Pitt, C. | bioRxiv Science

bioRxiv2025

Antibody responses against bacterial glycans affinity mature and diversify in germinal centers.

Anti-carbohydrate antibodies (Abs) play crucial roles in pathogen control, but their generation remains poorly understood. By studying responses to Streptococcus pyogenes in humans, we reveal that the glycan-targeted response shifts from IgM towards IgG and IgA memory with age and antigen exposure across blood, spleen, and tonsils. Both natural colonization and controlled human infection with S. pyogenes increased class-switched B cells, with evidence of within-clone switching. Glycan-specific B cells readily participated in germinal center (GC) responses and showed robust somatic hypermutation despite a molecular signature consistent with receiving reduced T cell help. We conclude that mucosal pathogen encounters elicit glycan responses that class-switch, evolve and diversify through the GC. These findings reveal how age and infection history can influence the quality, quantity, and isotype use of glycan-specific B cells, with implications for the design and schedule of glycan-containing vaccines.

immunology↗

bioRxiv2022

IL-21 lowers the B cell receptor affinity threshold for participation in a T cell dependent immune response.

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.

immunology↗