Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires

  1. Artem I Mikelov
  2. Evgeniia I Alekseeva
  3. Ekaterina A Komech
  4. Dmitry B Staroverov
  5. Maria A Turchaninova
  6. Mikhail Shugay
  7. Dmitriy M Chudakov
  8. Georgii A Bazykin
  9. Ivan V Zvyagin  Is a corresponding author
  1. Skolkovo Institute of Science and Technology, Russian Federation
  2. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Federation
  3. Pirogov Russian National Research Medical University, Russian Federation

Abstract

The stability and plasticity of B cell-mediated immune memory ensures the ability to respond to the repeated challenges. We have analyzed the longitudinal dynamics of immunoglobulin heavy chain repertoires from memory B cells, plasmablasts, and plasma cells from the peripheral blood of generally healthy volunteers. We reveal a high degree of clonal persistence in individual memory B cell subsets, with inter-individual convergence in memory and antibody-secreting cells (ASCs). ASC clonotypes demonstrate clonal relatedness to memory B cells, and are transient in peripheral blood. We identify two clusters of expanded clonal lineages with differing prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation and differentiation into ASCs. Negative selection contributes to both persisting and reactivated lineages, preserving the functionality and specificity of BCRs to protect against current and future pathogens.

Data availability

Sequencing data have been deposited in the ArrayExpress database (www.ebi.ac.uk/arrayexpress, acc. num. E-MTAB-11193). The code for repertoire analysis is available at https://github.com/amikelov/igh_subsets; the code for clonal lineage analysis is available at https://github.com/EvgeniiaAlekseeva/Clonal_group_analysis

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Artem I Mikelov

    Skolkovo Institute of Science and Technology, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1629-2373
  2. Evgeniia I Alekseeva

    Skolkovo Institute of Science and Technology, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  3. Ekaterina A Komech

    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  4. Dmitry B Staroverov

    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  5. Maria A Turchaninova

    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  6. Mikhail Shugay

    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7826-7942
  7. Dmitriy M Chudakov

    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0430-790X
  8. Georgii A Bazykin

    Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2334-2751
  9. Ivan V Zvyagin

    Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation
    For correspondence
    izvyagin@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1769-9116

Funding

Ministry of Science and Higher Education of the Russian Federation (075-15-2020-807)

  • Dmitriy M Chudakov

Russian Foundation for Basic Research (20-34-90153)

  • Evgeniia I Alekseeva

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

Ethics

Human subjects: Informed consent was obtained from each donor. The study was approved by the Local Ethical Committee of Pirogov Russian National Research Medical University, Moscow, Russia (abstract #190 18 Nov 2019).

Copyright

© 2022, Mikelov 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.

Metrics

  • 1,415
    views
  • 283
    downloads
  • 6
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Artem I Mikelov
  2. Evgeniia I Alekseeva
  3. Ekaterina A Komech
  4. Dmitry B Staroverov
  5. Maria A Turchaninova
  6. Mikhail Shugay
  7. Dmitriy M Chudakov
  8. Georgii A Bazykin
  9. Ivan V Zvyagin
(2022)
Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires
eLife 11:e79254.
https://doi.org/10.7554/eLife.79254

Share this article

https://doi.org/10.7554/eLife.79254

Further reading

    1. Immunology and Inflammation
    Matteo Napoli, Roland Immler ... Monika Pruenster
    Research Article

    S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions. Mechanistically, genetic deletion of S100A9 in mice caused dysregulated Ca2+ signatures in activated neutrophils resulting in reduced Ca2+ availability at the formed LFA-1/F-actin clusters with defective β2 integrin outside-in signaling during post-arrest modifications. Consequently, we observed impaired cytoskeletal rearrangement, cell polarization, and spreading, as well as cell protrusion formation in S100a9-/- compared to wildtype (WT) neutrophils, making S100a9-/- cells more susceptible to detach under flow, thereby preventing efficient neutrophil recruitment and extravasation into inflamed tissue.

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Lucia Csepregi, Kenneth Hoehn ... Sai T Reddy
    Research Article

    Diverse antibody repertoires spanning multiple lymphoid organs (i.e., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice and discovered that organ-specific antibody repertoire features (i.e., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.