Memory B cells (MBC) are essential mediators of immunological memory, facilitating humoral immune responses of increased magnitude and improved quality upon repeated pathogen exposure. Produced during a primary immune response, MBC can persist for the lifetime of an organism in a quiescent state. Transcriptional determinants of MBC differentiation are ill-defined, and, despite their specialist function, MBC resemble naïve B cells transcriptionally. Furthermore, the mature MBC compartment is phenotypically and functionally heterogeneous, though the extent and significance of this observation remains unclear. Numerous classification systems and functional hierarchies for murine MBC have been proposed, yet there are few unifying principals of MBC differentiation, complicated by the variety of model
systems employed in the field. I have implemented transcriptomic and epigenomic methodologies to characterise changes in gene expression and chromatin accessibility that coincide with MBC differentiation. I find, in agreement with previous observations, that murine MBC are heterogeneous. By unambiguously defining MBC by their activation history, several populations are apparent, which differ in their somatic hypermutation levels, isotype usage, surface marker expression and correspondence to subsets of naïve B cells. Different transcription factors are expressed, and inferred to be actively regulating gene expression, in different subsets of MBC. Specifically, I find a role for the Krüppel-like factor KLF2 in the generation of an MBC subset that exhibits hallmarks of germinal centre experience and affinity maturation. Deeper comprehension of transcriptional networks underlying the formation and survival of different MBC subsets will help to dissect how bona fide immunological memory is established at the cellular level.