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Cell. 2020 Jan 9;180(1):92-106.e11. doi: 10.1016/j.cell.2019.11.032. Epub 2019 Dec 19.

Restricted Clonality and Limited Germinal Center Reentry Characterize Memory B Cell Reactivation by Boosting.

Author information

1
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA.
2
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
3
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA; Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
4
Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Venice, Italy; European Centre for Living Technology (ECLT), Venice, Italy.
5
Laboratory for Tissue Dynamics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, Japan.
6
Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
7
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. Electronic address: victora@rockefeller.edu.

Abstract

Repeated exposure to pathogens or their antigens triggers anamnestic antibody responses that are higher in magnitude and affinity than the primary response. These involve reengagement of memory B cell (MBC) clones, the diversity and specificity of which determine the breadth and effectiveness of the ensuing antibody response. Using prime-boost models in mice, we find that secondary responses are characterized by a clonality bottleneck that restricts the engagement of the large diversity of MBC clones generated by priming. Rediversification of mutated MBCs is infrequent within secondary germinal centers (GCs), which instead consist predominantly of B cells without prior GC experience or detectable clonal expansion. Few MBC clones, generally derived from higher-affinity germline precursors, account for the majority of secondary antibody responses, while most primary-derived clonal diversity is not reengaged detectably by boosting. Understanding how to counter this bottleneck may improve our ability to elicit antibodies to non-immunodominant epitopes by vaccination.

KEYWORDS:

affinity maturation; antibody response; clonal dynamics; germinal center memory B cell; immunological memory; influenza A virus; memory reactivation

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