T-Lymphocyte-mediated cytolysis as an excitatory process of the target. I. Evidence that the target cell may be the site of Ca2+ action.
Delivery of the lethal hit signal to target cells (TC) by cytolytic T lymphocyte (CTL) has traditionally been considered strictly dependent upon the presence of external Ca2+ [( Ca2+]ext) in the medium, but neither the role of Ca2+ nor its site of action (effector or target) have been known. We have observed that in different CTL/TC systems the requirement for [Ca2+]ext varies, depending on the target. Some TC, like leukemia L1210, are strictly dependent on [Ca2+]ext for lysis while others, like EL4 (and P815), are not. It is therefore suggested that, where required, [Ca2+]ext exerts its effect(s) on the TC and not the CTL. In support of this conclusion are experiments showing that effector cells cytolytic to certain TC in the absence of [Ca2+]ext, require [Ca2+]ext when used themselves as TC of other effectors. Verapamil, a Ca2+-channel blocker, inhibits the lysis of L1210 but not of EL4 cells, suggesting involvement of Ca2+ flux into L1210 target cells and, if at all involved, Ca2+ mobilization from internal stores in EL4. The different lytic susceptibility of the two TC to the Ca2+ ionophore A23187, in the presence and absence of [Ca2+]ext, correlated with their responses to CTL. It suggests Ca2+ influx into both types of TC in the presence of [Ca2+]ext and its release from internal stores in the lysis of EL4 but not L1210 in the absence of [Ca2+]ext. In view of these results indicating that the target is the site of Ca2+ action, we propose that CTL induce a Ca2+-regulated activation of the TC leading to its lysis.