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.
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.
| Original language | English |
|---|---|
| Article number | e56221 |
| Number of pages | 27 |
| Journal | eLife |
| Volume | 9 |
| Early online date | 25 Aug 2020 |
| DOIs | |
| Publication status | Published - Aug 2020 |
Bibliographical note
e gratefully acknowledge the Chan Zuckerberg Biohub for support and for sequencing, and members of the Tabula Muris Consortium for technical assistance. CPP is funded by the MRC (MC_UU_00007/15). CPP, GH, JB and MDM were supported by the Wellcome Trust (grant 105045/Z/14/Z). JCM was supported by core funding from the European Molecular Biology Laboratory andfrom Cancer Research UK (award number 17197). GH and ICA was supported by the Swiss National Science Foundation (grant numbers IZLJZ3_171050 and 310030_184672). AEH was supported by a Clinical Lectureship from the NIHR. FD was supported by the Wellcome Trust [109032/Z/15/Z].