Extrafollicular B Cell Responses—Is One Tent Big Enough?

Initial description of extrafollicular B cell responses (EF) identified them as short-lived clusters of rapidly proliferating B cells and plasmablasts in splenic bridging channels and red pulp as well as lymph node medullary cord areas. Their physical location guided the nomenclature: outside, or at the edges of B cell follicles and near T cell zones of secondary lymphoid organs, thus distinct from the follicular situated germinal centers (GCs). Because EFs are often induced transiently and to both T-dependent and T-independent antigens, and because they generate IgM and class-switched antibodies often with no or little signs of somatic hypermutations, they were thought to be less impactful than GC-derived antibodies. However, highly protective antibodies are generated by these EFs rapidly after acute infections and their induction often correlates with pathogen clearance, while in autoimmunity EF-derived antibodies have been implicated as pathogenic drivers of disease. Moreover, subsets of memory B cells, including some CD11c+ "atypical" B cells/ABCs are generated independently of GC. Their diverse appearance and impact have initiated an ongoing debate about whether all "non-GC responses" are necessarily EF responses. The current debate is reflected also in the articles compiled for this issue of Immunological Reviews considering EF responses. Here, I briefly summarize the steps leading to B cell activation and EF and GC formation, providing context for the contributed reviews that span a breadth of topics from descriptions of non-GC responses in jawed non-mammalian vertebrates as possible orthologues of mammalian EF to the molecular and metabolic requirements and CD4 T cell helper quality of EF, tissue-specific B cell responses, and discussions on the origins and classifications of "atypical" memory B cells in mice and man.