Effect of interferon-γ, interleukin-2 and interleukin-4 on cyclosporin-a-mediated inhibition of anti-CD3-induced T-lymphocyte proliferation

It is generally believed that cyclosporin A (CsA) inhibits T-cell activation largely by blocking interleukin (IL)-2 production, although CsA also inhibits the secretion of other growth-promoting lymphokines. To investigate the importance of downregulated synthesis of IL-4 and interferon (IFN)-γ, in addition to IL-2, in CsA-mediated inhibition of T-lymphocyte proliferation, exogenous IL-2, IL-4, and IFN-γ were added to murine T-cells stimulated with anti-CD3 monoclonal antibody in the presence of an inhibitory concentration of CsA. Either IL-2 or IL-4 alone were able to partially counteract the inhibitory effect of CsA on anti-CD3-induced T-lymphocyte proliferation, whereas IFN-γ had no discernable effect. IL-2 and IL-4, in combination, were able to largely reverse the immunosuppressive activity of CsA. These results indicate that (1) CsA fails to block T-cell signal transduction pathways coupled to IL-2 and IL-4 receptors, and (2) IL-2 and IL-4 have an additive effect in promoting the proliferation of a heterogenous T-cell population stimulated with anti-CD3 monoclonal antibody.