The protein FOX3 acts on the DNA of T cells important to immune regulation. Researchers have suspected that this critical FOXP3+ T cell is important in at least the top three most common human autoimmune diseases and the four most deadly cancers. As there are over 8.5 million U.S. residents with an autoimmune disease, it is easy to appreciate the importance of understanding the mechanisms behind the development of this critical FOXP3+ T cell. Our long-term goal is to understand how the cytokine TGF, an extremely important cytokine to the intestinal environment, regulates the generation of these FOXP3+ T cells in the intestine. Our laboratory has discovered that the deficiency of a KLF family member in mice results in a block in intestinal FOXP3+ T cell generation and a tendency to develop colitis similar to human inflammatory bowel disease. Thus, our objective in this application is to determine the mechanism by which KLF family proteins mediate TGF-dependent Foxp3 gene transcription, and how disruption of this pathway leads to colitis. The three specific aims designed to achieve this objective include: (1) Test the hypothesis that KLF10 expression in T cells mediates a mechanism of resistance to colitis, (2) Test the hypothesis that KLF10 regulates distinct genomic control regions of Foxp3, and (3) Test the hypothesis that KLF10 works via distinct chromatin remodeling required for Foxp3 activation. We will use the KLF10-deficient mouse colony and adoptive transfer of immune cell compartments to determine the precise cell type in which KLF10 is critically required to prevent colitis. Subsequent TCR transgenic animals will be used to determine the mechanism by which KLF10 regulates the development of intestinal FOXP3+ T regulatory cells specific for a defined gut antigen. Human T cells lines and transient transfection methodology will be used to characterize the specific regulatory domains of KLF10 required for Foxp3 promoter function. Finally, a novel human T cell line with a defined Foxp3 promoter and luciferase reporter construct stably integrated into the host cell genome will be used to characterize KLF10-dependent chromatin modifications required for Foxp3 promoter activation. This project is significant because upon conclusion, we will understand the role for KLF10 in the regulation of Foxp3, elucidating pathobiological information into the pathogenesis of chronic inflammation and neoplasia. This in turn will stimulate new areas for experimental therapeutics in human chronic inflammatory diseases.
The public health burden of autoimmune disease is significant as these unregulated immune responses affect widely disparate organ systems causing such diseases as inflammatory bowel disease, rheumatoid arthritis and diabetes mellitus. This proposal addresses the mechanisms of development of T regulatory cells, cells expected to protect against autoimmune disease. Results from this proposal will stimulate new areas for experimental therapeutics in human chronic inflammatory diseases.
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