Differential effect of cyclosporin-A on the mixed-lymphocyte culture-induced proliferative and cytotoxic responses of T lymphocytes with different cell densities

We have analyzed the effect of cyclosporin-A (CsA) on the proliferative and cytotoxic responses induced by mixed-lymphocyte cultures (MLC-s) on low and high density T lymphocytes. Allogeneic stimulation had a different impact on the two subsets. Proliferative and cytotoxic responses were inversely correlated; i.e., high density cells proliferated but exerted low levels of cytotoxicity while the lytic activity of the low density subset was stronger and the proliferation was weak. CsA impaired the proliferative and cytotoxic responses of the high density T lymphocytes but influenced less markedly the response of the low density cells. In both subsets CsA inhibited the MLC-induced interleukin 2 (IL-2) production. The generation of specific cytotoxicity was markedly suppressed by CsA, whereas the generation of anomalous activity was less affected. Addition of exogenous IL-2 to the CsA-containing cultures fully restored the proliferation and the generation of nonspecific cytotoxicity. In contrast, addition of interferon gamma (IFN-gamma) restored neither of these responses. However, for complete restoration of the stimulation-specific cytotoxicity, addition of both lymphokines was required. Taken together these results suggest that the CsA-induced suppression of the lymphokine production has different consequences in the low and high density subsets; the expression of anomalous and specific cytotoxicities require different signals; CsA interferes with several steps in the T-cell activation.