We have addressed the restriction elements involved in the interaction of lamina propria lymphocytes (LPL) and intestinal epithelial cells using the model of primary mixed cell culture reaction. Whereas peripheral blood T cells proliferate in response to both allogeneic non T cells and class II antigen-bearing intestinal epithelial cells (non T cells > epithelial cells), LP T cells appear to proliferate preferentially in response to intestinal epithelial cells. The interaction between these cells does not appear to be restricted by conventional products of the major histocompatibility complex as neither monoclonal antibodies to class I nor to class II antigens inhibit the mixed cell cultures, whereas they are inhibitory in conventional mixed lymphocyte reactions. Furthermore, treatment of epithelial cells with interferon gamma fails to augment the cells' ability to induce proliferation of LPL while successfully enhancing proliferation of peripheral blood T cells in parallel cultures. Taken together, these data suggest that alternate restriction elements or mucosa-specific accessory molecules may exist on intestinal epithelial cells that are preferentially recognized by LPLs. Such a distinct regulatory network may be critical to the maintenance of immunologic homeostasis in the gut.