−PreBR, respectively. These cell lines are able to differentiate into immature B cells in vitro by removal of IL-7. In PreBR, apoptosis was moderately induced by F(ab′)2 anti-μ Ab, but not by intact anti-μ Ab. Phosphorylation of SH2-containing inositol 5-phosphatase (SHIP) and Dok, which are involved in FcγRIIB signaling, was induced by anti-μ cross-linking in PreBR. In contrast, apoptosis was strongly induced by both the F(ab′)2 and intact anti-μ Abs in Fcγ−/−PreBR, and the level of phosphorylation of SHIP or Dok was much lower in Fcγ−/−PreBR than those observed in PreBR. Restoration of FcγRIIB to Fcγ−/−PreBR followed by anti-μ cross-linking blocked severe apoptosis, and up-regulated SHIP and Dok phosphorylation. The results demonstrate that FcγRIIB negatively regulates pre-BCR-mediated signaling for apoptosis.

A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing FcγRIIb Alters Receptor Expression and Associates with Autoimmunity. II. Differential Binding of GATA4 and Yin-Yang1 Transcription Factors and Correlated Receptor Expression and Function

“…These two stages of negative selection are critical in maintaining immune tolerance to self-Ags. Although largely unexplored, Fc␥RIIb negatively regulates pre-BCR-mediated signaling for apoptosis in the pre-B cell stage (15). In our cell viability assays, Fc␥RIIb negatively regulates IgM BCR-induced decrease in cell viability in EBV-transformed peripheral blood B cells.…”

“…Similarly, on Langerhans cells, Fc␥RIIb mediates Ag internalization and presentation (9 -11). On B cells, at least in part by recruitment of phosphatases to its immunoreceptor tyrosine-based inhibitory motif, Fc␥RIIb engagement can shape the Ab repertoire through modulation of B cell Ag receptor (BCR)-mediated cell activation and proliferation (12,13), through signals for apoptosis independent of BCR (14), and through down-regulation of pre-BCR-mediated apoptosis (15). On myeloid lineage cells, Fc␥RIIb downregulates Ab-mediated phagocytosis and inflammatory responses when clustered with the activating Fc␥Rs, such as Fc␥RIa, Fc␥RIIa, and Fc␥RIIIa (16,17).…”

Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis

“…8 The presence of ITIMs is a common feature of many other receptors, such as CD32 (in particular, Fc␥RIIb), killer cell Ig-like receptors (KIRs), and gp49B1. [28][29][30] Among Siglecs, signaling involving downstream phosphatases such as SHP-1, SHP-2, and SLAM-associated proteins has been shown in association with ITIMs and SLAM, respectively. 7,[24][25][26] Examples of functional consequences mediated via Siglecs include studies in which antibody cross-linking of CD33 induced apoptosis of leukemic cells.…”

“…Aggregation has been reported to trigger a variety of inhibitory receptors, including CD32 and the cell-death receptor Fas/CD95. 28,31 Because neither Siglec-8 isoform has a recognizable death domain, another possibility is that antibodymediated cross-linking induces coaggregation with another cell surface receptor, such as CD32 or Fas. 13,20 A role for CD32 seems unlikely, because both intact and F(abЈ) 2 secondary antibodies were equally effective and anti-CD44, used as a binding control mAb, did not induce apoptosis.…”

Frameshift mutation in the Dok1 gene in chronic lymphocytic leukemia

“…After tyrosine-phosphorylation, Dok1 can interact with other signaling molecules containing SH2 domains, such as Ras-GTPase-activating protein (Ras-GAP), SHIP1, Nck, Csk and the X-linked lymphoproliferative syndrome (XLP) gene product SH2D1A (Neet and Hunter, 1995;Noguchi et al, 1999;Sylla et al, 2000;Sattler et al, 2001). Dok1 downregulates several cell signaling processes: for example, it inhibits MAP kinase activity, downregulates cell proliferation, affects T-and B-cell signaling and plays a role in activin-induced apoptosis (Tamir et al, 2000;Yamanashi et al, 2000;Di Cristofano et al, 2001;Martelli et al, 2001;Nemorin et al, 2001;Songyang et al, 2001;Wick et al, 2001;Zhao et al, 2001;Kato et al, 2002;Yamakawa et al, 2002). Dok1 can also affect cell adhesion, spreading and migration (Noguchi et al, 1999;Hosooka et al, 2001).…”