Synergy and antagonism in the integration of BCR and CD40 signals that control B-cell proliferation
Collaborator:
Dr. Hari Vaidehi Narayanan, Mark Xiang
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Principal Investigator: Dr. Alexander Hoffmann
2021.1 - 2025.6
Abstract: 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 NFκB. The model recapitulates NFκB 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, NFκB 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 NFκB-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.
Direct observation correlates NFκB cRel with activating and terminating the B cell proliferative program
Collaborators:
Dr. Hari Vaidehi Narayanan, Dr. Koushik Roy, Mark Xiang
​
Principal Investigator: Dr. Alexander Hoffmann
Significance: B cells must proliferate in proportion to an antigenic affinity-dependent stimulus, to selectively expand desirable genetic receptor variants. However, B cells given identical stimuli proliferate heterogeneously, due to non-genetic differences in their molecular networks. Knockout models established that NFκB cRel is essential for stimulus-driven B cell proliferation, but obscured quantitative relationships that may explain the observed variability. In this study, we developed a fluorescent reporter mTFP1-cRel mouse to directly observe natural cRel heterogeneity in B cells and correlate it to heterogeneous proliferative kinetics. We found that cRel abundance is tightly regulated by negative feedback, with high-expressors escaping this control. These high cRel cells divide faster, but fewer times. This may enable rapid early B cell responses, while leaving room for high-affinity clones to emerge later.
2021.1 - 2024.7
