The development of functionally mature T lymphocytes involves intrathymic differentiation and selection processes that eliminate self- reactive cells (negative selection) and promote survival of the cells interacting with foreign antigens in the context of the self major histocompatibility complex (positive selection). These processes require the coordinate regulation of an array of genes. The intracellular signals by which T cell receptor (TcR) may regulate gene expression during thymocyte differentiation are not well understood. The AP-1 and NFAT transcription factors are central to the activation of mature T cells, as they regulate the transcription of cytokine genes such as IL-2. Moreover, the three MAP kinases families (ERK, JNK and p38 MAP kinase) that regulate the activation of these and other transcription factors also play a major role in the activation of T cells in periphery. However, their role in the differentiation and positive and negative thymocyte selection has not been defined yet. It is important to dissect the intracellular signals involved in thymic development, since an unbalance of the signaling pathways may lead to the presence of large number of autoreactive T cells causing autoimmune disorders, or it may result in a massive deletion of mature T cells and a deficient immune response. Our previous studies indicate that AP-1 and NFAT transcription factors are differentially regulated during the generation of T cells in the thymus. AP-1 and NFAT are activated in CD4CD8 thymocytes, but these transcription factors cannot be induced in immature CD4+CD8+ thymocytes until they have undergone positive selection. In addition, while the ERK MAP kinase family is required for positive selection of thymocytes, our preliminary studies show that JNK MAP kinase could control the deletion of immature CD4+CD8+ thymocytes by apoptosis. The experiments described in this proposal have been designed to determine: 1) the mechanisms involved in the repression or activation of AP-1 and NFAT transcription factors as well as the relevance of their specific regulation during thymic maturation and selection, b) the specific regulation and the role of JNK and p38 MAP kinase pathways in thymic maturation and selection. Several genetically modified mice models have already been developed and they will be used for this study.
