INHIBITION OF PROTEIN-TYROSINE PHOSPHORYLATION PREVENTS T-CELL-MEDIATED CYTOTOXICITY

Several lines of evidence point to a central role for protein tyrosine kinases (PTKs) in the signal transduction cascade initiated by T-cell receptor (TCR) engagement. In cytotoxic T lymphocytes (CTL), TCR cros slinking leads to activation of the lytic process which includes conju gate formation, lethal hit delivery, and events leading to target cell death. We studied the role of PTKs in antigen-specific cytotoxicity e xerted by both in vivo activated and in vitro maintained CTL. We found that the PTK inhibitors herbimycin A and genistein blocked T-cell-med iated lysis in a dose-dependent manner. Lack of cytotoxic function was not due to abrogation of conjugate formation, but was associated with inhibition of both granule exocytosis and phosphatidylinositides turn over, thus indicating that PTK activity is an obligatory event for the activation of antigen-specific CTL effector function. (C) 1994 Academ ic Press, Inc.