Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells

JW Heusel, RL Wesselschmidt, S Shresta, JH Russell… - Cell, 1994 - cell.com
JW Heusel, RL Wesselschmidt, S Shresta, JH Russell, TJ Ley
Cell, 1994cell.com
We have generated H-2b mice with a homozygoua null mutation in the granzyme (gzm) B
gene. Gzm B is a neutral serine protease with Aspase activity that is found only in
thegranulesof activated cytolytlcT cells, natural killer cells, and lymphokine-activated killer
cells. Gzm Bl-mice develop normally and have normal hematopolesis and lymphopoiesis. In
vitro, cytotoxlc T lymphocytes (CTL) derived from gzm Bl-animals are able to induce% r
release from allotarget cells, but wlth reduced efflclency. However, gzm Bl-CTL have a …
Summary
We have generated H-2b mice with a homozygoua null mutation in the granzyme (gzm) B gene. Gzm B is a neutral serine protease with Aspase activity that is found only in thegranulesof activated cytolytlcT cells, natural killer cells, and lymphokine-activated killer cells. Gzm Bl-mice develop normally and have normal hematopolesis and lymphopoiesis. In vitro, cytotoxlc T lymphocytes (CTL) derived from gzm Bl-animals are able to induce% r release from allotarget cells, but wlth reduced efflclency. However, gzm Bl-CTL have a profound defect in their ability to induce rapid DNA fragmentation and apoptosis in allogeneic target cells. This defect is kinetic since DNA fragmentation Is partially compensated and “Cr release is completely rescued with long incubation times. We conclude that gzm B serves a critical and nonredundant role for the rapid induction of target cell DNA fragmentation and apoptosls by alloreactlve cytotoxic T lymphocytes. introduction
Cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and lymphokine-activated killer cells contribute to host cellmediated immunity against viral pathogens, parasites, and neoplastic transformation, as well as to host pathology associated with tissue and bone marrow graft rejection and avariety of autoimmune diseases (reviewed by Sitkovsky and Henkart, 1993; Groscurth, 1969; Lanier and Phillips, 1986). Although it is clear that these effector cells can kill their targets by multiple mechanisms, there is abundant evidence that the lethal hit delivered by cytotoxic cells in these immune responses invotves the componentsof their characteristic electron-dense cytoplasmic granules. In the presence of Caa, granules of CTL and NK cells are vectorally secreted into the intercellular space formed by the contact between the effector and target cells (conjugation), providing a mechanism for the delivery for the complement-like lesions in target cell membranes first observed by Dourmashkin et at.(1980) and later by Podack and Dennert (1983). These observations led to the granule-
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