A Pathway Switch Directs BAFF Signaling to Distinct NFκB Transcription Factors in Maturing and Proliferating B Cells

BAFF, an activator of the noncanonical NF kappa B pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NF kappa B family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB: p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric I kappa Bsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of I kappa Bsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NF kappa B network states during B cell biology, which causes BAFF to have context-dependent functional consequences.