Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers

  1. Carlos Castrillon  Is a corresponding author
  2. Lea Simoni
  3. Theo van den Broek
  4. Cees van der Poel
  5. Elliot H Akama-Garren
  6. Minghe Ma
  7. Michael C Carroll  Is a corresponding author
  1. Boston Children's Hospital, United States
  2. Harvard University, United States

Abstract

Affinity matured self-reactive antibodies are found in autoimmune diseases like systemic lupus erythematous. Here we used fate-mapping reporter mice and single cell transcriptomics coupled to antibody repertoire analysis to characterize the post-germinal center (GC) B cell compartment in a new mouse model of autoimmunity. Antibody secreting cells (ASCs) and memory B cells (MemBs) from spontaneous GCs grouped into multiple subclusters. ASCs matured into two terminal clusters, with distinct secretion, antibody repertoire and metabolic profiles. MemBs contained FCRL5+ and CD23+ subsets, with different in vivo localization in the spleen. GC-derived FCRL5+ MemBs share transcriptomic and repertoire properties with atypical B cells found in aging and infection and localize to the marginal zone, suggesting a similar contribution to recall responses. While transcriptomically diverse, ASC and MemB subsets maintained an underlying clonal redundancy. Therefore, self-reactive clones could escape subset-targeting therapy by perpetuation of self-reactivity in distinct subsets.

Data availability

The sequencing data presented in this study have been submitted to the Gene Expression Omnibus under accession number GSE203132(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE203132).

The following data sets were generated

Article and author information

Author details

  1. Carlos Castrillon

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    For correspondence
    castrilloncarlos@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2909-7371
  2. Lea Simoni

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Theo van den Broek

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2781-5731
  4. Cees van der Poel

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elliot H Akama-Garren

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1690-2055
  6. Minghe Ma

    Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4496-6240
  7. Michael C Carroll

    Department of Pediatrics, Harvard University, Boston, United States
    For correspondence
    michael.carroll@childrens.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3213-4295

Funding

National Institutes of Health (R01AI130307)

  • Michael C Carroll

National Institutes of Health (R01AR074105)

  • Michael C Carroll

National Institutes of Health (T32GM007753)

  • Elliot H Akama-Garren

National Institutes of Health (T32AI007529)

  • Elliot H Akama-Garren

National Institutes of Health (F30AI160909)

  • Elliot H Akama-Garren

H2020 Marie Skłodowska-Curie Actions (BEAT (No. 796988))

  • Theo van den Broek

Academy Ter Meulen Fund (TMB/16/285)

  • Theo van den Broek

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were bred and maintained in the AAALAC- accredited facility at Harvard Medical School. Mice were specific pathogen-free (SPF) and maintained under a 12 hr light/dark cycle with standard chow diet. Both male and female mice were used. All animal experiments were conducted in accordance with the guidelines of the Laboratory Animal Center of National Institutes of Health. The Institutional Animal Care and Use Committee of Harvard Medical School approved all animal protocols (protocol number IS111)

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Version history

  1. Received: June 13, 2022
  2. Preprint posted: June 23, 2022 (view preprint)
  3. Accepted: June 20, 2023
  4. Accepted Manuscript published: June 21, 2023 (version 1)
  5. Version of Record published: July 17, 2023 (version 2)

Copyright

© 2023, Castrillon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Carlos Castrillon
  2. Lea Simoni
  3. Theo van den Broek
  4. Cees van der Poel
  5. Elliot H Akama-Garren
  6. Minghe Ma
  7. Michael C Carroll
(2023)
Complex subsets but redundant clonality after B cells egress from spontaneous germinal centers
eLife 12:e81012.
https://doi.org/10.7554/eLife.81012

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