In Vivo Imaging of T-cell Differentiation in Inflammatory Bowel Disease

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DESCRIPTION (provided by applicant): Effector and regulator T cells play important roles in the homeostasis of the immune system. Recent studies showed that interleukin-17 producing effectors, known as TH-17 cells, and Foxp3+ regulator T cells, despite their apparently opposite roles, are differentiated from the same origin, naive CD4+ T cells. While the individual roles of these cells in inflammatory bowel disease have long been investigated, little is known about their reciprocal differentiation pathways in the inflammatory conditions in vivo. Considering the dynamic nature -varying in time and space- of complex immune system, in vivo studies in mouse models are highly attractive but have been challenging due to a lack of non-invasive approaches. The first specific aim of this program is to develop a novel high-resolution side-viewing fluorescence colonoscope capable of visualizing the colonic mucosa at the cellular level. Using this technology, we seek direct visualizations of naove CD4+, TH-17, and Foxp3+ T cells in a cell-mediated murine colitis models in vivo and over time. The second aim of the program is to quantify the reciprocal differentiation dynamics -where, when, and to what extent each pathway is activated- in the colon and lymphoid organs in the course of colitis development. This study will provide new insights into the role of the reciprocal differentiation in inflammatory bowel disease. Although the current focus is on T-cell differentiation, the technology and methods developed here will have broader applications ranging from colorectal cancer to numerous other studies, including inflammation-associated tumorgenesis and angiogenesis, that can benefit from minimally-invasive in vivo imaging. PUBLIC HEALTH RELEVANCE: Improved understanding of effector and regulator T cells in the gastrointestinal immune system can be used to develop novel treatment of inflammatory bowel disease. Cellular-level side-viewing colonoscopy may improve the clinical diagnosis of IBD as well as early detection of colorectal cancer.