PROJECT ABSTRACT Uncontrolled inflammation at mucosal sites underlies the pathogenesis and progression of multiple chronic human diseases including allergy, hypersensitivity, inflammatory bowel disease (IBD), cancer and graft-versus- host-disease (GVHD), and there is an urgent need to develop novel approaches to prevent, limit or reverse mucosal inflammation. Interleukin-2 (IL-2) is a pleiotropic cytokine that profoundly influences immunologic tolerance in mammals, and modulation of IL-2 is currently being developed as a therapeutic approach in the clinic. Since its discovery, a majority of research has focused on how IL-2 influences T cell activation or supports regulatory T cells (Tregs) within lymphoid tissues. Despite these advances, the critical cellular sources and functional regulation of IL-2 production at mucosal sites remains poorly defined. The fundamental focus of this research proposal is to interrogate novel cellular sources of IL-2 that critically influence immunologic homeostasis and inflammation within the mammalian gastrointestinal (GI) tract. We will employ innovative approaches and develop new tools to define the role and regulation of mucosal IL-2 during homeostasis or following intestinal inflammation and food allergy. Collectively, results from these studies will define the regulation and functional significance of novel cellular sources of IL- 2 within the intestine. These findings will critically inform ongoing therapeutic approaches to augment IL-2, or provoke the development of novel tractable strategies to promote tolerance and control mucosal inflammation.