Ageing compromises mouse thymus function and remodels epithelial cell differentiation

  1. Jeanette Baran-Gale
  2. Michael D Morgan
  3. Stefano Maio
  4. Fatima Dhalla
  5. Irene Calvo-Asensio
  6. Mary E Deadman
  7. Adam E Handel
  8. Ashley Maynard
  9. Steven Chen
  10. Foad Green
  11. Rene V Sit
  12. Norma F Neff
  13. Spyros Darmanis
  14. Weilun Tan
  15. Andy P May
  16. John C Marioni
  17. Chris P Ponting  Is a corresponding author
  18. Georg A Holländer  Is a corresponding author
  1. University of Edinburgh, United Kingdom
  2. Wellcome Sanger Institute, United Kingdom
  3. University of Oxford, United Kingdom
  4. University of Basel, and University Children's Hospital, Switzerland
  5. Chan Zuckerberg Biohub, United States
  6. Wellcome Trust Sanger Institute, United Kingdom

Abstract

Ageing is characterised by cellular senescence, leading to imbalanced tissue maintenance, cell death and compromised organ function. This is first observed in the thymus, the primary lymphoid organ that generates and selects T cells. However, the molecular and cellular mechanisms underpinning these ageing processes remain unclear. Here, we show that mouse ageing leads to less efficient T cell selection, decreased self-antigen representation and increased T cell receptor repertoire diversity. Using a combination of single-cell RNA-seq and lineage-tracing, we find that progenitor cells are the principal targets of ageing, whereas the function of individual mature thymic epithelial cells is compromised only modestly. Specifically, an early-life precursor cell population, retained in the mouse cortex postnatally, is virtually extinguished at puberty. Concomitantly, a medullary precursor cell quiesces, thereby impairing maintenance of the medullary epithelium. Thus, ageing disrupts thymic progenitor differentiation and impairs the core immunological functions of the thymus.

Data availability

Sequencing data have been deposited at ArrayExpress with accession numbers E-MTAB-8560 (ageing thymus) and E-MTAB-8737 (lineage traced thymus) or from SRA with accession number PRJNA551022 (TCR sequencing data).

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

Article and author information

Author details

  1. Jeanette Baran-Gale

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
  2. Michael D Morgan

    Wellcome Sanger Institute, Wellcome Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0757-0711
  3. Stefano Maio

    Department of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  4. Fatima Dhalla

    Department of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  5. Irene Calvo-Asensio

    Department of Biomedicine, University of Basel, and University Children's Hospital, Basel, Switzerland
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9356-6008
  6. Mary E Deadman

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
  7. Adam E Handel

    Department of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8385-6346
  8. Ashley Maynard

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Steven Chen

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  10. Foad Green

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  11. Rene V Sit

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  12. Norma F Neff

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  13. Spyros Darmanis

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  14. Weilun Tan

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  15. Andy P May

    Chan Zuckerberg Biohub, San Francisco, United States
    Competing interests
    No competing interests declared.
  16. John C Marioni

    Wellcome Trust Sanger Institute, Hinxton, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9092-0852
  17. Chris P Ponting

    MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Chris.Ponting@igmm.ed.ac.uk
    Competing interests
    Chris P Ponting, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0202-7816
  18. Georg A Holländer

    Department of Paediatrics and the Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
    For correspondence
    georg.hollander@paediatrics.ox.ac.uk
    Competing interests
    No competing interests declared.

Funding

Medical Research Council (MC_UU_00007/15)

  • Chris P Ponting

Wellcome (105045/Z/14/Z)

  • Jeanette Baran-Gale
  • Michael D Morgan
  • Georg A Holländer

Wellcome (109032/Z/15/Z)

  • Fatima Dhalla

Swiss National Science Foundation (IZLJZ3_171050)

  • Irene Calvo-Asensio
  • Georg A Holländer

Swiss National Science Foundation (310030_184672)

  • Irene Calvo-Asensio
  • Georg A Holländer

Chan Zuckerberg Biohub

  • Ashley Maynard
  • Steven Chen
  • Foad Green
  • Rene V Sit
  • Norma F Neff
  • Spyros Darmanis
  • Weilun Tan
  • Andy P May

European Molecular Biology Laboratory (17197)

  • John C Marioni

NIHR

  • Adam E Handel

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 maintained under specific pathogen-free conditions and experiments were approved by the University of Oxford Clinical Medicine Ethical Review Committee and licensed under the Animals Scientific Procedures Act of the UK Home Office or Swiss cantonal and federal regulations and permissions (Permit *2321), depending where the mice were housed.

