Dysregulated T cell homeostasis and its regulation by the key cytokine, IL-15, is implicated in the pathogenesis of the intestinal inflammatory diseases, inflammatory bowel disease (IBD) and celiac disease. IL- 15 levels are elevated in both diseases and can correlate with disease severity in celiac disease. IL-15 levels also correlate with the ability of IBD patients to respond to anti-TNF treatment. Moreover, IL-15 has recently been found to promote the killing of intestinal epithelial cells by intraepithelial lymphocytes (IELs) in the small intestine suggesting the cytokine is central to the initiation of celiac disease. Our lab has also demonstrated that the IELs are critically dependent on IL-15 for survival. In order to better therapeutically target this pathway in these intestinal inflammatory diseases, our goal is to define the components of IL-15 signaling regulation. To this effect, we hypothesize that the deubiquitylating enzyme, Otubain 1, regulates T cell homeostasis by restricting IL-15 signaling in CD8+ T cells. Preliminary data with a novel knockout mouse of Otubain 1 (Otub1-/-) generated in our lab suggest an expanded proportion of activated Otub1-/- CD8+ T cells. This phenotype is consistent with CD8+ T cells with excessive IL-15 signaling, either from overexpression or loss of the negative regulator, SOCS-1. Our preliminary data also suggest Otub1-/- CD8+ T cells hyperrespond to IL-15 stimulation. The proposed research has two specific aims. The first specific aim seeks to define the disrupted homeostasis of Otub1-/- CD8+ T cells in both the periphery and intestine. We will address whether the expansion of activated CD8+ cells is cell- autonomous, if it requires IL-15 presentation, and how the IL-15 dependent IEL population is affected by Otub1-deficiency. The second specific aim seeks to ascertain the underlying molecular mechanism by which Otub1 restricts IL-15 signaling. This will be done through careful dissection of Otub1's effect on and interaction with specific IL-15 signaling components and identify structural domains necessary for its function. These studies are essential to uncovering both a novel molecule and a novel mechanism of regulating IL-15 signaling, opening a new direction for studies examining the pathogenesis of intestinal inflammation and therapeutic interventions. This research project also presents a unique training opportunity for Albert. By working on a project that uses a wide-array of tools in the context of fundamental inflammatory gastrointestinal diseases, he will acquire first-rate scientific skills and acumen guided by clinically important questions. Additionally, by working in a gastrointestinal lab led by Dr. Averil Ma, Director of the Center for Colitis and Crohn's Disease and well- respected mucosal immunologist, Albert will be surrounded by role models who can foster his interest in becoming a gastrointestinal physician-scientist.
Through its function in regulating the homeostasis of T cells, the cytokine, IL-15, has been demonstrated by several correlative and mechanistic studies to be important in two clinically significant gastrointestinal diseases, inflammatory bowel disease and celiac disease. This project proposes Otubain 1 as a novel well-conserved protein that regulates T cell homeostasis by restricting IL-15 signaling in T cells. Our studies to expand on this preliminary finding have broad implications for future attempts to design targeted interventions for inflammatory bowel disease and celiac disease.
