1. Immunology and Inflammation
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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
Research Article
  • Cited 16
  • Views 3,126
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Cite this article as: eLife 2020;9:e56221 doi: 10.7554/eLife.56221

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.

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