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Mechanisms responsible for granzyme B-independent cytotoxicity
S Shresta, JH Russell and TJ Ley
Department of Medicine, Washington University Medical School, St Louis, MO
63110-1093, USA.
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.
Volume 89,
Issue 11,
pp. 4085-4091,
06/01/1997
Copyright © 1997 by The American Society of Hematology
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