Cyclosporin A (CsA) is a strong inhibitor of skin allograft rejection. It has been also reported to act, not only on helper T cells, but also on the antigen-presenting functions of mouse epidermal cells (EC) enriched in Langerhans cells (LC). We tested the effects of CsA on the human allogeneic mixed epidermal cell-lymphocyte reaction (MECLR) using whole EC and freshly isolated LC as stimulator cells. Results were as follows. 1) CsA inhibited the lymphocyte proliferative response in a dose-dependent fashion, by about 80% for a CsA concentration of 10(-7) M. To evaluate the effects of the drug on the two cell populations involved in MECLR, stimulator EC and responder PBMC were separately pulsed for 2 h with CsA, washed, and combined to form MECLR. Inhibition by CsA of the alloantigen-dependent lymphocyte proliferation appeared to be multifactorial, because CsA-pulsed EC and CsA-pulsed effector PBMC led to identical reductions of 40% each in proliferation. 2) The nature of EC sensitivity to CsA during MECLR was then analyzed after freshly separating highly purified CD1-positive LC (greater than 95%) and LC-depleted EC (mainly keratinocytes), using an immunomagnetic particle technique. When responder PBMC were cultured with CsA-pulsed LC, a highly significant reduction of lymphocyte proliferation was observed, indicating that CsA has direct effects on LC. 3) Some of the possible mechanisms by which CsA might act on LC were studied. Substantial IL-1 activity and PGE2 amounts were induced during MECLR by LC and keratinocytes, but CsA did not act via these factors. Neither did it significantly modify HLA-DR, DQ, or DP antigen expressions on EC. In conclusion, CsA directly inhibits antigen presentation by human LC. This inhibition may partly explain the beneficial effects of CsA on skin allografts and certain cutaneous immune reactions.