Reviewing Editor

  1. Ellen A Robey, University of California, Berkeley, United States

Publication history

  1. Received: February 20, 2020
  2. Accepted: August 22, 2020
  3. Accepted Manuscript published: August 25, 2020 (version 1)
  4. Version of Record published: September 14, 2020 (version 2)

Copyright

© 2020, Baran-Gale 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

  • 6,377
    Page views
  • 898
    Downloads
  • 50
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

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. Jeanette Baran-Gale
  2. Michael D Morgan
  3. Stefano Maio
  4. Fatima Dhalla
  5. Irene Calvo-Asensio
  6. Mary E Deadman
  7. Adam E Handel
  8. Ashley Maynard
  9. Steven Chen
  10. Foad Green
  11. Rene V Sit
  12. Norma F Neff
  13. Spyros Darmanis
  14. Weilun Tan
  15. Andy P May
  16. John C Marioni
  17. Chris P Ponting
  18. Georg A Holländer
(2020)
Ageing compromises mouse thymus function and remodels epithelial cell differentiation
eLife 9:e56221.
https://doi.org/10.7554/eLife.56221

Further reading

    1. Immunology and Inflammation
    Sindhu Mohandas, Prasanna Jagannathan ... RECOVER Mechanistic Pathways Task Force
    Review Article

    With a global tally of more than 500 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections to date, there are growing concerns about the post-acute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Recent studies suggest that exaggerated immune responses are key determinants of the severity and outcomes of the initial SARS-CoV-2 infection as well as subsequent PASC. The complexity of the innate and adaptive immune responses in the acute and post-acute period requires in-depth mechanistic analyses to identify specific molecular signals as well as specific immune cell populations which promote PASC pathogenesis. In this review, we examine the current literature on mechanisms of immune dysregulation in severe COVID-19 and the limited emerging data on the immunopathology of PASC. While the acute and post-acute phases may share some parallel mechanisms of immunopathology, it is likely that PASC immunopathology is quite distinct and heterogeneous, thus requiring large-scale longitudinal analyses in patients with and without PASC after an acute SARS-CoV-2 infection. By outlining the knowledge gaps in the immunopathology of PASC, we hope to provide avenues for novel research directions that will ultimately lead to precision therapies which restore healthy immune function in PASC patients.

    1. Computational and Systems Biology
    2. Immunology and Inflammation
    Magdalena L Russell, Noah Simon ... Frederick A Matsen IV
    Research Article

    To appropriately defend against a wide array of pathogens, humans somatically generate highly diverse repertoires of B cell and T cell receptors (BCRs and TCRs) through a random process called V(D)J recombination. Receptor diversity is achieved during this process through both the combinatorial assembly of V(D)J-genes and the junctional deletion and insertion of nucleotides. While the Artemis protein is often regarded as the main nuclease involved in V(D)J recombination, the exact mechanism of nucleotide trimming is not understood. Using a previously published TCRβ repertoire sequencing data set, we have designed a flexible probabilistic model of nucleotide trimming that allows us to explore various mechanistically interpretable sequence-level features. We show that local sequence context, length, and GC nucleotide content in both directions of the wider sequence, together, can most accurately predict the trimming probabilities of a given V-gene sequence. Because GC nucleotide content is predictive of sequence-breathing, this model provides quantitative statistical evidence regarding the extent to which double-stranded DNA may need to be able to breathe for trimming to occur. We also see evidence of a sequence motif that appears to get preferentially trimmed, independent of GC-content-related effects. Further, we find that the inferred coefficients from this model provide accurate prediction for V- and J-gene sequences from other adaptive immune receptor loci. These results refine our understanding of how the Artemis nuclease may function to trim nucleotides during V(D)J recombination and provide another step toward understanding how V(D)J recombination generates diverse receptors and supports a powerful, unique immune response in healthy humans.