Local antibody feedback enforces a checkpoint on affinity maturation in the germinal center and promotes epitope spreading.
Publication/Presentation Date
3-10-2026
Abstract
Circulating antibodies from previous immune encounters impact subsequent humoral responses. Here, we investigated how local epitope-specific competition shapes ongoing germinal center (GC) responses by delivering an mRNA-LNP-encoded membrane-bound immunogen displaying three conserved HIV-1 envelope (Env) epitopes to mouse models bearing B cell receptors (BCRs) of defined affinities. High-affinity B cells exhibited shorter GC residency than lower-affinity counterparts. B cells engaged GC reactions at equivalent rates in the presence or absence of clonal lineages binding the same epitope with similar affinities; however, higher-affinity clones suppressed lower-affinity counterparts targeting the same epitope. Spatial transcriptomics revealed plasma-like cells within and adjacent to the GC, and early immunoglobulin G (IgG) was detectable in draining lymph nodes. Our findings suggest that a self-modulating local antibody feedback loop limits epitope-specific recognition-dampening selection for higher-affinity B cells and facilitating epitope spreading by redirecting the response toward alternative epitopes.
Volume
59
Issue
3
First Page
746
Last Page
767
ISSN
1097-4180
Published In/Presented At
Yan, Y., Wang, X., Xie, Z., Bader, D. L. V., Lim, R. H., Ma, K. M., Cottrell, C. A., Steichen, J. M., Xu, L., Villavicencio, P. M., Akauliya, M., Koo, J. H., Shen, J. M., Vernich, A., Kalyuzhniy, O., Allen, J. D., Albowaidey, A. A., Alicea, A., Chen, B., Georgeson, E., … Batista, F. D. (2026). Local antibody feedback enforces a checkpoint on affinity maturation in the germinal center and promotes epitope spreading. Immunity, 59(3), 746–767.e9. https://doi.org/10.1016/j.immuni.2026.01.011
Disciplines
Medicine and Health Sciences
PubMedID
41690309
Department(s)
Medical Education
Document Type
Article