| First Author | Huang H | Year | 2025 |
| Journal | Mol Syst Biol | Volume | 21 |
| Issue | 8 | Pages | 1119-1146 |
| PubMed ID | 40473841 | Mgi Jnum | J:383483 |
| Mgi Id | MGI:8297681 | Doi | 10.1038/s44320-025-00124-2 |
| Citation | Huang H, et al. (2025) Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell population expansion. Mol Syst Biol 21(8):1119-1146 |
| abstractText | In response to infection or vaccination, lymph nodes must select antigen-reactive B-cells while eliminating auto-reactive B-cells. 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 NFkappaB. The model recapitulates NFkappaB 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, NFkappaB 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 NFkappaB-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. |
