HUMAN INTESTINAL EPITHELIAL CELL-INDUCED CD8(-CELL ACTIVATION IS MEDIATED THROUGH CD8 AND THE ACTIVATION OF CD8-ASSOCIATED P56(LCK)() T)

The activation of CD8(+) suppressor T cells by normal intestinal epith elial cells in antigen-specific or allogeneic mixed cell. culture syst ems has significant implications for the regulation of mucosal immune responses. In this study, we found that the capacity of epithelial cel ls to induce CD8(+) suppressor T cell activation appeared to be linked to the binding of CD8 molecules on the T cell surface. This appears t o be mediated by a non-class I molecule expressed on the epithelial ce ll surface, which binds to CD8 and results in the activation of the CD 8-associated src-like tyrosine kinase, p56(lck). Epithelial cell-stimu lated p56(lck) activation is an early event (in contrast to monocytes) and is essential for T cell activation, since proliferation could be completely abrogated by pretreatment of T cells with genestein or herb amycin, both of which are protein tyrosine kinase inhibitors. Pretreat ment of T cells with anti-CD8 or of intestinal epithelial cells with a n anti-epithelial cell mAb B9 inhibited p56(lck) activation and furthe r confirmed that CD8 on the T cell and a CD8 ligand on the epithelial cell were involved in this T cell activation event. The specificity of this reaction was confirmed in experiments in which murine transfecta nts 3G4 and 3G8, expressing CD4 or CD8, respectively, were used. Cocul ture of 3G8 with epithelial cells but not with monocytes activated p56 (lck) in this cell line, whereas p56(lck) was preferentially activated in 3G4 cells when monocytes were used as the stimulator cells. Althou gh stimulation through CD8- and CD8-associated p56(lck) was important for epithelial cell-induced T cell activation, T cell proliferation co uld not be induced by crosslinking CD8 alone with monoclonal antibody anti-CD8. These data suggest that a second signal, possibly through th e T cell antigen receptor since activation of the T cell receptor-asso ciated kinase fyn was also seen, is required for epithelial cell-drive n T cell proliferation.