Celiac disease (CD) is a chronic immune-mediated intestinal inflammatory disorder afflicting genetically susceptible individuals triggered by the consumption of dietary cereals with high gluten content. As with many other organ-specific autoimmune diseases, the dominant tissue-destructive inflammation in CD is T cell-mediated. The proinflammatory cytokine IL-15 that is overexpressed in the intestinal epithelium of CD patients has emerged as a pivotal element that orchestrates intestinal inflammation and T cell-mediated autoimmune tissue destruction. Although no animal model exists that recapitulates the full spectrum of CD pathophysiology, we have previously reported that transgenic mice that overexpress human IL-15 in enterocytes (T3b-hlL-15 Tg) display many of the T cell-mediated pathologic features seen in CD. Extending these observations, we now report that T3b-hlL-15 Tg mice in addition to recapitulating T cell-mediated effects also display autoantibodies including those against tissue transglutaminase 2 and extensive lamina propria plasmacytosis, all of which are characteristic of CD, thereby reflecting the possibility that locally expressed IL-15 drives both T and B cell pathologic effects seen in CD. More importantly, these findings support the validity and utility of T3b-hlL-15 Tg mice as a reasonable model to investigate not only tissue-destructive pathologic processes in CD, but also to explore novel therapeutic modalities for the treatment of this disease.