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

Eur J Immunol. 2001 Jan;31(1):39-47. doi: 10.1002/1521-4141(200101)31:1<39::aid-immu39>;2-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cytotoxicity, Immunologic
  • DNA Fragmentation
  • Granzymes
  • Killer Cells, Natural / enzymology
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology*
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / physiology*
  • T-Lymphocytes, Cytotoxic / enzymology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Cells, Cultured


  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases