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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089714-04
Application #
8605155
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2011-02-15
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kosinsky, Robyn Laura; Chua, Robert Lorenz; Qui, Martin et al. (2018) Loss of RNF40 decreases NF-?B activity in colorectal cancer cells and reduces colitis burden in mice. J Crohns Colitis :
Dietz, Allan B; Dozois, Eric J; Fletcher, Joel G et al. (2017) Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn's Disease. Gastroenterology 153:59-62.e2
Sarmento, Olga F; Svingen, Phyllis A; Xiong, Yuning et al. (2017) The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD). J Biol Chem 292:706-722
Velez, Gabriel; Lin, Marisa; Christensen, Trace et al. (2016) Evidence supporting a critical contribution of intrinsically disordered regions to the biochemical behavior of full-length human HP1?. J Mol Model 22:12
Mathison, Angela; Escande, Carlos; Calvo, Ezequiel et al. (2015) Phenotypic Characterization of Mice Carrying Homozygous Deletion of KLF11, a Gene in Which Mutations Cause Human Neonatal and MODY VII Diabetes. Endocrinology 156:3581-95
Sarmento, Olga F; Svingen, Phyllis A; Xiong, Yuning et al. (2015) A novel role for KLF14 in T regulatory cell differentiation. Cell Mol Gastroenterol Hepatol 1:188-202.e4
Papadakis, Konstantinos A; Krempski, James; Reiter, Jesse et al. (2015) Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-? signaling in CD8+ T lymphocytes. Am J Physiol Cell Physiol 308:C362-71
Dave, Maneesh; Hayashi, Yujiro; Gajdos, Gabriella B et al. (2015) Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion. Gastroenterology 148:978-90
Papadakis, Konstantinos A; Krempski, James; Svingen, Phyllis et al. (2015) Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation. Am J Physiol Gastrointest Liver Physiol 309:G900-9
Dave, Maneesh; Mehta, Kathan; Luther, Jay et al. (2015) Mesenchymal Stem Cell Therapy for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 21:2696-707

Showing the most recent 10 out of 20 publications