Epidermal cell suspensions were produced containing 3–6% HLA-DR-positive Langerhans cells. By using mixtures of epidermal cells and allogeneic T lymphocytes from donors sensitized to purified protein derivative of tuberculin (PPD) and herpes simplex virus (HSV), we could show that a proliferative in vitro response to these antigens, similar in strength to that seen in autologous combinations of macrophages or epidermal cells and T cells, could be obtained provided the epidermal cells shared both HLA-D/DR determinants with the T-cell donor. No antigen-specific response was obtained in fully HLA-D/DR-disparate combinations. These results, together with previously reported data using other antigen-presenting cells, further emphasize that one minimal requirement for antigen-specific activation of T cells is co-recognition of products of the self HLA-D region.