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.

Automated summary

Germinal centers (GCs) are transient structures within B cell follicles that require coordinated behavior of T and B cells. IL-21, a cytokine derived from T cells, plays a key role in GC biology through its independent actions on T and B cells. IL-21 promotes the expansion and differentiation of CD4(+) T cells and specifically impacts B cell centroblast identity and plasma cell differentiation within the GC. IL-21's activity is not solely dependent on T-B interactions but also on its own growth-promoting effects.