Abstract: In response to vaccination or infection, a successful antibody response must enrich high-affinity antigen-reactive B-cells through positive selection, but eliminate autoreactive B-cells by negative selection. Reactive B-cells undergo proliferative bursts that are governed by signaling from the B-cell receptor (BCR) which binds the antigen and the CD40 signal provided by neighboring T-cells that recognize the antigen via its own MHC T cell receptor complex, when it is presented with the antigen. Both signals are a function of the BCR’s affinity to the antigen. Little is known about the mechanism by which BCR and CD40 signaling are integrated, and thus jointly determine B-cell selection and proliferation. We quantitatively evaluated the population dynamics after stimulating B-cells in vitro through their BCR and CD40 receptors. We interpreted the data with a newly developed mathematical model of the BCR and CD40 signaling pathways and their control of B-cell fate decision machineries. Our results show that while CD40 and BCR costimulation induces more NFκB activity, no such potentiation is seen at the level of population expansion. Model simulations reveal that functional antagonism may be mediated by BCR-induced caspase activity triggering apoptosis in founder cells. We investigated in silico and in vitro the temporal relationship between these antagonistic signals and found that within a limited time window CD40 signaling may effectively rescue cell death triggered by BCR signaling. The window size depends on the strength of the BCR and CD40 signals, but a longer time gap does not allow for B-cell population expansion. We thus propose a form of kinetic proofreading that governs the T-cell dependent humoral immune response.