Antigen affinity controls pre germinal centser B cell selection by promoting Mcl 1 induction through BAFF receptor signaling
Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. Already before formation of the germinal center, activated B cells of low affinity are negatively selected in a process that is molecularly not well understood. In this study, we investigated the mechanism behind pre GC affinity mediated B cell selection. We applied affinity mutants of HEL antigen and found that rapidly after activation B cells become highly dependent on the cytokine BAFF. Moreover, expression of BAFF receptor CD268 is regulated in a BCR affinity dependent fashion. High affinity responses via BAFF correlated with PI3K activation, which controlled expression of the pro survival protein Mcl 1, and thereby increased survival. In the presence of excess BAFF, or in absence of the Mcl 1 antagonist Noxa, more low affinity B cells survived the first two days after antigen encounter. This resulted in increased numbers of antigen specific B cells of low affinity upon immunization and reduced the overall affinity of cells that contributed to the germinal center reaction. Our findings elucidate a crucial molecular pathway of B cell selection in the earliest phases of activation by identifying a novel link between BCR affinity and BAFF R signaling towards Mcl 1.
Scientific reports