Commitment and efficiency of extrathymic T cell precursors - towards improved T lineage reconstitution after bone marrow transplantation

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T cells develop in the thymus, but ultimately derive from Hematopoietic Stem Cells (HSC) in the bone marrow (BM). An understanding of developmental steps linking HSC to intrathymic T lineage-committed progenitors is important for understanding cancer in T lineage cells, for improving T cell reconstitution after BM transplantation, for gene therapy approaches to curing defective T cell development or function, and will also be relevant for ameliorating immunological defects in aging. Several extrathymic candidate progenitors have been described that range from pluripotent cells, to lymphoid cell committed progenitors and even largely T lineage committed precursors. However, the efficiency of the different progenitors to generate T cells under physiological conditions and signals that determine commitment to the T lineage remain largely elusive. Here we propose to study the differentiation pathways of different T lineage precursors in vivo and in vitro, both phenotypically and molecularly. The molecular analysis will focus on the signals inducing commitment to the T lineage, such as signals transmitted via the Notch pathway. In a second major aim the efficacy of thymus homing and T cell generation of different extrathymic T cell precursors will be compared. Finally, we will translate our findings to the human system. These experiments will help clarify the relative contribution of different extrathymic precursors to T cell development both under physiological and pathophysiological conditions and may thus ultimately lead to improved BM transplantation protocols.