NATURAL-KILLER AND LYMPHOKINE-ACTIVATED KILLER-CELLS REQUIRE GRANZYME-B FOR THE RAPID INDUCTION OF APOPTOSIS IN SUSCEPTIBLE TARGET-CELLS

Granzyme (Gzm) B-deficient mice obtained by gene targeting were used t o assess the role of Gzm B in the mechanisms used by natural killer (N K) and lymphokine-activated killer (LAK) cells to destroy target cells , Gzm B--/- NK cells, LAK cells, and cytotosic T lymphocytes (CTL) all are defective in their ability to rapidly induce DNA fragmentation/ap optosis in susceptible target cells, This defect can be partially corr ected with long incubation times of effector and target cells, Moreove r, Gzm B--/- NK cells (but not CTL or LAK cells) exhibit a defect in C r-51 release from susceptible target cells, This Cr-51 release defect in Gzm B-deficient NK cells is also not overcome by prolonged incubati on times or high effector-to-target cell ratios, We conclude that Gzm B plays a critical and nonredundant role in the rapid induction of DNA fragmentation/apoptosis by NK cells, LAK cells, and CTL, Gzm B may ha ve an additional role in NK cells (but not in CTL or WK cells) for med iating Cr-51 release.