Identification of Thymus Settling Progenitors.

T cells develop in the thymus, but are ultimately derived from hematopoietic stem cells (HSCs) that reside in the bone marrow. In order to produce T cells throughout adult life, the thymus must be periodically seeded by bone marrow progenitors via the blood. The identity of progenitors that seed the adult thymus is unknown. To determine which bone marrow progenitors that have access to they thymus, we analyzed the blood of adult mice (Schwarz & Bhandoola, Nature Immunology 2004). We found that the only progenitors in blood with T lineage potential were lineage negative cells with high expression of Sca-1 and c-Kit (LSK). Such LSK cells in blood were potent T lineage progenitors, with the capacity to expand over a million fold in the thymus. Like the corresponding population in the bone marrow, the blood LSK population was heterogeneous, containing HSCs and downstream multipotent progenitors (MPPs) including RAG-expressing early lymphoid progenitors (ELPs) and CD62L+ cells. In order to determine which of these LSK subsets can settle in the thymus, we developed a quantitative assay for thymic seeding in normal adult mice. We find that the fraction of LSK cells that settle in the thymus from the blood is extremely small. Of the estimated 3,000 to 4,000 LSK cells that pass through the thymic circulation each day, less than 10 cells are able to settle in the thymus. Our data suggest that any decrease in thymic seeding, as may occur in aging, would lead to a decrease in total thymic output.