To clarify the role of IL-15 at local sites, we engineered a transgenic (Tg) mouse (T3 b-IL-15 Tg) to overexpress human IL-15 preferentially in intestinal epithelial cells by the use of T3 b-promoter. Although IL-15 was expressed in the entire small intestine (SI) and large intestines of the Tg mice, localized inflammation developed in the proximal SI only. Histopathologic study revealed reduced villus length, marked infiltration of lymphocytes, and vacuolar degeneration of the villus epithelium, beginning at∼ 3–4 mo of age. The numbers of CD8+ T cells, especially CD8αβ+ T cells expressing NK1. 1, were dramatically increased in the lamina propria of the involved SI. The severity of inflammation corresponded to increased numbers of CD8αβ+ NK1. 1+ T cells and levels of production of the Th1-type cytokines IFN-γ and TNF-α. Locally overexpressed IL-15 was accompanied by increased resistance of CD8αβ+ NK1. 1+ T cells to activation-induced cell death. Our results suggest that chronic inflammation in the SI in this murine model is mediated by dysregulation of epithelial cell-derived IL-15. The model may contribute to understanding the role of CD8+ T cells in human Crohn’s disease involving the SI.