Growth-factor receptor-bound protein-2 (Grb2) signaling in B cells controls lymphoid follicle organization and germinal center reaction

Abstract

Grb2 (growth-factor receptor-bound protein-2) is a signaling adaptor that interacts with numerous receptors and intracellular signaling molecules. However, its role in B-cell development and function remains unknown. Here we show that ablation of Grb2 in B cells results in enhanced B-cell receptor signaling; however, mutant B cells do not form germinal centers in the spleen after antigen stimulation. Furthermore, mutant mice exhibit defects in splenic architecture resembling that observed in B-cell-specific lymphotoxin-β-deficient mice, including disruption of marginal zone and follicular dendritic cell networks. We find that grb2 −/− B cells are defective in lymphotoxin-β expression. Although lymphotoxin can be up-regulated by chemokine CXCL13 and CD40 ligand stimulation in wild-type B cells, elevation of lymphotoxin expression in grb2 −/− B cells is only induced by anti-CD40 but not by CXCL13. Our results thus define Grb2 as a nonredundant regulator that controls lymphoid follicle organization and germinal center reaction. Loss of Grb2 has no effect on B-cell chemotaxis to CXCL13, indicating that Grb2 executes this function by connecting the CXCR5 signaling pathway to lymphotoxin expression but not to chemotaxis.B-cell signaling and activation | follicular dendritic cell development | germinal center development | regulation of lymphotoxin expression | chemokine signaling

Impact of Ca2+ signaling on B cell function

“…It has been noted that a study suggests that defective FcgRIIB1 signals are involved in enhancement of Ca 2+ response in B cells from systemic lupus erythematosis (SLE) patients [45]. In addition, mice lacking Grb2 specifically in B cells do not develop lupus-like autoimmune diseases, but produce anti-dsDNA IgM and have antibody deposits in the kidneys, in addition to defective B cell development [32]. Furthermore, a gain-of-function mutation has been identified in the murine Plcg2 gene, leading to hyper-reactive Ca 2+ mobilization in B cells and severe spontaneous autoimmune inflammation [46].…”

“…The growth factor receptor-bound protein 2 (Grb2), which is an ubiquitous adapter protein, is also a negative regulator of Ca 2+ signals. The ablation of Grb2 in B cells enhances BCR-mediated Ca 2+ release from ER and SOCE [31][32][33]. Following BCR stimulation, Grb2 interacts with another adapter protein, downstream of tyrosine kinases 3 (Dok3), in a phosphorylation-dependent manner, leading to translocation of the Grb2ÀDok3 complex to the PtdIns(3,4,5)P 3 in the PM, and inhibition of PLC-g2 activation [34].…”

The Dok-3/Grb2 Protein Signal Module Attenuates Lyn Kinase-dependent Activation of Syk Kinase in B Cell Antigen Receptor Microclusters

“…These complexes attenuate PLC-␥2 activation, which results in decreased inositol-1,4,5-trisphosphate production and Ca 2ϩ mobilization (21). Consistently, Grb2-or Dok-3-deficient DT40 B cells as well as grb2 Ϫ/Ϫ or dok-3 Ϫ/Ϫ primary B cells mount enhanced BCR-induced Ca 2ϩ responses (21)(22)(23)(24)(25), which is associated with augmented T cell-independent immune responses and elevated serum IgM titers in Dok-3-deficient mice (22). Hence, Dok-3 appears to adjust differential BCR signals and contribute to divergent cellular responses like proliferation and differentiation or anergy and apoptosis (16,26).…”

Role of Calcium Signaling in B Cell Activation and Biology

“…The genetic ablation of Grb2 in B cells enhances the BCR-mediated Ca 2+ release from the ER and SOCE in DT40 B cells (Stork et al 2004) and mouse B cells (Ackermann et al 2011;Jang et al 2011). The adaptor protein downstream of tyrosine kinases 3 (Dok3) is responsible for this inhibitory effect of Grb2 (Stork et al 2007).…”