Ageing compromises mouse thymus function and remodels epithelial cell differentiation

Jeanette Baran-Gale, Michael D Morgan, Stefano Maio, Fatima Dhalla, Irene Calvo-Asensio, Mary E Deadman, Adam E Handel, Ashley Maynard, Steven Chen, Foad Green, Rene V Sit, Norma F Neff, Spyros Darmanis, Weilun Tan, Andy P May, John C Marioni, Chris P Ponting, Georg A Holländer

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article numbere56221
JournaleLIFE
Volume9
Issue number8
Early online date25 Aug 2020
DOIs
Publication statusE-pub ahead of print - 25 Aug 2020

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