IL-21 Shapes the B Cell Response in a Context-Dependent Manner

Abstract

The cytokine interleukin-21 (IL-21) is a pivotal T cell-derived signal crucial for germinal center (GC) responses, but the precise mechanisms by which IL-21 influences B cell function remain elusive. Here, we investigated the B cell-intrinsic role of IL-21 signaling by employing a novel IL-21 receptor (Il21r) conditional knock-out mouse model andex vivoculture systems and uncovered a surprising duality of IL-21 signaling in B cells. While IL-21 stimulation of naïve B cells led to Bim-dependent apoptosis, it promoted robust proliferation of pre-activated B cells, particularly class-switched IgG1+B cellsex vivo. Consistent with this, B cell-specific deletion ofIl21rled to a severe defect in IgG1 responsesin vivofollowing immunization. Intriguingly,Il21r-deleted B cells are significantly impaired in their ability to transition from a pre-GC to a GC state following immunization. AlthoughIl21r-deficiency did not affect the proportion of IgG1+B cells among GC B cells, it greatly diminished the proportion of IgG1+B cells among the plasmablast/plasma cell population. Collectively, our data suggest that IL-21 serves as a critical regulator of B cell fates, influencing B cell apoptosis and proliferation in a context-dependent manner.