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Rapid antibody production in response to invading pathogens requires a dramatic expansion of antigen-specific B cells followed by differentiation into plasma cells. The B cell population dynamic consists of heterogeneous responses of individual B cells. This is apparent by snapshot assays at a single-cell resolution such as flow cytometry and has led to the notion that the B cell fate decision is stochastic. Here, we perform high-throughput single-cell lineage tracking using live-cell microscopy, which reveals deterministic cell fate decision, contrary to the previously described stochastic decision. We computationally predicted and experimentally confirmed molecular determinants that are predictive of proliferative capacity. Similarly, we hypothesized that plasma cell fate decision is deterministic. Utilizing iterative systems biology approach, we discovered a new regulatory network (mutual antagonism of cRel and Blimp1) of plasma cell differentiation. The dynamics of cRel and RelA is predictive of B cell proliferation and differentiation. If the plasma cell fate decision is deterministic similarly to B cell proliferation, then B cell mediates immune response is predictable. Thus, this may be amenable to diagnostic and therapeutic development than previously thought. |