title: 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.
authors.affiliation: Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA.
authors.forename: Ihn Kyung
authors.initials: IK
authors.lastname: Jang
authors.forename: Darran G
authors.initials: DG
authors.lastname: Cronshaw
authors.forename: Luo-kun
authors.initials: LK
authors.lastname: Xie
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Fang
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhang
authors.forename: Hyunju
authors.initials: H
authors.lastname: Oh
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
authors.forename: Yongrui
authors.initials: Y
authors.lastname: Zou
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation; D054382:Chemokine CXCL13 / Q000276:immunology; D051380:GRB2 Adaptor Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D053308:Lymphotoxin-beta / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054380:Receptors, CXCR5 / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: C513179:CXCR5 protein, mouse; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C505887:Ltb protein, mouse; D053308:Lymphotoxin-beta; D054380:Receptors, CXCR5; D023201:CD40 Ligand