Thymocytopoiesis in aging: The bone marrow-thymus axis

Manifestations of aging in the mature T lymphocyte compartment have been attributed. to a major extent, to effects of the involuted thymus, at the thymic microenvironment level. However, since generation of T lymphocytes starts from hemopoietic stem cells that settle in the thymus and differentiate there, aging effects on the stem cells, and as a consequence, on the bone marrow (BM)-thymus axis, may also have an impact on patterns of thymocytopoiesis and on age-related thymus remodeling. This communication reviews our studies designed to determine whether BM cells manifest any aging effects that become overt in the resulting thymocytes. The experiments were performed by seeding of BM cells onto lymphoid-depleted fetal thymus (FT) explants, to enable distinguishing between processes that occur in the BM and those that are caused by the aging thymic microenvironment. The data show changes in the developmental potential of BM-derived cells, as reflected from the kinetics of cell cycle and intermediate steps from stem cell settling in the thymus to an early stage at the transition from CD4^-CD8^-, double negative (DN), to CD4⁺CD8⁺, double positive (DP) thymocytes. In addition, we have demonstrated that these early developmental steps of thymocytopoiesis are subject to feedback regulation by mature T cells, and the extent of regulation may be altered in old age. The pattern of T lymphocyte generation in aging is thus a result of dynamic changes in thymic, as well as extrathymic functions, along the sequential developmental steps from the stem cell to the ultimate mature cell.