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Affinity gaps among B cells in germinal centers drive the selection of MPER precursors.
Ray, Rashmi; Schiffner, Torben; Wang, Xuesong; Yan, Yu; Rantalainen, Kimmo; Lee, Chang-Chun David; Parikh, Shivang; Reyes, Raphael A; Dale, Gordon A; Lin, Ying-Cing; Pecetta, Simone; Giguere, Sophie; Swanson, Olivia; Kratochvil, Sven; Melzi, Eleonora; Phung, Ivy; Madungwe, Lisa; Kalyuzhniy, Oleksandr; Warner, John; Weldon, Stephanie R; Tingle, Ryan; Lamperti, Edward; Kirsch, Kathrin H; Phelps, Nicole; Georgeson, Erik; Adachi, Yumiko; Kubitz, Michael; Nair, Usha; Crotty, Shane; Wilson, Ian A; Schief, William R; Batista, Facundo D.
Affiliation
  • Ray R; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Schiffner T; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  • Wang X; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
  • Yan Y; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
  • Rantalainen K; Institute for Drug Discovery, Leipzig University Medical Faculty, Leipzig, Germany.
  • Lee CD; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Parikh S; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Reyes RA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  • Dale GA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
  • Lin YC; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
  • Pecetta S; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
  • Giguere S; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
  • Swanson O; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • Kratochvil S; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Melzi E; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Phung I; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Madungwe L; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Kalyuzhniy O; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Warner J; Moderna, Inc., Cambridge, MA, USA.
  • Weldon SR; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Tingle R; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  • Lamperti E; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
  • Kirsch KH; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
  • Phelps N; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Georgeson E; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Adachi Y; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
  • Kubitz M; Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA, USA.
  • Nair U; Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Crotty S; The Ragon Institute of Mass General, MIT and Harvard, Cambridge, MA, USA.
  • Wilson IA; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  • Schief WR; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.
  • Batista FD; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, USA.
Nat Immunol ; 25(6): 1083-1096, 2024 Jun.
Article in En | MEDLINE | ID: mdl-38816616
ABSTRACT
Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.
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Full text: 1 Database: MEDLINE Main subject: B-Lymphocytes / HIV Antibodies / HIV-1 / Germinal Center / Antibody Affinity Limits: Animals / Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2024 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: B-Lymphocytes / HIV Antibodies / HIV-1 / Germinal Center / Antibody Affinity Limits: Animals / Humans Language: En Journal: Nat Immunol Journal subject: ALERGIA E IMUNOLOGIA Year: 2024 Type: Article Affiliation country: United States