The cutaneous lymphocyte-associated antigen recognized by the monoclonal antibody HECA-452 has been thought to play a major role in the homing of memory T-cell subsets to the skin by virtue of its ability to bind to E-selectin of dermal microvascular endothelial cells. Considering that the homing of different leukocyte populations to the skin may involve similar mechanisms, we studied the expression of HECA-452-reactive molecules on CD1a+ epidermal Langerhans cells. Immunofluorescence double-labeling of cryostat sections and epidermal sheets of normal skin revealed HECA-452 immunoreactivity on a subpopulation of dermal and epidermal CD1a+ cells, whereas upon flow-cytometric analysis of epidermal single cell suspensions virtually all CD1a+ cells bound HECA-452 antibodies. We observed a marked upregulation of HECA-452-antigen expression on CD1a+ epidermal cells and a pronounced increase in the number of HECA-452+/CD1a+ dermal cells in lesional skin from inflammatory and neoplastic lymphocytic skin diseases, compared to normal skin. The molecule detected by the HECA-452 antibody on Langerhans cells is neuraminidase sensitive and contains a CD15 (LewisX) carbohydrate backbone. Because Langerhans cells react with the sialyl-LewisX-specific antibody CSLEX1, it is very likely that the HECA-452-reactive structure is or contains sialyl-LewisX. Our data are compatible with the view that i) resident epidermal Langerhans cells upregulate HECA-452-antigen expression due to the cytokine profile generated in the disease process or ii) that Langerhans cell precursors express HECA-452-antigens and show an enhanced immigration into lesional skin. The characterization of HECA-452+ cells in peripheral blood may not only clarify this issue but may also help to identify the still elusive Langerhans cell-precursor.