GENE REGULATORY EVENTS IN ESTABLISHING MATURE T CELL TOLERANCE

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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 tolerance has revealed that they may undergo deletion or enter a functionally unresponsive state termed anergy. In anergy, a T-helper cell can be induced to "turn off" IL-2 production if it is stimulated through its T-cell receptor in the absence of costimulation. T cell anergy cannot be demonstrated in the transformed T lymphoma cells typically used for gene regulation studies so we have developed a system to study gene regulation in antigen-specific nontransformed T lymphocytes. We found that decreased production of IL-2 bioactivity is reflected in decreased steady-state mRNA and is due to decreased transcription of the IL-2 gene in anergic cells. An analysis of the transactivator proteins in the IL-2 promoter, showed that the NFAT, NF-kB, and octamer binding proteins are induced to similar levels in normal and anergized cells, but there was a specific defect in the induction of AP-1. AP-1 is a gene regulatory complex that is comprised of the protein products of the proto-oncogenes c-jun and c-fos. In order to assess the functional role of this decrease in AP-1 activity, we produced a number of stable transfectants of A.E7 cells with various reporter constructs. Results indicate that a 300 bp enhancer fragment of the IL-2 gene and constructs bearing only the AP-1 site have decreased activity in anergic cells. These findings suggest an intriguing mechanism by which the protein products of two proto-oncogenes may participate in a mechanism of T cell tolerance.