Yu Yan, Xuesong Wang, Zhenfei Xie, Daniel L.V. Bader, Ryan H. Lim, Krystal M. Ma, Christopher A. Cottrell, Jon M. Steichen, Liling Xu, Paula Maldonado Villavicencio, Madhav Akauliya, Ja-Hyun Koo, Jacqueline Ming Shen, Alexandra Vernich, Kalyuzhniy Oleksandr, Joel D. Allen, Ali Albowaidey, Anthony Alicea, Bingxian Chen, Erik Georgeson, Jordan Renae Ellis-Pugh, Nushin Alavi, Abigail Esposito, Hannah Naili, Nicole Phelps, Brendon Kelley, Michael Kubitz, Quynh Anh Phan, Alessia Liguori, Thavaleak Prum, Ryan Tingle, Danny Lu, Saman Eskandarzadeh, Xiao Liu, John E. Warner, Stephanie R. Weldon, Sunny Himansu, Max Crispin, Usha Nair, Sophia Liu, William R. Schief, Facundo D. Batista
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.