T cells in explants of human fetal small intestine in organ culture were stimulated in situ with PWM or anti-CD3 antibody to test the hypothesis that activated T cells produce enteropathy in human small intestine. T cell activation was measured by the appearance of CD25+ cells in the lamina propria of the explants and IL-2 production into the organ culture supernatant. We have previously shown that the number of T cells in human fetal gut increased between 14 and 22 wk gestation. Accordingly, after the addition of PWM to cultured explants of fetal intestine the number of CD25+ cells in the lamina propria and the amounts of IL-2 secreted into the organ culture supernatant increased with the age of the explanted tissue. The addition of PWM also produced an age-related enteropathy, most noticeably crypt epithelial cell hyperplasia and villous atrophy, with relatively minor changes in 14-17-wk-old intestine but severe tissue damage in 18-22-wk-old fetal intestine. These enteropathic effects were also produced when mucosal T cells were activated with anti-CD3 mAb. Cyclosporin A completely inhibited the PWM-induced development of CD25+ cells and related tissue damage. These experiments show that activated T cells in human small intestine produce enteropathy. The model provides a new system with which to dissect the mechanisms of T cell-mediated intestinal damage.