The multilayered identity of B cell memory

The distinctive feature of the adaptive immune system is its ability to generate immunological memory that can provide defense against subsequent infections. In the case of antibody-mediated immune responses, this memory comes in two cellular forms: plasma cells (PCs) and memory B cells (MBCs). PCs protect against reinfection by constitutively producing antibodies. The presence of a diverse pool of MBCs, which can expand and differentiate into PCs in secondary immune responses, is thought to be particularly important for defense against new pathogen variants. Recent studies have shown that the MBC compartment is far more heterogeneous than previously anticipated. This heterogeneity, among other factors, is shaped by their developmental pathway (germinal center (GC) vs non-GC-derived MBCs), the duration and strength of antigenic stimulation, anatomical and microanatomical localization, and the timing of generation in ontogeny. Combinations of these "layers" of MBC identities can define MBCs' properties and their fate in recall responses. Here, we review the mechanisms underlying MBC differentiation, maintenance, and reactivation and explore how the layered identity of MBCs contributes to the functions of these cells.