Tonic B cell antigen receptor signals supply an NF-κB substrate for prosurvival BLyS signaling

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Abstract
Mature B cell survival requires signals from the BCR and from the BLyS receptor BR3. Michael Cancro and colleagues demonstrate crosstalk between these pathways, as BCR signals supply a substrate needed for BR3 signal transmission. The survival of transitional and mature B cells requires both the B cell antigen receptor (BCR) and BLyS receptor 3 (BR3), which suggests that these receptors send signals that are nonredundant or that engage in crosstalk with each other. Here we show that BCR signaling induced production of the nonclassical transcription factor NF-κB pathway substrate p100, which is required for transmission of BR3 signals and thus B cell survival. The capacity for sustained p100 production emerged during transitional B cell differentiation, the stage at which BCR signals begin to mediate survival rather than negative selection. Our findings identify a molecular mechanism for the reliance of primary B cells on continuous BR3 and BCR signaling, as well as for the gradual resistance to negative selection that is acquired during B cell maturation.