Direct Contact of Cytotoxic T-Lymphocyte Receptors with Target Cell Membrane Determinants Induces a Prelytic Rise of [Ca²⁺]_i in the Target That Triggers Disintegration

Abstract

Because of the central role of cytotoxic T lymphocytes (CTL) (both CD4⁺ and CD8⁺ cells) in immune responses against viruses, tumors, and transplants, in AIDS and in autoimmunity, it is important to understand the precise molecular mechanism(s) whereby CTL destroy target cells (TC). No single mechanism proposed till now provides a satisfactory explanation of the entire process (Clark et al., 1988; Berke, 1991; Krähenbühl and Tschopp, 1991; Podack et al., 1991). CTL-TC interactions are initiated by specific binding of the TC by CTL (Brondz, 1968; Golstein et al., 1971; Berke and Levey, 1972), which results in conjugate formation (Berke et al., 1975; Martz, 1975, 1977; Berke, 1985; Dustin and Springer, 1991). The Mg²⁺-dependent binding step (Stulting and Berke, 1973) is frequently, but not always (Tirosh and Berke, 1985b) followed by a Ca²⁺- and temperature-dependent delivery of the effector’s lethal hit. The lethal hit [also referred to as “kiss of death” or “programming for lysis” (Ginsburg et al., 1969; Martz, 1977; Golstein and Smith, 1977)], induces the prelytic fragmentation of TC DNA into units consisting of multiples of 180 bp (Russell, 1983; Duke and Cohen, 1988). The subsequent temperature-dependent but killer-independent TC dissolution (Berke et al., 1972b; Martz, 1977) completes one round of the lytic process. The effector can then recycle to start a new lytic interaction (Berke et al., 1969, 1972a, Zagury et al., 1975). For extensive reviews of the process of TC lysis by CTL, see Wilson and Billingham (1967), Berke and Amos (1973), Cerottini and Brunner (1974), Martz (1977), Golstein and Smith (1977), Henney (1977), Sanderson (1981), Henkart (1985), Berke (1980, 1989, 1991), and Podack et al. (1991).