T cells in thymus develop from hematopoietic stem cells (HSCs) in bone marrow (BM), but the cellular intermediates linking HSCs in BM via blood to early T lineage progenitors in thymus remain poorly defined. The long-term goal of the proposed work is to elucidate the cellular and molecular basis for early T cell development. It has recently been determined that early T lineage progenitors (ETPs) in thymus derive from a BM progenitor population distinct from previously described common lymphoid progenitors (CLPs), and that the pathways leading to T and B cells diverge earlier than had been previously appreciated. Experiments are proposed to further define and characterize the intermediate populations that lead from multipotent progenitors in BM, through a circulating progenitor cell in blood, eventually leading to ETPs and their downstream T lineage progeny within the thymus. While cytokines and Notch signals are known to be critical for early T cell development, the cellular intermediates receiving and integrating these multiple signals are largely uncharacterized. Notch signals are probably received by blood-borne hematopoietic progenitors shortly after thymic colonization, but ETP subsets within which these signals operate to result in T lineage commitment are also not characterized. Our goal is to identify a complete lineage of cells leading from HSCs in bone marrow to T lineage cells in thymus. An understanding of the key cellular intermediates in T lineage development is necessary to understand disorders in this process, and will be of basic and critical use in a wide variety of diagnostic and therapeutic endeavors. Hence understanding the T cell defects in aging, the process of malignant transformation in T lineage cells, and gene therapy to correct defects of T cell development and function all require that the steps of hematopoiesis linking HSCs to T cells be understood.
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