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).
-
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.
Metrics
-
- 8,110
- views
-
- 1,075
- downloads
-
- 101
- 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)
Ageing compromises mouse thymus function and remodels epithelial cell differentiation
eLife 9:e56221.
https://doi.org/10.7554/eLife.56221
Further reading
-
- Immunology and Inflammation
SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as ‘sustainers’), but not in ‘decliners’. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.
-
- Chromosomes and Gene Expression
- Immunology and Inflammation
Ikaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While Ikzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.
