Antibody feedback establishes an affinity brake in the germinal center

Abstract

Recent advances in mRNA vaccine technology have opened the door to novel types of antigen display, but little is yet known as to how B cells recognize and respond to these formats. By delivering an mRNA-LNP encoded membrane-bound immunogen displaying three conserved HIV-1 Envelope (Env) epitopes to knock-in mouse models with B cell receptors (BCRs) of defined affinities, we investigated how epitope-specific competition shapes germinal center (GC) responses. Co-activation of B cells targeting different epitopes did not alter GC kinetics observed in individual activations, but a striking inverse correlation was observed between BCR affinity and GC residence time in either scenario: high-affinity B cells exhibited shorter persistence in GCs, while those with lower affinity to the antigen were maintained. Furthermore, B cells were able to engage in GC reactions at equivalent rates in the presence or absence of clonal lineages binding the same epitope with similar affinities, while higher-affinity clones suppressed lower-affinity counterparts targeting the same epitope. Spatial transcriptomics revealed plasma-like cells within and adjacent to the GC which, together with the detection of early IgG in draining lymph nodes, suggests that local antibody production from these cells may contribute to feedback-driven kinetics. These findings indicate that a self-modulated local antibody feedback loop may act as a "brake" on epitope-specific recognition--dampening further affinity enhancement for high-affinity B cells and facilitating epitope spreading by redirecting the response toward alternative epitopes.