Synergy between interleukin 4 and interleukin 2 conveys resistance to cyclosporin A during primary in vitro activation of murine CD8 cytotoxic T cell precursors.

Even though cyclosporin A (CsA) suppresses in vitro production of lymphokines such as interleukin 2 (IL 2) and responsiveness of cytotoxic T cell (CTL) precursors to IL 2, thereby inhibiting the in vitro generation of CTL, in vivo CsA does not affect the induction of alloreactive CTL. This paradox suggests that CsA-resistant signals are operating in vivo. Using an in vitro model system in which the requirement for antigen-presenting cells during primary activation of resting murine CD8 T cells is bypassed by immobilized anti-CD3 monoclonal antibodies, we here describe conditions in which IL 4 conveys CsA resistance to murine CD8 T cells triggered by immobilized anti-CD3 monoclonal antibodies to respond to IL 2. CsA resistance of IL 4 and IL 2-responsive CD8 T cell parallels conditions in which signals provided by IL 4 and IL 2 synergize with each other. CsA dissociates in vitro proliferative and differentiative events by suppressing the former while enhancing the latter. In addition to the known pleiotropic effects of IL 4, our results define an IL 4-dependent, CsA-resistant signal pathway which allows CTL differentiation in the absence of significant cell proliferation.