Multiple prethymic defects underlie age-related loss of T progenitor competence (81.6)

Abstract

Abstract Aging in mice and humans is characterized by declining T lymphocyte production in the thymus, yet it is unclear whether aging impacts the T lineage potential of hematopoietic progenitors. Although alterations in the lymphoid progenitor content of aged mouse bone marrow have recently been described, irradiation- reconstitution experiments have failed to reveal defects in T lineage potential of bone marrow (BM) progenitors or purified hematopoietic stem cells (HSC) from aged mice. Here, we assessed T progenitor potential in young recipient mice without conditioning irradiation. T potential was reduced in aged BM compared to young BM and this reduction was apparent at the earliest stages of intrathymic differentiation. Further, purified populations of aged HSC or multipotent progenitors (MPP) also gave rise to fewer T lineage cells than their young counterparts. Limiting dilution experiments in vitro showed that the T precursor frequency within the MPP pool was unchanged. However, there was a fourfold reduction in T precursor frequency within the aged HSC pool, indicating that there is an accumulation of T-incompetent cells in this population. Additionally, among the T-competent HSC clones, there were fewer highly proliferative clones in the aged HSC pool than in the young HSC pool. These results define the nature and cellular sites of prethymic age-related defects in T lineage differentiation potential.