Stochasticity and epigenetic heritability of B-cell fate decisions are necessary for efficient affinity maturation of the antibody repertoire

Antibody-mediated immunity relies on Darwinian evolution to produce a diverse repertoire of high-affinity antibodies. According to classical clonal selection theory, this involves generation of B-cell receptor (BCR) diversity through somatic hypermutation, followed by selection, where BCR affinity for antigen determines B cell fate decisions of survival, proliferation, or differentiation into plasma cells. However, prior studies have shown substantial stochastic variability in B-cell fate decisions that muddies the relationship to BCR affinity. It is unclear how this cell fate stochasticity impacts the effectiveness of clonal selection and affinity maturation. We developed a mathematical model to investigate how affinity maturation outcomes are affected by cell fate stochasticity among founder B-cells and their progeny. Our results show that stochasticity is indeed detrimental to a simple Darwinian process where B-cell fitness is proportional to affinity. However, when plasma cell differentiation is considered, cell fate stochasticity among founder B-cells actually increases the rate of antibody affinity maturation. That is because the stochasticity in cell fate decisions allows some high affinity cells to escape plasma cell differentiation, i.e. removal from the Darwinian process. This is enhanced by within-burst heritability of cell fates among progeny, which maximizes affinity-enhancing mutations at the highest BCR affinities. These findings underscore the importance of considering non-genetic cell fate stochasticity in antibody-mediated immunity, with implications for vaccine development.