IL ‐21 has a critical role in establishing germinal centers by amplifying early B cell proliferation

Abstract

The proliferation and differentiation of antigen‐specific B cells, including the generation of germinal centers (GC), are prerequisites for long‐lasting, antibody‐mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation, and competitiveness in the response, largely through determining access to T cell help. However, how T cell‐derived signals contribute to these outcomes is incompletely understood. Here, we report how the signature cytokine of follicular helper T cells, IL‐21, acts as a key regulator of the initial B cell response by accelerating cell cycle progression and the rate of cycle entry, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and correlates with elevated AKT and S6 phosphorylation. Moreover, the resultant increased proliferation can explain the IL‐21‐mediated promotion of plasma cell differentiation. Collectively, our data establish that IL‐21 acts from the outset of a T cell‐dependent immune response to increase cell cycle progression and fuel cyclic re‐entry of B cells, thereby regulating the initial GC size and early plasma cell output. image The cytokine IL‐21 is integral to protective humoral immunity. IL‐21 acts on B cells from the outset of an adaptive immune response to promote their expansion and contribution to the ensuing germinal center reaction. IL‐21 promotes early B cell expansion by increasing cell cycle speed and cyclic re‐entry. IL‐21 synergizes with BCR and CD40 to increase AKT and S6 phosphorylation. B cell responses with a wide range of initial antigen affinities are promoted by IL‐21. Increased B cell response size explains IL‐21‐mediated promotion of plasma cells.