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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 19; pp. 7926 - 7931
• Main Authors: Jang, Ihn Kyung, Cronshaw, Darran G., Xie, Luo-Kun, Fang, Guoqiang, Zhang, Jinping, Oh, Hyunju, Fu, Yang-Xin, Gu, Hua, Zou, Yongrui, Rajewsky, Klaus
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 10.05.2011
• Subjects: Antibodies; Antigens; B lymphocytes; Chimeras; Follicles; Lymph nodes; Lymphoid tissue; Mice; Physiological regulation; Spleen
• ISSN: 0027-8424; 1091-6490

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.