Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

Chen, Liane; Woo, Minna; Hakem, Razqallah; Miller, Richard G.

doi:10.1002/eji.200323783

Cited by 19 publications

(13 citation statements)

References 47 publications

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“…Interestingly, perforin-deficient CD8 + T cells were also found to outcompete WT CD8 + T cells (Supplemental Fig. 3), which is consistent with previous reports that perforin also plays an important role in AICD for CD8 + T cells (26)(27)(28)(29). Next, we used Annexin V staining to measure CD8 + T cell death in the tumorbearing hosts (Fig.…”

Section: Gzmb-mediated Activation-induced Cell Death Of Donor Cd8 + supporting

confidence: 87%

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Bian

Ding

Leigh

et al. 2013

The Journal of Immunology

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Allogeneic hematopoietic cell transplantation is an established treatment for hematologic and other malignancies. Donor-derived immune cells can identify and attack host tumor cells, producing a graft-versus-tumor (GVT) effect that is crucial to the treatment. Using multiple tumor models and diverse donor–host combinations, we have studied the role of granzyme B (GzmB) in GVT effect. We first confirmed previous findings that GzmB deficiency diminished the ability of a high dose of CD8+ T cells to cause lethal graft-versus-host disease. However, when GVT studies were performed using a moderate cell dose that the hosts could tolerate, GzmB−/− CD8+ T cells demonstrated a significantly enhanced GVT effect. GzmB-mediated, activation-induced cell death in wild-type CD8+ T cells was found responsible for their reduced GVT activity. Conversely, GzmB−/− CD8+ T cells exhibited enhanced expansion, skewed toward an effector or effector memory phenotype, and produced higher amounts of IFN-γ and Fas ligand that might contribute to GzmB-independent tumor control. These findings demonstrate for the first time, to our knowledge, that GzmB-mediated damage of CD8+ T cells impairs the desired GVT effect. This study suggests that inhibiting donor-derived GzmB function may represent a promising strategy to improve GVT effect without exacerbating graft-versus-host disease.

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Section: Gzmb-mediated Activation-induced Cell Death Of Donor Cd8 + supporting

confidence: 87%

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Bian

Ding

Leigh

et al. 2013

The Journal of Immunology

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“…Early AICD is a perforin-dependent form of apoptosis that occurs before and independently of Fas-dependent death (45,46). Although Fas-mediated AICD cultures require a minimum of 4 days to allow down-regulation of cFLIP before restimulation, perforin-dependent AICD requires only 2 days of activation in culture and are thus independent of regulation by cFLIP (32,45).…”

Section: Discussionmentioning

confidence: 99%

CD28 Regulates the Translation of Bcl-xL via the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Pathway

Rose

Chen

et al. 2005

The Journal of Immunology

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In concert with the TCR, CD28 promotes T cell survival by regulating the expression of the antiapoptotic protein Bcl-xL. The mechanism by which CD28 mediates the induction of Bcl-xL remains unknown. We show that although signaling through the TCR is sufficient to stimulate transcription of Bcl-xL mRNA, CD28, by activating PI3K and mammalian target of rapamycin, provides a critical signal that regulates the translation of Bcl-xL transcripts. We observe that CD28 induced 4E-binding protein-1 phosphorylation, an inhibitor of the translational machinery, and that CD28 costimulation directly augmented the translation of a Bcl-xL 5′-untranslated region reporter construct. Lastly, costimulation by CD28 shifted the distribution of Bcl-xL mRNA transcripts from the pretranslation complex to the translationally active polyribosomes. These results demonstrate that CD28 relieves the translational inhibition of Bcl-xL in a PI3K/mammalian target of rapamycin-dependent manner.

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“…Reviewing the literature we noticed several examples in which caspase-3 is activated independently of the mitochondrial pathway (33,34). Moreover, caspase-3 can be directly activated by non-caspase enzymes like the calcium-dependent enzyme calpain, lysosomal enzymes (35), or enzymes contained in the granules of cytotoxic cells like granzymes and perforins (36,37). Often caspase-3 activation represents the crucial effector in which inhibition blocks apoptosis (38).…”

Section: Discussionmentioning

confidence: 99%

Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways

Grassilli

Ballabeni

Maellaro

et al. 2004

Journal of Biological Chemistry

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c-Myc plays an essential role in proliferation, differentiation, and apoptosis. Because of its relevance to cancer, most studies have focused on the cellular consequences of c-Myc overexpression. Here, we address the role of physiological levels of c-Myc in drug-induced apoptosis. By using c-MYC null cells we confirm and extend recent reports showing a c-Myc requirement for the induction of apoptosis by a number of anticancer agents. In particular, we show that c-Myc is required for the induction of apoptosis by doxorubicin and etoposide, whereas it is not required for camptothecin-induced cell death. We have investigated the molecular mechanisms involved in executing doxorubicin-induced apoptosis and show caspase-3 activation by both mitochondria-dependent and -independent pathways. Moreover, serine proteases participate in doxorubicin-induced apoptosis partly by contributing to caspase-3 activation. Finally, a complete rescue from doxorubicininduced apoptosis is obtained only when serine proteases, caspase-3, and mitochondrial activation are inhibited simultaneously. Interestingly, doxorubicin requires c-Myc for the activation of all of these pathways. Our findings therefore support a model in which doxorubicin simultaneously triggers multiple c-Myc-dependent apoptosis pathways.

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Perforin‐dependent activation‐induced cell death acts through caspase 3 but not through caspases 8 or 9

Cited by 19 publications

References 47 publications

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

Granzyme B–Mediated Damage of CD8+ T Cells Impairs Graft-versus-Tumor Effect

CD28 Regulates the Translation of Bcl-xL via the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Pathway

Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways

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