Ageing compromises mouse thymus function and remodels epithelial cell differentiation
- University of Edinburgh, United Kingdom
- Wellcome Sanger Institute, United Kingdom
- University of Oxford, United Kingdom
- University of Basel, and University Children's Hospital, Switzerland
- Chan Zuckerberg Biohub, United States
- 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).
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Large-scale single cell mapping of the thymic stroma identifies a new thymic epithelial cell lineageNCBI Gene Expression Omnibus, GSE103970.
Article and author information
Author details
Irene Calvo-Asensio
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.
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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Ageing compromises mouse thymus function and remodels epithelial cell differentiation
eLife 9:e56221.
https://doi.org/10.7554/eLife.56221
