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B-cells are instructed via B-cell receptor (BCR), which binds antigen, and CD40 receptor by antigen-recognizing T-cells. How BCR and CD40 signaling are integrated quantitatively to jointly determine B-cell fate decisions remains unclear. Here, we developed a differential-equations-based model of BCR and CD40 signaling networks activating NF\u03baB. The model recapitulates NF\u03baB dynamics upon BCR and CD40 stimulation, and when linked to established cell decision models of cell cycle and survival control, the resulting cell population dynamics. However, upon costimulation, NF\u03baB dynamics were correctly predicted but the predicted potentiated population expansion was not observed experimentally. We found that this discrepancy was due to BCR-induced caspase activity that may trigger apoptosis in founder cells, unless timely NF\u03baB-induced survival gene expression protects them. Iterative model predictions and sequential co-stimulation experiments revealed how complex non-monotonic integration of BCR and CD40 signals controls positive and negative selection of B-cells. Our work suggests a temporal proof-reading mechanism for regulating the stringency of B-cell selection during antibody responses.<\/jats:p>","DOI":"10.1038\/s44320-025-00124-2","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T05:19:17Z","timestamp":1749100757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion"],"prefix":"10.1038","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6308-346X","authenticated-orcid":false,"given":"Helen","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haripriya","family":"Vaidehi Narayanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Yankai","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhava","family":"Kesarwani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5607-3845","authenticated-orcid":false,"given":"Alexander","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"124_CR1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.it.2013.11.001","volume":"35","author":"A Aguzzi","year":"2014","unstructured":"Aguzzi A, Kranich J, Krautler NJ (2014) Follicular dendritic cells: origin, phenotype, and function in health and disease. 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