IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

TLDR

During T cell–dependent responses, B cells either become short‑lived plasma cells or enter follicles to form germinal centers, a process that requires T follicular helper cell interactions and is influenced by interleukin‑21, which has been implicated in Tfh development and B‑cell growth, survival, and isotype switching. The study aimed to determine whether IL‑21’s effect on germinal center formation is primarily mediated through direct action on Tfh cells or directly on GC B cells. IL‑21 signals directly in GC B cells, where IL‑21R is essential for Bcl‑6 expression and maximal GC B‑cell formation, and its absence impairs affinity maturation and reduces IgG1+ GC B cells while leaving early memory B cells and extrafollicular IgG2a responses intact.

Abstract

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.