Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells

Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity. [Display omitted] •Paracrine IL-21 promotes CD4+ T cell expansion, differentiation, and IL-21 production•Initial germinal center magnitude depends on Tfh numbers and IL-21•IL-21 maintains germinal center B cells irrespective of the cognate T-B synapse•IL-21 bioavailability regulates dark zone CB identity and plasma cell differentiation The formation and maintenance of germinal centers is fundamental to humoral immunity and requires interleukin 21 (IL-21). Quast et al. show that IL-21 independently regulates germinal center T and B cells and that its effects occur in paracrine, related to amount and outside the confines of the T-B synapse.