Using granzyme B-deficient mice obtained by gene targeting, we previously demonstrated that granzyme B is required for the rapid induction of apoptotic target cell death by cytotoxic T lymphocytes (CTLs); however, CTLs are also equipped with additional effector mechanisms. In the present study, we examined the mechanisms responsible for granzyme B-independent cytotoxicity using in vitro lytic assays with CTLs derived from mice deficient for both granzyme B and Fas ligand (FasL) (granzyme B(-/-) x gld/gld or for perforin and FasL (perforin x gld/gld. Our results show that primary mixed lymphocyte reaction (MLR)-derived CTLs from granzyme B(-/-) x gld/gld mice induce apoptosis of allogeneic targets with less efficiency and a longer delay than CTLs deficient for granzyme B alone. The residual cytotoxicity in granzyme B(-/-) x gld/gld CTLs is primarily accounted for by a perforin-dependent mechanism, since perforin(-/-) x gld/gld CTLs have virtually no residual cytotoxic activity in our assays. Granzyme B- independent cytotoxicity is therefore partially accounted for by the Fas pathway and partially by another perforin-dependent mechanism.
|Number of pages||7|
|State||Published - Jun 1 1997|