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Abstract

High-affinity antibodies are a key component of protective immunity conferred by vaccines. They are developed through a process termed affinity maturation, relying on the natural selection of B cells with the strongest antigen-binding capacities within specialized structures called germinal centers. However, B cells can also undergo an alternative fate upon antigen encounter, differentiating into short-lived antibody-secreting cells called plasmablasts. These cells produce low-affinity antibodies and wane within a few days, representing an undesirable outcome for vaccination. Despite its significant impact on vaccine efficacy, the precise factors governing the early B cell fate decisions remain incompletely understood.

This study unveils the critical role of activation strength in dictating B cell fate choices through in vitro and mathematical modeling of B cell activation and flow cytometric and scRNA-seq analysis of B cells responding to vaccination in vivo. I demonstrate that a range of factors contributing to heightened activation, including high antigen valency, strong B-cell receptor (BCR) affinity, the absence of suppressive antibody feedback, or presence of robust non-BCR stimulation, all promote preferential recruitment of B cells into the plasmablast compartment.

These findings extend the existing view that high BCR affinity is the main factor directing B cells towards the plasmablast fate. This work paves the way for novel vaccine strategies that optimize affinity maturation and generate long-lasting, high-affinity antibody responses.