Direct and Indirect Modes of Action of Cyclosporine on Cytotoxic T Lymphocytesa

There is extensive evidence to show that the immunosuppressive agent, cyclosporine A (CsA), inhibits immune responses by blocking the induction of a number of cytokines. Factors whose generation is inhibited by CsA, and which might be involved in immune responses, include interleukin-2 (IL-2),'-5 interferon gamma,4ss and colony-stimulating factor^.^^^ Inhibition of IL-2 synthesis could account for the ability of CsA to block cytotoxic T lymphocyte (CTL) responses, and could also be at least partly responsible for its ability to inhibit the appearance of IL-2 receptors in peripheral blood cells (PBL),8 inasmuch as IL-2 up-regulates its own r e ~ e p t o r . ~ On the other hand, in cultures of cloned cells, CsA has little effect on the expression of IL-2 r e~ep to r .~ .~ . ' Overall, CsA affects the expession of only a small subset of genes in T lymphocytes, and this subset includes several known lymphokines.I0 The proliferation and cytotoxicity of IL-2-dependent1 antigen-independent CTL lines is typically insensitive to CsA.', ' ' The inhibition of lymphokine synthesis by CsA can account for many of its suppressive effects on cellular and humoral immunity. Besides inhibiting lymphokine production and response, however, CsA exhibits other modes of immunosuppression. Inhibition of antigen presentation by macrophages to induce T cells to produce IL-2 has been observed.'* In another study,l3 activation of resting B lymphocytes by BSF-1 was found to be resistant to CsA, but stimulation with BSF-1 in conjunction with anti-immunoglobulin was sensitive. In addition, the effect of BCGF-I1 on preactivated B lymphocytes was also CsA-sensitive. One of the difficulties in assessing the precise modes of action of CsA in many studies is the use of uncloned cell populations. In this paper, we describe a direct effect of CsA on a class of cloned CTL that is not mediated by an inhibition of IL-2 synthesis. In these cells, CsA blocks both the antigen-dependent activation and the resulting cytotoxic activity.