The initial age‐associated decline in early T‐cell progenitors reflects fewer pre‐thymic progenitors and altered signals in the bone marrow and thymus microenvironments

Age‐related thymus involution results in decreased T‐cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)‐derived thymus seeding progenitors (TSPs) that differentiate into early T‐cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre‐thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre‐thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age‐associated thymus involution. Early T‐cell progenitor (ETP) cellularity declines as early as 3 months (3MO) of age in the murine thymus, despite maintenance of functional thymus seeding progenitor niches. The early decline in ETPs reflects a sharp drop in circulating thymus seeding progenitors and upstream bone marrow lymphoid progenitors. Notch signaling declines in bone marrow lymphoid progenitors and in thymic ETPs by 3MO of age.