Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; Cancer Research United Kingdom - Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
Stefano Maio
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Cancer Research, Oxford, United Kingdom
Fatima Dhalla
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Cancer Research, Oxford, United Kingdom
Department of Biomedicine, University of Basel, and University Children’s Hospital, Basel, Switzerland
Mary E Deadman
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Cancer Research, Oxford, United Kingdom
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; Cancer Research United Kingdom - Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom; EMBL-EBI, Wellcome Genome Campus, Hinxton, United Kingdom
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Department of Paediatrics, University of Oxford, Cancer Research, Oxford, United Kingdom; Department of Biomedicine, University of Basel, and University Children’s Hospital, Basel, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
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.
