An early decline in circulating lymphoid progenitors contributes to the age-associated reduction in ETP numbers

Abstract Age-associated thymic involution is characterized by the decreased generation and export of T cells from the thymus, which in turn, is associated with increased susceptibility to infections. Elucidating the cause of thymic involution will inform strategies to restore thymopoiesis with age. T cells develop from thymus seeding progenitors that migrate from the bone marrow (BM) to the thymus. Early T-cell progenitors (ETPs) require signals from the thymic microenvironment to undergo T-lineage commitment and differentiation. In mice, we find that there is a significant decline in thymocyte cellularity as early as 3 months of age (3MO), which is mirrored by a striking reduction in ETPs. This early thymic involution could be driven by changes in hematopoietic progenitors and/or thymic stromal cells. Using a multicongenic BM transplantation approach, we determined that the number of ETP-supportive niches does not diminish with age. However, modulating the thymic stromal compartment sustains ETP cellularity, suggesting that age-associated defects in ETP niche quality may contribute to ETP decline. Notably, the number of lymphoid progenitors in the BM and blood declines dramatically by 3MO, although their cell-intrinsic capacity to seed and differentiate in the thymus is unimpaired. Together, our findings suggest that the early decline in ETP numbers is due to both hematopoietic and stromal age-associated changes. This work was supported by P01 AG052359 from the NIH-National Institute of Aging.