Granzyme B leakage‐induced cell death: a new type of activation‐induced natural killer cell death

Ida, Hiroaki; Nakashima, Tomoki; Kedersha, Nancy; Yamasaki, Satoshi; Huang, Mingguo; Izumi, Yuichi; Miyashita, Taiichiro; Origuchi, Tomoki; Kawakami, Atsushi; Migita, Kiyoshi; Bird, Phillip I.; Anderson, Paul S.; Eguchi, Katsumi

doi:10.1002/eji.200324376

Cited by 70 publications

(70 citation statements)

References 35 publications

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“…The marked increase in cytotoxicity associated with coexposure to ABT-737 in this model is therefore likely due to sensitization to the pro-apoptotic effects of perforin/granzyme-B. From a mechanistic standpoint, it is significant that the pro-apoptotic BH3-only protein Bid is cleaved to its active form by granzyme-B, allowing it to trigger cytochrome-c release from mitochondria, caspase activation and apoptosis (Ida et al, 2003). Bcl-2 expressed by tumour cells could sequester activated Bid (Letai et al, 2002), and therefore block apoptosis in the face of immune cell-derived granzyme-B.…”

Section: Discussionmentioning

confidence: 91%

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

et al. 2007

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The cytotoxic effects of anticancer immune cells are mediated by perforin/granzyme-B, Fas ligand and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), and therefore depend on intact apoptotic responses in target tumour cells. As killing by all three of these mechanisms is blocked by the frequently overexpressed antiapoptotic oncoprotein Bcl-2, we hypothesised that coexposure to a Bcl-2 inhibitor might enhance anticancer immune responses. We evaluated this in U937 lymphoma cells, and A02 melanoma cells, which both show strong Bcl-2 expression. Va24 þ Vb11 þ natural killer T (NKT) cells expanded from peripheral blood of normal donors (n ¼ 3) were coincubated with PKH26-labelled U937 cells, and cytotoxicity was determined by flow cytometry after annexin-V-FITC and 7-AAD staining. In all cases, addition of the HA14-1 small-molecule Bcl-2 inhibitor to the cocultures significantly increased apoptosis in the target U937 cells. Using a similar assay, killing of A02 cells by the cytotoxic T-lymphocyte clone 1H3 was shown to be amplified by coexposure to the potent small-molecule Bcl-2 inhibitor ABT-737. Experiments with immune effectors preincubated with concanamycin-A suggested that sensitisation to perforin/granzyme-B may underlie enhanced target-cell killing observed in the presence of Bcl-2 inhibitors. We conclude that immune destruction of malignant cells can be amplified by molecular interventions that overcome Bcl-2-mediated resistance to apoptosis.

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Section: Discussionmentioning

confidence: 91%

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

et al. 2007

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“…1D, 2C), suggesting functional heterogeneity of effector CD8 + T cells. Recently, the relation between granzyme Bmediated programmed cell death and generation of memory CD8 + T cells was discussed [34,35]. In mouse models, elevated expression of serine protease inhibitor (Spi) 6, which makes a complex with granzyme B, in CD8 + T cells led to an increase in memory CD8 + T cells after infection of mice with lymphocytic choriomeningitis virus [35].…”

Section: Discussionmentioning

confidence: 99%

Bcl6 controls granzyme B expression in effector CD8⁺ T cells

et al. 2006

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Bcl6, a sequence-specific transcriptional repressor, is important for generation and maintenance of memory CD8 + T cells. Although memory CD8 + T cells are generated from effector CD8 + T cells, a role for Bcl6 in effector CD8 + T cells is largely unknown. We show here that Bcl6 expression was transiently induced in activated CD8 + T cells and continuously up-regulated in effector CD8 + T cells. The amount of granzyme B mRNA among effector molecules produced by effector CD8 + T cells inversely correlated with the amount of Bcl6 mRNA in CD8 + T cells. Overexpression of Bcl6 in CD8 + T cells resulted in lower killing activity at their effector phase, supporting the reduction of granzyme B expression in effector CD8 + T cells by Bcl6. We identified a putative Bcl6-binding DNA sequence in the promoter region of the granzyme B gene. Binding of Bcl6 to the Bcl6-binding sequence was detected in naive CD8 + T cells but not in activated CD8 + T cells by chromatin immunoprecipitation assay. Furthermore, the Bcl6-binding sequence was required for Bcl6 to repress the luciferase reporter gene expression controlled by the granzyme B promoter. Thus, the granzyme B gene is a molecular target of Bcl6 in effector CD8 + T cells.

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“…Although the trafficking of granzymes within CTLs is designed to minimize leakage of active enzyme out of granules, any stray molecules in the cytoplasm could cause cell death (86). During granule exocytosis, some granzymes might inadvertently reenter the effector cells.…”

Section: Granzyme Inhibitors-endogenous Viral and Syntheticmentioning

confidence: 99%

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

Chowdhury

Lieberman

2008

Annu. Rev. Immunol.

569

580

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The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.

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Granzyme B leakage‐induced cell death: a new type of activation‐induced natural killer cell death

Cited by 70 publications

References 35 publications

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

Bcl6 controls granzyme B expression in effector CD8⁺ T cells

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

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Granzyme B leakage‐induced cell death: a new type of activation‐induced natural killer cell death

Cited by 70 publications

References 35 publications

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

Small-molecule Bcl-2 inhibitors sensitise tumour cells to immune-mediated destruction

Bcl6 controls granzyme B expression in effector CD8+ T cells

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

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Bcl6 controls granzyme B expression in effector CD8⁺ T cells