Immunosuppressive effects of cyclosporin A on cloned T cells.

Abstract

The effects of the immunosuppressive agent Cyclosporin A (CsA) on the immune response of T lymphocytes are not clearly understood. Much of the previous data are conflicting, possibly due to the study of bulk populations of cells. Therefore, we studied the effects of CsA on cloned murine helper T lymphocytes (HTL) and cytolytic T lymphocytes (CTL) after stimulation with Con A or with monoclonal antibodies to the cells' antigen receptors. In the HTL L2, proliferative responses and production of the lymphokines interleukin 2, interleukin 3, and interferon-gamma were blocked to background levels when CsA was added to cultures at a concentration of 0.1 to 1 microgram/ml. This inhibition of lymphokine production was found to occur at a pretranslational level, because the mRNA for these proteins was not detected when the L2 cells were stimulated in the presence of CsA. In addition, when CsA was added to cultures 3 hr after the cells had first been stimulated with the lectin Con A, levels of mRNA for the lymphokines isolated from the L2 cells 3 hr later were reduced approximately twofold. In the CTL L3, production of lymphokine (interferon-gamma) was also inhibited by CsA at a pretranslational level. However, proliferative responses to maximal stimulation with the clonotypic antibody 384.5 were not inhibited. In both HTL and CTL, the proliferative responses to recombinant IL 2 were not affected. To test whether CsA affects expression and function of the antigen receptor, we studied the effects of the drug on binding of anti-antigen receptor antibodies KJ 16-133 and 384.5 to the cell surfaces and the ability of L3 cells to lyse P815 target cells. At dosages which inhibited lymphokine production, CsA did not compete with binding of KJ 16-133 to L2 cells or 384.5 to L3 cells, as measured by flow cytometry, and the ability of L3 cells to lyse targets was unaffected. We conclude the following. CsA inhibits production of interleukin 2, interleukin 3, and interferon-gamma by L2 cells and interferon-gamma by L3 cells. This appears to occur as a result of a block in the transcription of the lymphokine genes. This pretranslational inhibition of lymphokine production can be invoked after transcription has begun. CsA does not affect expression of the T cell receptor for antigen as measured by monoclonal antibodies reactive with the receptors and by cytolytic activities of cytotoxic lymphocytes. CsA does not affect proliferative responses of HTL and CTL induced by interleukin 2.(ABSTRACT TRUNCATED AT 400 WORDS)