Direct inhibition of human CD8+ lymphocyte activation by cyclosporine A and Rapamune-Sirolimus

Cyclosporin A (CsA) and Rapamune-Sirolimus (RAP) have been shown to inhibit the in vitro activation of heterogeneous lymphocytes populations, but little is known about their direct actions on isolated CD8+ lymphocytes. In this study the direct effects of RAP and CsA on a highly purified population of CD8+ lymphocytes were examined. Human CD8+ lymphocytes were purified to near homogeneity and stimulated with anti-CD3 antibody, OKT3, or allogeneic cells in the presence of exogenous human recombinant interleukin 2 (IL2). The effects of CsA and RAP on cell proliferation, the entry into the S phase of the cell cycle, the surface expression of Tac antigen, and the release of soluble IL2 receptor and soluble CD8 were analyzed. When CsA and RAP were included in the stimulated CD8+ lymphocyte cultures, these responses were inhibited. OKT3-stimulated CD8+ lymphocytes were sensitive to lower concentrations of the immunosuppressants than those previously reported for peripheral blood mononuclear cells. RAP was effective at a lower dose than CsA and when the agents were applied in combination, cell proliferation was synergistically inhibited. These results demonstrate that CsA and RAP can inhibit the activation and proliferation of purified CD8+ lymphocytes in response to OKT3 or alloantigen in the presence of IL2.