Many tissues are found to contain populations of cells with an unusual dendritic shape, high levels of surface expression of MHC class II (Ia) gene products, and strong accessory function for the stimulation of specific clones of quiescent T lymphocytes. Dendritic cells (DC) represent major population of "professional" APC in various lymphoid and nonlymphoid tissues, distinct from cells of the monocyte/macrophage lineage. Among the best characterized nonlymphoid dendritic cells are epidermal Langerhans cells, but it has been shown that interstitium and epithelium of other organs also contain irregularly shaped, strongly MHC class II positive cells. In recent years, DC have been localized to alveolar septa in the lung, as well as within and just beneath airway epithelium, comprising a tightly meshed network that is reminiscent of epidermal Langerhans cells. In the gastrointestinal tract, conventional immunohistochemical analysis of mucosal class II MHC (Ia) staining reveals a morphologically heterogeneous pattern of staining in the lamina propria. DC that exhibit strong Ag-presenting activity in vitro have been extracted from enzymatic digests of colonic mucosa, but no previous reports of MHC class II-positive cells with pleiomorphic morphology have been recorded within the epithelium of the intestine. Employing a novel combination of nonconventional section planes, pre-embedding fixation, and immunohistochemical techniques, we now demonstrate Ia staining of cells with classical DC morphology within the epithelium of the intestine in normal specific pathogen-free rats. Our investigation suggests that cells with the morphologic and phenotypical characteristics of DC are present within the mucosal epithelium of the rat jejunum and colon, comprising a significant organized network. The number of DC within epithelium of the colon was 117 +/- 20 per 10-microns-thick cross-section. These findings have important theoretical implications for research on Ag processing and T cell activation in the context of allergic and infectious diseases in the gastrointestinal tract.