What Will B Will B: Identifying Molecular Determinants of Diverse B-Cell Fate Decisions Through Systems Biology

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.