The deletion of autoreactive T cells specific for peripheral antigens, and the regulation of peripherally restricted antigens by stromal cells in thymic have not been well defined. Autoimmune regulator (AIRE) is a newly discovered transcriptional factor that regulates the ectopic expression of peripherally restricted antigens in the thymus. Upstream pathways that regulate AIRE expression, however, are undefined. Our preliminary data show that lymphotoxin (LT) signaling controls the expression of AIRE and its downstream target genes. The failure to induce AIRE in the thymi of Ita -/- and Itbr -/- mice may contribute to overt autoimmunity against self-antigens. LTbR signaling appears to activate multiple NF-kB pathways en route to AIRE. We hypothesize that LTbR signals a specific NF-kB pathway to induce the ectopic expression of autoantigens, in both AIRE dependent and independent pathways, for negative selection. The goal of this project is to define how LTbR signaling on stromal cells in thymic tissues participates in the selection and regulation of autoreactive T cells specific for peripherally restricted antigens. 1) We will define whether and how LTbR signaling controls the expression of autoantigens in AIRE dependent and independent pathways for negative selection. LT mediated thymic self-antigen expression will be assessed in the absence or presence of AIRE. 2) To study downstream of the LTbR pathway for AIRE expression, we will define which LT-mediated NF-kB pathway, namely p52/RelB, p50/RelB, or p50/RelA, is essential for the induction of autoantigens and AIRE. 3) We will study the consequences of impaired negative selection in the development of local autoimmune destruction. We will then test whether impaired negative selection is required for the development of severe tissue-specific autoimmune destruction after persistent local inflammation. Therefore, this study will dissect the regulatory mechanisms of AIRE dependent and independent pathways for negative selection, from extracellular ligand-receptor interaction to intracellular signaling cascade, and define the contributions to autoimmune disease that results from the disruption of this checkpoint.
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