posted on 2023-06-07, 06:35authored bySimon MitchellSimon Mitchell, Koushik Roy, Thomas A Zangle, Alexander Hoffmann
Rapid antibody production in response to invading pathogens requires the dramatic expansion of pathogen-derived antigen-specific B-lymphocyte populations. Whether B-cell population dynamics are based on stochastic competition between competing cell fates, as in the development of competence by the bacterium Bacillus subtilis, or on deterministic cell fate decisions that execute a predictable program, as during the development of the worm Caenorhabditis elegans, remains unclear. Here, we developed long term live-cell microscopy of B-cell population expansion and multi-scale mechanistic computational modeling in order to characterize the role of molecular noise in determining phenotype heterogeneity. We show that the cell lineage trees underlying B-cell population dynamics are mediated by a largely predictable decision-making process where the heterogeneity of cell fates at any given timepoint largely derives from non-genetic heterogeneity in the founder cells. This means that contrary to previous models only a minority of genetically identical founder cells contribute the majority to the population response. We computationally predict and experimentally confirm non- genetic molecular determinants that are predictive of founder cells’ proliferative capacity. While founder cell heterogeneity may arise from different exposure histories, we show that it may also be due to the gradual accumulation of small amounts of intrinsic noise during the lineage differentiation process of hematopoietic stem cells to mature B cells. Our finding of the largely deterministic nature of B-lymphocyte responses may provide opportunities for diagnostic and therapeutic development.