Local antibody feedback enforces a checkpoint on affinity maturation in the germinal center and promotes epitope spreading

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 M Villavicencio; Madhav Akauliya; Ja-Hyun Koo; Jacqueline Ming Shen; Alexandra Vernich; Oleksandr Kalyuzhniy; Joel D Allen; Ali A 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; Xiaotie Liu; John E Warner; Stephanie R Weldon; Sunny Himansu; Max Crispin; Usha Nair; Sophia Liu; William R Schief; Facundo D Batista

doi:10.1016/j.immuni.2026.01.011

Local antibody feedback enforces a checkpoint on affinity maturation in the germinal center and promotes epitope spreading

Immunity. 2026 Mar 10;59(3):746-767.e9. doi: 10.1016/j.immuni.2026.01.011. Epub 2026 Feb 13.

Authors

Yu Yan¹, Xuesong Wang¹, Zhenfei Xie¹, Daniel L V Bader², Ryan H Lim³, Krystal M Ma⁴, Christopher A Cottrell⁴, Jon M Steichen⁴, Liling Xu¹, Paula M Villavicencio¹, Madhav Akauliya¹, Ja-Hyun Koo¹, Jacqueline Ming Shen⁵, Alexandra Vernich⁶, Oleksandr Kalyuzhniy⁴, Joel D Allen⁷, Ali A Albowaidey¹, Anthony Alicea¹, Bingxian Chen⁸, Erik Georgeson⁴, Jordan Renae Ellis-Pugh¹, Nushin Alavi⁴, Abigail Esposito¹, Hannah Naili¹, Nicole Phelps⁴, Brendon Kelley¹, Michael Kubitz⁴, Quynh Anh Phan¹, Alessia Liguori⁴, Thavaleak Prum¹, Ryan Tingle⁴, Danny Lu⁴, Saman Eskandarzadeh⁴, Xiaotie Liu¹, John E Warner¹, Stephanie R Weldon¹, Sunny Himansu⁹, Max Crispin⁷, Usha Nair¹, Sophia Liu¹⁰, William R Schief¹¹, Facundo D Batista¹²

Affiliations

¹ Batista Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Liu Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Batista Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Liu Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA.
⁷ Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK.
⁸ Batista Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA; Liu Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA.
⁹ Moderna, Cambridge, MA 02142, USA.
¹⁰ Liu Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address: sophia.liu@mgh.harvard.edu.
¹¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Moderna, Cambridge, MA 02142, USA. Electronic address: schief@scripps.edu.
¹² Batista Laboratory, Ragon Institute of Mass General Brigham, MIT, and Harvard, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: fbatista1@mgh.harvard.edu.

PMID: 41690309
DOI: 10.1016/j.immuni.2026.01.011

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.

Keywords: B cell; HIV; affinity maturation; antibody feedback; germinal center; local antibody pool; plasma cells; sequential immunization; vaccine.

MeSH terms

Animals
Antibody Affinity* / immunology
B-Lymphocytes* / immunology
Epitopes / immunology
Epitopes, B-Lymphocyte* / immunology
Feedback, Physiological
Germinal Center* / immunology
HIV Antibodies / immunology
HIV-1* / immunology
Humans
Immunoglobulin G / immunology
Mice
Mice, Inbred C57BL
Receptors, Antigen, B-Cell / immunology
Receptors, Antigen, B-Cell / metabolism

Substances

Receptors, Antigen, B-Cell
Epitopes, B-Lymphocyte
Epitopes
Immunoglobulin G
HIV Antibodies