Non-epithelial mesenchymal and neuroectodermal cells occur between the keratinocytes in the stratified squamous epithelium of the oral mucosa. These cells cannot be classified adequately by light microscopy. The oral mucosa of the lip, cheek and tongue of 50 mice were studied by light microscopy and EM. Mononuclear interepithelial cells (3025) were documented and analyzed. Monocytogenic macrophages, plasma cells and mast cells were not found interepithelially and cannot be regarded as a regular constituent of the epithelium. Only a few neuroectodermal cells.sbd.in mice these are exclusively Merkel cells, with no melanocytes.sbd.were localized in the epithelium. The majority of the interepithelial cell population is made up of lymphocytes (22.8%) and Langerhans cells (56.8%). They are an integral constituent of the epithelium. Lymphocytes with rounded and indented nuclei can be identified. The larger and dendritic Langerhans cells are a specific cell of squamous epithelium and also occur in the oral mucosa. Not all cells which feature the cytological characteristics of Langerhans cells contain Langerhans or Birbeck granules. These granules cannot be considered an exclusive identification characteristic. Two types of Langerhans cells can be differentiated. Those with a more or less typical appearance known from the epidermis [80.9%] were termed macrophagocytoid Langerhans cells. The nuclei are irregularly indented and moderately heterochromatic; 19.1% possessed conspicuous large, spherical, euchromatic nuclei and an electron-lucent cytoplasm and were termed reticuloid Langerhans cells. About 20% of the interepithelial cell population could not be identified, either as typical lymphocytes or as Langerhans cells. These were small to medium sized cells with deeply indented, cerebriform strongly heterochromatic nuclei. They are similar to the Sezary cells or mycosis fungoides cells of epidermotropic human T[thymus-derived]-cell lymphomas. The lymphocytic nature of these cells was confirmed. Differentiation of lymphocytes to cerebriform cells occurs within the epithelium. Cerebriform cells may be precursors of Langerhans cells, a conclusion suggested morphologically by transitional forms. Langerhans cells may originate from lymphocytes and the cerebriform cell is an intermediate step of differentiation. The microenvironment of the squamous epithelium may play a role in the process of differentiation, which could explain the epitheliotropy of lymphocytes. Langerhans cells and interdigitating reticulum cells of the T-cell area of lymph nodes are identical. The close functional cooperation of Langerhans cells, lymphocytes and interdigitating reticulum cells in immunological defenses against external antigens is discussed.
