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Th17, T-Regs, & Maintenance of Immune Homeostasis in Peripheral Tissues It is well recognized that the function of the intestinal immune system depends on the fine balance between effector, tolerogenic, and regulatory mechanisms. This balance is important not only in preventing disease, but also in providing flexibility and thus instructing the appropriate immune response. Dysregulation in any components of this homeostasis has been known to contribute to inflammatory bowel disease (IBD). Intestinal commensal bacteria are known to affect multiple immune mechanisms and mouse models of IBD depend on the presence of microbiota. However, the role of the composition of the microbiota has not been investigated, and whether different taxons of commensal bacteria activate specific branches of the immune system is not known. Th17 cells are a newly discovered helper T cell population proposed to have pro-inflammatory functions in IBD and other autoimmune diseases. At steady state Th17 cells are exclusively present in the small intestinal lamina propria where they co-exist in a well-regulated balance with Foxp3+ regulatory T cells (Treg). The role of different components of the intestinal microbiota in regulating this balance is currently unknown. We have discovered that the Th17:Treg ratio depends on the composition of the intestinal microbiota. Specific components of the commensal intestinal microbiota appear to induce Th17 cells that protect from infection with pathogenic microbes but can also have harmful inflammatory functions. We are studying bacterial taxons that specifically induce Th17 cell differentiation, examining the host signaling pathways that they engage, and investigating their involvement in both mucosal and systemic immunity. Information gathered from these studies will advance our understanding of the regulation of intestinal immune responses by commensal bacteria. The ultimate goal will be to provide knowledge for the rational design of therapeutic strategies for IBD and, potentially, other autoimmune diseases, based on modulating the composition or function of the intestinal microbiota. In related studies, we are investigating the roles of transcriptional and post-transcriptional regulation in the differentiation program of Th17 cells. A major effort is focused on the function of the orphan nuclear receptor RORgt, the central transcriptional coordinator for the Th17 program. We are characterizing the transcriptional regulatory targets for this factor and for a series of other transcription factors that are required for expression of the Th17 cytokines (IL-17, IL-17F, IL-22) and Th17 surface molecules. We are also using genetic and biochemical approaches to identify a natural ligand for RORgt as well as inhibitors that can be employed in anti-inflammatory therapies. Another interest is the role of non-coding RNAs in the differentiation of Th17 and Treg cells. We have found that inhibition of the micro-RNA biosynthetic machinery results in defective differentiation of Treg cells and in exaggerated expression of inflammatory cytokines. We are comparing the different functions of the RNaseIII enzymes Drosha and Dicer in discrete developmental stages in T cells and other cell types.
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