Strength in diversity: Phenotypic, functional, and molecular heterogeneity within the memory B cell repertoire

The vast majority of vaccines exploit antibody memory to induce lasting immunity. Memory B cells are generated during the initial response to infection, but persist long after the infection has cleared. Immune memory success relies on its adaptability: in response to different pathogens, variants of a single pathogen, and in balancing persistence with reactivation and plasma cell differentiation. This is likely achieved by producing a B cell memory population that is highly diverse, and recent work has highlighted the importance of memory B cell subsets in mediating the dichotomous roles of the population. This review will detail the characterization, function and both intrinsic and extrinsic regulation of different memory B cell subsets: memory B cell precursors within the germinal center, phenotypic, and functional heterogeneity of the memory B cell population, and memory B cell subsets that reside in tissues. In particular, understanding the genetic and epigenetic regulation of memory B diversity may be critical for gaining insight into B cell memory responses to pathogens that have evaded effective vaccine design. Therefore, there is a vital need to understand the mechanisms underlying the origin, function and translational potential of the heterogeneity within the memory B cell population.