In vitro- and ex vivo-derived cytolytic leukocytes from granzyme A x B double knockout mice are defective in granule-mediated apoptosis but not lysis of target cells

J Exp Med. 1997 Nov 17;186(10):1781-6. doi: 10.1084/jem.186.10.1781.


Granzyme (gzm) A and gzmB have been implicated in Fas-independent nucleolytic and cytolytic processes exerted by cytotoxic T (Tc) cells, but the underlying mechanism(s) remains unclear. In this study, we compare the potential of Tc and natural killer (NK) cells of mice deficient in both gzmA and B (gzmAxB-/-) with those from single knockout mice deficient in gzmA (-/-), gzmB (-/-), or perforin (-/-) to induce nuclear damage and lysis in target cells. With the exception of perforin-/-, all in vitro- and ex vivo-derived Tc and NK cell populations from the mutant strains induced 51Cr-release in target cells at levels and with kinetics similar to those of normal mice. This contrasts with their capacity to induce apoptotic nuclear damage in target cells. In gzmAxB-/- mice, Tc/NK-mediated target cell DNA fragmentation was not observed, even after extended incubation periods (10 h), but was normal in gzmA-deficient and only impaired in gzmB-deficient mice in short-term (2-4 h), but not long-term (4-10 h), nucleolytic assays. This suggests that gzmA and B are critical for Tc/NK granule- mediated nucleolysis, with gzmB being the main contributor, while target cell lysis is due solely to perforin and independent of both proteases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Cytoplasmic Granules / enzymology*
  • Cytoplasmic Granules / immunology
  • Cytotoxicity Tests, Immunologic
  • Cytotoxicity, Immunologic*
  • DNA Fragmentation
  • Female
  • Granzymes
  • Leukemia L1210
  • Lymphoma
  • Male
  • Mast-Cell Sarcoma
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Serine Endopeptidases / deficiency*
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / physiology
  • T-Lymphocytes, Cytotoxic / enzymology*
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tumor Cells, Cultured


  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Perforin
  • Granzymes
  • Gzmb protein, mouse
  • Serine Endopeptidases