Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways

• DOI: 10.1016/j.celrep.2013.10.022
• Publication Date: 2013-11-14T16:45:18Z
• Authors: Julia Jellusova; Ana V. Miletic; Matthew H. Cato; Wai-Wai Lin; Yinling Hu; Gail A. Bishop; Mark J. Shlomchik; Robert C. Rickert
• Keywords: Mice, Knockout; 0301 basic medicine; B-Lymphocytes; Lymphoma, B-Cell; TNF Receptor-Associated Factor 3; QH301-705.5; Cell Survival; Lymphopoiesis; Antigens, CD19; PTEN Phosphohydrolase; Lymphocyte Activation; I-kappa B Kinase; Enzyme Activation; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; NF-kappa B p52 Subunit; B-Cell Activating Factor; Animals; Biology (General); Cells, Cultured; B-Cell Activation Factor Receptor; Cell Proliferation; Signal Transduction

BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff(-/-) animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.