Abstract
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.
Highlights
Upon antigen encounter, the responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity
High- and low-affinity B cells actively compete with each other for T cell-derived help. The nature of this help and whether T cell help is the only mechanism of pre-germinal center (GC) B cell selection, is currently unknown
B cells were cultured in the presence of purified Hen Egg Lysozyme (HEL), or HEL mutants carrying two (HEL2x) or three (HEL3x) substitutions, resulting in a 250 and 13.000 fold lower affinity for MD4 respectively[13]
Summary
The responsive B cell pool undergoes stringent selection which eliminates cells with low B cell receptor (BCR) affinity. 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. To prevent sub-optimal B cells from consuming precious nutrients and cytokines, the antigen-responsive cell pool is subject to selection for only those cells with the highest specificity[3] This process is most rigorous in the germinal center (GC), a structure which arises several days after antigen encounter[4]. How Noxa mediates pre-GC selection on a molecular level is currently unknown
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