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

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. [Display omitted] •IKK1 loss creates a bottleneck, but not an impasse, in transitional B cell maturation•Acute BAFF-dependent survival of mature B cells is IKK1 independent•Coinactivation of Cd19 and Ikk1 prevents the generation of mature B cells•Activation of the PI3K pathway partially rescues B cell defects in Baff−/− mice BAFF is an essential survival factor for B cell homeostasis. BAFF-R signaling is thought to depend mainly on the IKK1-dependent noncanonical NF-κB pathway. Rickert and colleagues now show that although this pathway is important for the transitional stage of B cell development, it is not required for the acute survival of mature recirculating B cells responding to BAFF. They also provide evidence that activation of the phosphatidylinositol 3-kinase pathway is likely of key importance for BAFF-R function.