Celiac disease (CeD) is a dietary gluten-triggered autoimmune disorder that is characterized by CD8+ T cell mediated killing of intestinal epithelial cells (IECs) ultimately resulting in small intestinal villous atrophy. The genetic and immunological determinants of disease have been relatively well characterized, with all patients having at least one copy of HLA-DQ2 or HLA-DQ8, and more than two-thirds of patients having high levels of proinflammatory cytokine interleukin 15 (IL-15) in their small intestinal mucosa. We used this knowledge to reverse-engineer a mouse model of disease that involves the overexpression of IL-15 in both the epithelium (villin-IL15 transgenic; denoted IL-15IEC) and lamina propria (Dd-IL15 tg, denoted IL-15LP) of the small intestine in mice that have the expression of human MHC class II molecule HLA-DQ8 on the surface of their antigen presenting cells (HLA-DQ8 tg). These DQ8-IL-15LPxIEC mice have the development of villous atrophy upon gluten feeding as well as CeD-associated cellular, serological, and transcriptional signatures. The development and characterization of this model allowed us to investigate the cellular requirements for disease and importantly will be an indispensable tool for the validation of preclinical therapies. One important therapeutic target is transglutaminase 2 (TG2), an enzyme that is thought to be required for the pathogenesis of CeD, although this has never been demonstrated in vivo. We used the DQ8-IL-15LPxIEC mice to investigate how TG2 becomes enzymatically activated in the context of inflammation and gluten feeding, and used two different TG2 inhibitors to demonstrate the requirement for TG2 in tissue destruction and other CeD associated phenotypes.