Granzyme A and B‐deficient killer lymphocytes are defective in eliciting DNA fragmentation but retain potent in vivo anti‐tumor capacity

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.