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Antibody responses are a major form of defense against microbes and require terminal differentiation of B cells into plasma cells. This differentiation can occur within follicles, as B cells differentiate into germinal centers (GCs), or in extrafollicular foci. Stochastic competition and asymmetric cell division have been proposed to explain how B cells follow the follicular or extrafollicular fate. Lineage and location also appear to play a role, with marginal zone B cells and memory B cells readily forming robust extrafollicular plasma cell foci. Localization to follicles or extrafollicular sites is determined by key changes in transcription factors and receptors for chemoattractants. Extrafollicular responses develop faster than GC responses, but also are relatively short lived and of lower affinity, due to limited accumulation of somatic mutations. They provide an important early wave of protection upon infection. In the context of protein antigens, B cell differentiation along both follicular and extrafollicular routes requires priming by follicular helper T cells that produce the key cytokine IL-21. Extrafollicular antibody responses can be an important source of autoantibodies in the context of autoimmunity. Furthermore, inflammatory conditions can increase the life span of extrafollicular plasma cells in secondary lymphoid tissues enhancing their pathogenicity.

Helper T cells are required for the generation of a potent immune response to foreign antigens. Amongst them, T follicular helper (Tfh) cells are specialized in promoting protective, long-lived antibody responses that arise from germinal centers. Within these structures, the specificity of B cell receptors may change, due to the process of random somatic hypermutation aimed at increasing the overall affinity of the antibody response. The danger of emerging self-reactive specificities is offset by a stringent selection mechanism delegated in great part to Tfh cells. Only those B cells receiving survival signals from Tfh cells can exit the germinal centers to join the long-lived pools of memory B cells and bone marrow-homing plasma cells. Thus, a crucial immune tolerance checkpoint to prevent long-term autoantibody production lies in the ability to tolerize Tfh cells and to control positive and negative selection signals delivered by this subset. This review tackles the known mechanisms that ensure Tfh tolerance, many of them shared by other T helper subsets during thymic development and priming, but others unique to Tfh cells. Amongst the latter are checkpoints at the stages of Tfh differentiation, follicular migration, growth, longevity, and quality control of selection signals. Finally, we also discuss the consequences of a breakdown in Tfh tolerance.