NK-Lineage Cells Circulating Hematopoietic Progenitors to T-Differentiation Potentials of Human Age-Associated Changes in the Brink and Yoichiro Kusunoki

Age-associated changes of T and NK cell (T/NK) potential of human hematopoietic stem cells are unknown. In this study, we enumerate and characterize T/NK precursors among CD34 + Lin 2 cell populations circulating in normal human adult peripheral blood (PB) by a limiting-dilution assay using coculture with OP9-DL1 stroma cells expressing Notch 1 ligand, Delta–like 1. The frequency of T cell precursors in CD34 + Lin 2 cells was found to decrease with donor age, whereas the ratio of NK to T cell precursor frequency (NK/T ratio) increased with age, suggesting that lymphoid differentiation potential of PB progenitors shifts from T to NK cell lineage with aging. Clonal analyses of CD34 + Lin 2 cells showed that differences in the NK/T ratio were attributable to different distributions of single-and dual-lineage T/NK precursor clones. Because nearly all of the clones retained monocyte and/or granulocyte differentiation potentials in coculture with OP9-DL1 cells, T/NK precursors in PB are considered to be contained in the pool of T/NK/myeloid multipotent progenitors. The age-associated increase in NK over T cell commitment might occur in precursor cells with T/NK/myeloid potential. O ne of the most characteristic features of immunological aging is the decline of T cell production associated with thymic involution. Consequently, the peripheral naive T cell pool gradually reduces in size during aging. The main causes of age-associated thymic dysfunction are thought to involve impairments in both hematopoietic stem cells (HSCs) and thymic microenvironment (1–3). Studies in mice have shown the age-related loss of T cell potential in both prethymic and intra-thymic progenitors (4, 5), and a recent report suggested that human HSCs exhibited myeloid-biased differentiation potentials with aging (6). Furthermore, a recent paper reported that T cell potential was lower in human adult bone marrow (BM) than cord blood (CB), suggesting high T cell potential in human neonate HSCs (7). However, precise age-associated changes in the T cell potential of human adult HSCs and downstream progenitors have not been well characterized. In contrast with age-associated decline in T cell development, both the proportion and absolute number of NK cells in the periphery have been reported to increase with age (8–10). These findings suggest that aging has either no effect or a positive effect on NK-lineage differentiation, which could lead to the observed increase in peripheral NK cells. The T/NK-lineage differentiation pathway is well defined, and it is widely accepted that both T and NK cells …