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The broad lytic properties of high buoyant density CD4+ and CD8+ T cell subsets were examined by activating these populations with anti-CD3 mAb and IL-2 for 1 to 5 days and testing their cytotoxic activity against various target cells. The effects of a variety of metabolic inhibitors and anti-TNF antibodies were examined to distinguish several different mechanisms of cytotoxicity used by CD4+ and CD8+ T cell effectors isolated from human PBL. In particular, activated CD4+ and CD8+ T cells were cytotoxic when redirected by an anti-nitrophenyl (NP)-anti-CD3 mAb heteroconjugate against NP-modified nucleated target cells (TC) and anucleated SRBC and also lysed L929 in a TNF-alpha-dependent manner. CD4+ and CD8+ T cells displayed distinct pathways of antibody-redirected lysis against NP-EL4, yet common mechanisms of SRBC redirected lysis by CD4+ and CD8+ efforts were implied by a similar pattern of sensitivity to cholera toxin, cyclosporin A (CsA), and EGTA. CsA inhibited CD4+ and CD8+ T cell redirected lysis of SRBC, but not EL4, suggesting that T cells redirectedly lyse nucleated and anucleated TC by different mechanisms. Cholera toxin, CsA, or EGTA pretreatment also significantly inhibited their release of alpha-N-benzyloxycarbonyl-L-lysine-thiobenzylester-esterase activity suggesting that degranulation of CD4+ and CD8+ effectors may be a critical step in their redirected lysis of SRBC. Overall, these findings suggested that activated human PBL CD4+ or CD8+ effectors can lyse TC by at least three distinct mechanisms: 1) a CsA-sensitive redirected lysis of SRBC that correlates with exocytosis and presumably occurs via membrane lesions; 2) a CsA-insensitive redirected lysis of NP-modified nucleated TC that does not appear to involve exocytosis and is metabolically distinct in activated CD4+ and CD8+ T cell effectors; and 3) a direct TNF-dependent lysis of TNF-sensitive TC.