Local antibody feedback enforces a checkpoint on affinity maturation in the germinal center and promotes epitope spreading
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.
Authors
- John E. Warner (ORCID: https://orcid.org/0009-0001-1043-1643)
- Zhenfei Xie (ORCID: https://orcid.org/0009-0006-9341-4721)
- Usha Nair (ORCID: https://orcid.org/0000-0002-1927-6889)
- Jon M. Steichen (ORCID: https://orcid.org/0000-0002-4586-3251)
- Sophia Liu (ORCID: https://orcid.org/0000-0003-3614-9731)
- Madhav Akauliya (ORCID: https://orcid.org/0009-0009-0325-6080)
- Jacqueline Ming Shen
- Danny Lu (ORCID: https://orcid.org/0000-0002-2340-3377)
- Ryan Tingle (ORCID: https://orcid.org/0000-0003-2874-7010)
- Michael Kubitz (ORCID: https://orcid.org/0000-0002-3917-453X)
- Ali Albowaidey
- Sunny Himansu (ORCID: https://orcid.org/0000-0002-7954-9674)
- Paula Maldonado Villavicencio (ORCID: https://orcid.org/0009-0008-2321-9669)
- Xiao Liu (ORCID: https://orcid.org/0000-0003-0588-5699)
- Saman Eskandarzadeh (ORCID: https://orcid.org/0000-0002-0671-0770)
- Alessia Liguori (ORCID: https://orcid.org/0000-0002-8606-574X)
- Stephanie R. Weldon (ORCID: https://orcid.org/0000-0001-5384-9946)
- Nicole Phelps (ORCID: https://orcid.org/0000-0001-9613-3921)
- Nushin Alavi (ORCID: https://orcid.org/0000-0003-3848-6280)
- Quynh Anh Phan (ORCID: https://orcid.org/0000-0003-2199-262X)
- Erik Georgeson (ORCID: https://orcid.org/0000-0001-5137-4625)
- Bingxian Chen
- Thavaleak Prum (ORCID: https://orcid.org/0009-0004-6973-5053)
- Kalyuzhniy Oleksandr
- Jordan Renae Ellis-Pugh
- Alexandra Vernich
- Anthony Alicea
- Hannah Naili
- Joel D. Allen
- Daniel L.V. Bader
- Facundo D. Batista
- Ja-Hyun Koo
- Brendon Kelley
- Yu Yan
- William R. Schief
- Abigail Esposito
- Christopher A. Cottrell
- Ryan H. Lim
- Max Crispin
- Krystal M. Ma
- Liling Xu
- Xuesong Wang
Institutions
- Scripps Research Institute (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Moderna Therapeutics (United States) (US)
- University of Southampton (GB)
Publication Details
- Journal
- Immunity
- Published
- 2026-02-13
- DOI
- https://doi.org/10.1016/j.immuni.2026.01.011
- Citations
- 1
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 24.43