Molecular programming of B cell memory

Key Points High-affinity B cell memory emerges across three separable phases of development. Each phase involves antigen recognition by specific B cells and contact with cognate T follicular helper (T FH ) cells. Initial commitment to the memory B cell pathway occurs before germinal centre (GC) formation, following first contact with antigen-specific T FH cells (pre-GC phase). Molecular interactions at the cellular interface involve cell-associated contacts and signals from secreted molecules such as cytokines. The GC reaction supports reiterative cycles of B cell receptor (BCR) diversification, clonal expansion and class-switch recombination (GC phase) that promote the positive selection of high-affinity GC B cell variants into the memory B cell compartment. Following antigen recall, memory B cells require regulation by antigen-specific T FH cells to proliferate and differentiate into memory-response plasma cells (memory phase). Affinity maturation of the antibody response continues at this stage using mechanisms that are poorly understood. Antigen-specific T FH cells regulate each phase of development and consolidate memory B cell fate in high-affinity pre-memory and memory B cells. Beyond antigen recognition, antibody class determines immune function and antibody affinity controls the sensitivity of memory B cells. Understanding the molecular events that orchestrate the formation of high-affinity memory B cells will help to improve vaccination strategies. In this Review article, McHeyzer-Williams and colleagues discuss the cellular and molecular interactions that regulate commitment to B cell memory, the germinal centre reaction and the generation of memory plasma cells following antigen recall. The development of high-affinity B cell memory is regulated through three separable phases, each involving antigen recognition by specific B cells and cognate T helper cells. Initially, antigen-primed B cells require cognate T cell help to gain entry into the germinal centre pathway to memory. Once in the germinal centre, B cells with variant B cell receptors must access antigens and present them to germinal centre T helper cells to enter long-lived memory B cell compartments. Following antigen recall, memory B cells require T cell help to proliferate and differentiate into plasma cells. A recent surge of information — resulting from dynamic B cell imaging in vivo and the elucidation of T follicular helper cell programmes — has reshaped the conceptual landscape