Mechanisms responsible for granzyme B-independent cytotoxicity.
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.
Shresta
S
S
Department of Medicine, Washington University Medical School, St Louis, MO 63110-1093, USA.
Russell
J H
JH
Ley
T J
TJ
D000818:Animals; D003602:Cytotoxicity, Immunologic; D053804:Granzymes; D051379:Mice; D008817:Mice, Mutant Strains; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D019014:fas Receptor; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases