Granzyme B-induced apoptosis.

Abstract

In the last several years the major mechanisms by which both cytotoxic T lymphocytes (CTL) and natural killer (NK) cells mediate cell death and apoptosis have been identified. Cytotoxic lymphocytes of both types induce apoptosis through granule-or Fas-dependent pathway 1-4and perhaps TNF-α5. The granule exocytosis mechanism of CTL killing’ appears to be primarily responsible for resistance to viruses and can mediate lysis of a wide variety of tumors and allogeneic cells6,7. The mechanism by which granulated cytotoxic cells lyse target cells requires their transient but intimate contact with the target1,8. Cytotoxic lymphocytes contain cytoplasmic granules that rapidly reorient to the area of target cell contact through a kinesin-based motor mechanism, then fuse with the plasma membrane and release their contents into the intercellular space formed between the lymphocyte and target cell1,9,10. The target cell then undergoes disintegration with the nucleus of the target cell rapidly breaking down in a manner similar to that seen in programmed cell death or apoptosis in which the nucleus collapses with severe chromatin condensation and oligonucleosomal-sized DNA fragments are released during DNA degradation1. Plasma membrane damage is also observed and is accompanied by the appearance of C9 complement-like pores and calcium permeability’. Morphologically the target cells exhibit the features of apoptosis with typical nuclear changes, as well as necrosis with evidence of plasma membrane damage8,10,11