This project is designed to determine the important molecular events that control T cell development within the thymus. It is known that blood precursor cells appear in the embryonic region that will become the thymus at day 10/11 of embryogenesis in the mouse. These cells then undergo a series of developmental stages during which they acquire various capacities that will be eventually needed by the mature T cell to carry out appropriate immune functions. We and others have shown that the cells that form the stromal shell of the thymus provide signals to blood precursor cells. One of the consequences of the thymic stromal signals is to cause the precursors to become T cells and not other types of lymphocytes such as B or natural killer (NK) cells. We have found that the earliest thymic precursors can be subdivided by the NK1.1 cell surface marker allowing the identification of committed and uncommitted precursors. We have also identified the p53 molecule as a checkpoint in thymic development once the precursor cells have committed to becoming T cells. Finally, we have succeeded in pursuing gene knock-outs in mice for the signalling molecules Ly-GDI and RLK which are highly expressed within developing thymocytes. Interestingly, homozygous deficiencies of these genes did not detectably alter thymocyte development but rather caused functional abnormalities in mature T cells. Thus our results define important aspects of T cell maturation and define the function of two recently identified signalling molecules in T cells. These results may have important implications for bone marrow transplantation and diseases involving T cells.
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