The structural similarities of CD1a molecules to major histocompatibility complex (MHC) class I antigens, as well as their expression on epidermal antigen-presenting cells suggest that CD1a molecules might be involved in the cutaneous immune response. In the present study, we investigated the effect of different anti-CD1a monoclonal antibodies (BL6, DMC1, and Na1/34) on T cell proliferation induced by allogeneic epidermal cells in vitro. A significant inhibition of the mixed skin cell-lymphocyte reaction was obtained with BL6 and DMC1 monoclonal antibodies (MoAb), which recognize the same epitope on CD1a molecule. The observed inhibition could not be related to a steric hindrance of MHC class II molecules, because Na1/34 MoAb, which reacts with another epitope on CD1a molecule, had no significant effect. BL6 and DMC1 MoAb interfered with an early event of T-cell activation, as shown by a time-course study. In the presence of these MoAb, the addition of exogenous interleukin 2 did not restore T-cell proliferation. Furthermore, the inhibitory effect of anti-CD1a MoAb was not mediated by a suppressor factor released by Langerhans cells (LC). These present data suggest that CD1a molecule may have an important function in self peptide presentation by human Langerhans cells.