Clonal replacement sustains long-lived germinal centers primed by respiratory viruses

Renan V H de Carvalho; Jonatan Ersching; Alexandru Barbulescu; Alvaro Hobbs; Tiago B R Castro; Luka Mesin; Johanne T Jacobsen; Brooke K Phillips; Hans-Heinrich Hoffmann; Roham Parsa; Maria Cecilia C Canesso; Carla R Nowosad; Allan Feng; Sarah R Leist; Ralph S Baric; Emily Yang; P J Utz; Gabriel D Victora

doi:10.1016/j.cell.2022.11.031

Clonal replacement sustains long-lived germinal centers primed by respiratory viruses

Cell. 2023 Jan 5;186(1):131-146.e13. doi: 10.1016/j.cell.2022.11.031. Epub 2022 Dec 23.

Authors

Renan V H de Carvalho¹, Jonatan Ersching¹, Alexandru Barbulescu², Alvaro Hobbs¹, Tiago B R Castro³, Luka Mesin¹, Johanne T Jacobsen¹, Brooke K Phillips⁴, Hans-Heinrich Hoffmann⁵, Roham Parsa⁶, Maria Cecilia C Canesso³, Carla R Nowosad³, Allan Feng⁷, Sarah R Leist⁸, Ralph S Baric⁹, Emily Yang⁷, P J Utz⁷, Gabriel D Victora¹⁰

Affiliations

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; Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
⁴ Rutgers Robert Wood Johnson Medical School and Princeton University MD/PhD Program, Piscataway, NJ, USA.
⁵ Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
⁶ Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
⁷ Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
¹⁰ Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY, USA. Electronic address: victora@rockefeller.edu.

Abstract

Germinal centers (GCs) form in secondary lymphoid organs in response to infection and immunization and are the source of affinity-matured B cells. The duration of GC reactions spans a wide range, and long-lasting GCs (LLGCs) are potentially a source of highly mutated B cells. We show that rather than consisting of continuously evolving B cell clones, LLGCs elicited by influenza virus or SARS-CoV-2 infection in mice are sustained by progressive replacement of founder clones by naive-derived invader B cells that do not detectably bind viral antigens. Rare founder clones that resist replacement for long periods are enriched in clones with heavily mutated immunoglobulins, including some with very high affinity for antigen, that can be recalled by boosting. Our findings reveal underappreciated aspects of the biology of LLGCs generated by respiratory virus infection and identify clonal replacement as a potential constraint on the development of highly mutated antibodies within these structures.

Keywords: B cells; Immunology; SARS-CoV-2; clonal dynamics; germinal centers; influenza; viruses.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes* / cytology
B-Lymphocytes* / immunology
COVID-19
Clone Cells
Germinal Center* / cytology
Germinal Center* / immunology
Influenza, Human
Mice
RNA Virus Infections* / immunology
RNA Virus Infections* / pathology
RNA Virus Infections* / virology
SARS-CoV-2

Abstract

Publication types

MeSH terms

Grants and funding