My laboratory investigates the mechanisms underlying the development of complex inflammatory disorders. We combine human ex vivo studies, in vitro human model systems, and mouse models to determine the role of tissue and microbial signals in the regulation of tissue resident effector T cell responses. In human, we focus on the study of celiac disease, inflammatory bowel disease and type-1 diabetes. In early studies we identified a regulatory loop whereby stressed or infected tissue epithelial cells arm cytolytic T cells to kill them through the interplay of the cytokine IL-15, activating receptors of the natural killer (NK) family, and the stress-induced MHC-like ligands MIC and HLA-E. This innate tissue-mediated control of effector CTL constitutes a new layer of immune regulation with implications for disease mechanisms and treatments. We further characterized the innate signaling pathway regulating NK receptor and IL-15-mediated regulation of effector cytolytic T cells. These discoveries have led to the initiation of clinical trials aimed at targeting IL-15 in refractory celiac disease. In parallel, we characterized the role played by tissues and bacteria in the regulation of T helper cell responses. In particular, we demonstrated that retinoic acid acquired adjuvant properties under conditions of sterile inflammation associated with IL-15 overexpression in the lamina propria. More recently, my laboratory is developing new lines of investigations aimed at addressing the role of host-viral interactions in the loss of tolerance to dietary antigens and the role of epigenetic in the shaping of T cell responses by the tissue environment in which they reside.