CYTOTOXIC-CELL PROTEINASE GENE-EXPRESSION AND CYTOLYTIC ACTIVITY BY ANTI-CD3-ACTIVATED CYTOTOXIC T-LYMPHOCYTES IS SENSITIVE TO CYCLOSPORINE-A BUT IS NOT DEPENDENT ON INTERLEUKIN-2 SYNTHESIS

We have examined the role of interleukin (IL) 2 in the expression of cytotoxic cell proteinases (CCP) 1 and 2, as well as in the induction of major histocompatibility complex (MHC)-unrestricted cytotoxic activity in murine T cell cultures following stimulation with anti-CD3 monoclonal antibody. A dramatic reduction in CCP-1 and CCP-2 gene expression and near absence of cytolytic activity was shown to occur in these cultures when the expression of IL-2 was inhibited by 10(-6) M Cyclosporin A (CsA). The inhibitory effect of CsA could not be eliminated by the addition to culture of recombinant IL-2 at concentrations typically present in anti-CD3-stimulated T cell culture supernatants. Furthermore, when endogenous IL-2 (45-60 U/ml) present in anti-CD3-stimulated T cell cultures was neutralized with anti-mouse IL-2 antibody there was no effect on CCP-1 and CCP-2 mRNA expression and only a slight decrease in cytolytic activity. The expression of CCP-1 and CCP-2 gene products and the induction of MHC-unrestricted cytotoxic activity in anti-CD3-stimulated T cell cultures therefore occur independently of IL-2 synthesis but are regulated by a CsA-sensitive mechanism.