Recent studies have demonstrated that
granzymes A and B make an important contribution to the clearance of the orthopoxvirus
ectromelia, and in
graft versus host disease. To test whether
granzymes are generally necessary for lymphocyte-mediated cytotoxicity in vivo, we assessed the cytotoxic capacity of
granzyme A and/or B-deficient lymphocytes in several
perforin-dependent settings. Splenocytes and allogeneic CTL of
granzyme A and/or B-deficient mice were defective for induction of DNA fragmentation, but induced significant membrane damage and target cell death. These results correlated well with the behavior of
granzyme A/B-deficient CTL and NK cells in three different
perforin-dependent
tumor models. In a classical assay of NK cell-mediated rejection,
granzyme A and/or B-deficient mice inoculated with RMA-S cells were as susceptible to
tumor as wild-type mice.
Perforin-deficient mice were also considerably more susceptible to
tumor initiation by
methylcholanthrene than
granzyme A and/or B-deficient mice. Furthermore, rejection of the K1735-melanoma expressing MHC class I and II molecules was mediated by adoptively transferred H-2b anti-k CTL from immunized
granzyme A and/or B-deficient mice. In summary, these data suggest that
granzymes A and B are not critical for most anti-
tumor effector functions of NK cells and CTL that are
perforin mediated.