CD1+ antigen-presenting cells in involved epidermis of patients with cutaneous T-cell lymphoma exhibit and enhanced functional capacity to activate autologous CD4+ T cells compared with CD1+ antigen-presenting cells from uninvolved and normal epidermis. Class II major histocompatibility complex molecules are involved in antigen presentation, and their expression on CD1+ Langerhans cells is known to vary. The expression of all three class II (HLA-DR, -DQ, -DP) molecules was therefore determined on CD1+ epidermal cells from both involved and uninvolved epidermis, using flow cytometry. The involved CD1+ epidermal cells exhibited a 1.5-1.6-fold, statistically significant increase in fluorescence intensity after staining of the class II molecules (HLA-DR, -DQ, -DP) compared with CD1+ epidermal cells from uninvolved epidermis. The autologous CD4+ T cells, activation was almost completely blocked by anti-HLA-DR, and partly by anti-HLA-DQ and anti-HLA-DP. In contrast, an antibody against class I, and an irrelevant control antibody, had no blocking effect. In a pokeweed mitogen assay it was demonstrated that autologous CD4+ T cells, activated by involved epidermal cells, demonstrated suppressor activity rather than helper activity. The suppressor activity was dependent on the presence of HLA-DR-positive epidermal cells. Thus, in cutaneous T-cell lymphoma, class II molecules on the individual CD1+ antigen-presenting cell are upregulated in clinically involved compared with uninvolved epidermis, and these molecules are crucially involved in activation of CD4+ T cells.