GENE REGULATORY EVENTS IN T CELL TOLERANCE AND THYMIC T CELL MATURATION

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Increasing evidence suggests important events in T cell maturation in the thymus and tolerance induction are governed by specific gene regulation. T cell tolerance has been found to occur in immature T cells in the thymus and also extrathymically in mature T cells. Our studies of mature T cell non-responsiveness have shown that expression of the IL-2 gene is disabled by down-regulation of a cellular proto-oncogene that forms part of the AP-1 gene activation complex. Extra-thymic deletion of mature T cells also involves IIL-2 which has been found to program these cells for death following antigen receptor occupancy. In the thymus, precursor cells undergo a complex set of developmental events and emerge as mature T lymphocytes capable of specific antigen recognition. We have found that gene expression varies at different stages of thymic development in a variety of transformed cell lines that represent discrete stages of thymic development. We are focusing on regulation of the genes for IL-2 and its receptor alpha and beta chains. We are also trying to identify gene products associated with clonal deletion in the thymus. Finally we are trying to understand the role of genes, especially cellular proto-oncogenes, in the progression of thymocytes through their maturation pathway.