Degranulating Cytotoxic Lymphocytes Inflict Multiple Damage Pathways on Target Cells

Abstract

In this review, we will describe our recent studies on lymphocyte cytotoxicity using a molecular approach to the understanding of cytotoxic lymphocyte function. However, before describing this work, it is important to place these studies in a broader perspective, as providing a biochemical basis to the general physiological picture of lymphocyte cytotoxic mechanisms which had emerged previously. After the development of the ⁵¹Cr release assay, which allowed convenient quantitation of cell death in vitro, several excellent laboratories studying alloreactive cytotoxic T lymphocytes (CTLs) established a number of important properties of what might be called the physiology of CTL-mediated cytotoxicity (Green and Henney 1981; Golstein and Smith 1977; Martz 1977). Three distinct phases of the cytotoxic process were distinguished: (1) adhesion; (2) lethal hit; and (3) target cell disintegration, or killer cell-independent lysis. The first two of these phases occurred within minutes at 37° C), and required the divalent cations Mg⁺², Ca⁺², respectively. They could be blocked by various inhibitors of energy production and cytoskeletal function. The target disintegration step, which occurred after the CTL had delivered the “kiss of death” to the target, occurred over the course of hours and was difficult to block by drugs. This multihour “death agony” of the target cell is relevant to considerations of the pathways described below.