The mechanism of cell-mediated cytotoxicity. IV. K-76 COONa, which inhibits the activity of Factor I and of C5, inhibits early events in cytotoxic T-lymphocyte-mediated cytolysis and in T-lymphocyte activation.
K-76 COONa is a derivative of a fungal product which blocks complement (C)-mediated lysis by combining with C5 and preventing its activation to C5b. K-76 COONa can also combine with Factor I and inhibit its ability to hydrolyze C3b to iC3b. The inclusion of K-76 COONa at concentrations similar to those which inhibit C lysis blocked both murine cytotoxic-T-lymphocyte (CTL)-mediated lysis (CML) and the lectin-stimulated proliferative response of murine and human T lymphocytes. A modified cation pulse procedure has been used to determine which phases of CML were most sensitive to the drug. K-76 COONa was inhibitory when it was added to CML prior to the early Mg+2-dependent binding phase, but was much less effective when it was added at any time after the formation of CTL-target conjugates. The principal effect of the drug on the proliferative response was also exerted during an early phase of the response. K-76 COONa did not appreciably decrease the production of T-cell growth factor (TCGF), but it did inhibit the induction of TCGF receptor expression by both functional criteria, i.e., induction of responsiveness to TCGF, and by morphological criteria, i.e., the expression of the Tac antigen. Later events, such as the TCGF-dependent proliferation of cycling T cells, were less sensitive to the drug. Evidence is discussed suggesting that molecules similar to Factor I and to C3 may be involved both in the early events of CML and of T-lymphocyte activation.
D002478:Cells, Cultured; D003180:Complement C3b Inactivator Proteins / Q000037:antagonists & inhibitors*; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D015375:Receptors, Interleukin-2; D012717:Sesquiterpenes / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*
D003180:Complement C3b Inactivator Proteins; D003182:Complement C5; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid