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

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, high-affinity 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 activating AKT and S6, IL-21 accelerates cell cycle progression and the rate of cycle entry of B cells, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and 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. SummaryThe cytokine IL-21 is a regulator of B cell responses, increasing antibody quantity and quality. Here, we report that during germinal center initiation, IL-21 acts to increase the response magnitude by accelerating cell cycle speed and rate of entry.