Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell proliferation

Abstract

In response to infection or vaccination, a successful antibody response must enrich high-affinity antigen-reactive B-cells through positive selection, but eliminate auto-reactive B-cells through negative selection. B-cells receive signals from the B-cell receptor (BCR) which binds the antigen, and the CD40 receptor which is stimulated by neighboring T-cells that also recognize the antigen. How BCR and CD40 signaling are integrated quantitatively to jointly determine B-cell fate decision and proliferation remains unclear. To investigate this, we developed a differential-equations-based model of the BCR and CD40 signaling networks activating NF{kappa}B. Our model accurately recapitulates the NF{kappa}B dynamics of B-cells stimulated through their BCR and CD40 receptors, correctly predicting that costimulation induces more NF{kappa}B activity. However, when linking it to established cell fate decision models of cell survival and cell cycle control, it predicted potentiated population expansion that was not observed experimentally. We found that this discrepancy was due to a time-dependent functional antagonism exacerbated by BCR-induced caspase activity that can trigger apoptosis in founder cells, unless NF{kappa}B-induced survival gene expression protects B-cells in time. Guided by model predictions, sequential co-stimulation experiments revealed how the temporal dynamics of BCR and CD40 signaling control the fate decision between negative and positive selection of B-cell clonal expansion. Our quantitative findings highlight a complex non-monotonic integration of BCR and CD40 signals that is controlled by a balance between NF{kappa}B and cell-death pathways, and suggest a mechanism for regulating the stringency of B-cell selection during an antibody response. HighlightsO_LICD40 and BCR signaling in B-cells synergize to potentiate NF{kappa}B cRel activation C_LIO_LIBCR-apoptotic signaling may enhance or antagonize CD40-driven proliferation C_LIO_LIBCR-induced apoptosis may be rescued by CD40 within a temporal window C_LIO_LIA mathematical model reveals regulators of the dose-dependent selection stringency C_LI