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.
Reviewing Editor
- Ellen A Robey, University of California, Berkeley, United States
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.
Version history
- Received: February 20, 2020
- Accepted: August 22, 2020
- Accepted Manuscript published: August 25, 2020 (version 1)
- 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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Ageing compromises mouse thymus function and remodels epithelial cell differentiation
eLife 9:e56221.
https://doi.org/10.7554/eLife.56221
Further reading
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Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.
