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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.<\/jats:p>","DOI":"10.7554\/elife.56221","type":"journal-article","created":{"date-parts":[[2020,8,25]],"date-time":"2020-08-25T10:00:11Z","timestamp":1598349611000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.56221","source":"Crossref","is-referenced-by-count":201,"title":["Ageing compromises mouse thymus function and remodels epithelial cell differentiation"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8779-328X","authenticated-orcid":true,"given":"Jeanette","family":"Baran-Gale","sequence":"first","affiliation":[{"name":"MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0757-0711","authenticated-orcid":true,"given":"Michael D","family":"Morgan","sequence":"additional","affiliation":[{"name":"Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom"},{"name":"Cancer Research United Kingdom - 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