Canonical NF-κB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation

The maintenance of mature B cells hinges on signals emitted from the BAFF-R cell-surface receptor, but the nature of these signals is incompletely understood. Inhibition of canonical NF-kappa B transcription factor activity through ablation of the essential scaffold protein NEW arrests B cell development at the same stage as BAFF-R deficiency. Correspondingly, activation of this pathway by constitutively active I kappa B Kinase2 renders B cell survival independent of BAFF-R:BAFF interactions and prevents proapoptotic PKC8 nuclear translocation. In addition, canonical NF-kappa B activity mediates differentiation and proper localization of follicular and marginal zone B cells in the absence of BAFF-R, but not CD19. By replacing BAFF-R signals, constitutive canonical NF-kappa B signaling, a hallmark of various B cell lymphomas, causes accumulation of resting B cells and promotes their proliferation and survival upon activation, but does not per se induce lymphomagenesis. Therefore, canonical NF-kappa B activity can substitute for BAFF-R signals in B cell development and pathogenesis.