Aging and T cell development: Role of the hematopoietic stem cell and downstream T progenitors in bone marrow and thymus

Production of T lymphocytes by the thymus declines with age, and is associated with declining immune function in the elderly. Despite many years of investigation, it is unknown what role hematopoietic progenitors play in the process of thymic involution. In this work, I have assessed the ability of hematopoietic progenitors in bone marrow (BM) and thymus of aged mice to produce T lineage cells. Using in vitro assays and in vivo transplant assays that do not involve host irradiation, I have found that aged hematopoietic stem cells (HSC), multipotent progenitors (MPP), and early thymocytes are all defective in their ability to give rise to T lineage progeny. These defects are specific to the T or lymphoid lineages, because myeloid cell production by aged BM progenitors is intact. In the HSC compartment, reduced T cell production can be attributed to complete loss of T potential in a portion of the aged HSC pool, and a reduced T lineage clonal burst size in the remaining cells. Defects in T cell production are intrinsic to the hematopoietic stem cell, as they persist after transplant into young hosts. Inefficient T production by aged MPP results from lower clonal burst size. Further, the age of the thymus microenvironment dictates how defects in aged BM progenitors manifest in the thymus. I conclude that aging defects within the hematopoietic progenitor compartment contribute to reduced T lymphopoiesis in aged organisms, and by extension, to functional consequences of aging in peripheral T cells. These results strengthen the hypothesis that changes within tissue stem cells are causative for age-induced inefficiency in tissue maintenance and function