Abstract
B-cells are the poster child for cellular diversity and heterogeneity. The diverse repertoire of B lymphocytes, each expressing unique antigen receptors, provides broad protection against pathogens. However, B-cell diversity goes beyond unique antigen receptors. Side-stepping B-cell receptor (BCR) diversity through BCR-independent stimuli or engineered organisms with monoclonal BCRs still results in seemingly identical B-cells reaching a wide variety of fates in response to the same challenge. Identifying to what extent the molecular state of a B-cell determines its fate is key to gaining a predictive understanding of B-cells and consequently the ability to control them with targeted therapies. Signals received by B-cells through transmembrane receptors converge on intracellular molecular signaling networks, which control whether each B-cell divides, dies, or differentiates into a number of antibody-secreting distinct B-cell subtypes. The signaling networks that interpret these signals are well known to be susceptible to molecular variability and noise, providing a potential source of diversity in cell fate decisions. Iterative mathematical modeling and experimental studies have provided quantitative insight into how B-cells achieve distinct fates in response to pathogenic stimuli. Here, we review how systems biology modeling of B-cells, and the molecular signaling networks controlling their fates, is revealing the key determinants of cell-to-cell variability in B-cell destiny.
Highlights
Following antigen exposure, B-cells are activated, often with the help of T-cells, to secrete antibodies essential for resolving infections
Subsequent kinetic modeling found that interactions between Irf4, Bcl6, and Blimp1 were sufficient to capture a broad variety of B-cell differentiation dynamics (Martínez et al, 2012). These results show that cell-to-cell differences in terminal differentiation of B-cells result from differences in Interferon Regulatory Factor 4 (IRF4) signaling
Mitchell et al (2018) used this model to determine the source of cell-to-cell variability using singlecell lineage tracking experiments and discovered that B-cell fates were determined by molecular differences in the naïve B-cell population that are reliably inherited during proliferation
Summary
B-cells are activated, often with the help of T-cells, to secrete antibodies essential for resolving infections. An inherited molecular source of cell-to-cell variability is consistent with results from lineage-tracking of division times across multiple generations in proliferating B lymphocytes (Duffy et al, 2012; Mitchell et al, 2018).
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