ArticleJournal of immunology (Baltimore, Md. : 1950)2014
Real-time detection of CTL function reveals distinct patterns of caspase activation mediated by Fas versus granzyme B.
Article in Journal of immunology (Baltimore, Md. : 1950), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
What it found
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Who cites it
15 citing papers in PubMed, 31 citations in OpenAlex.
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- Ex Vivo Expanded and Activated Natural Killer Cells Prolong the Overall Survival of Mice with Glioblastoma-like Cell-Derived Tumors.International journal of molecular sciences · 2021Article
- NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing.The Journal of experimental medicine · 2019Article
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- IFN-γ orchestrates tumor elimination, tumor dormancy, tumor escape, and progression.Journal of leukocyte biology · 2018Review
- Single-Fluorescent Protein Reporters Allow Parallel Quantification of Natural Killer Cell-Mediated Granzyme and Caspase Activities in Single Target Cells.Frontiers in immunology · 2018Article
- Imaging Proteolytic Activities in Mouse Models of Cancer.Methods in molecular biology (Clifton, N.J.) · 2018Article
- Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation.Journal of immunology research · 2016Review
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Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Activation of caspase-mediated apoptosis is reported to be a hallmark of both granzyme B- and Fas-mediated pathways of killing by CTLs; however, the kinetics of caspase activation remain undefined owing to an inability to monitor target cell-specific apoptosis in real time. We have overcome this limitation by developing a novel biosensor assay that detects continuous, protease-specific activity in target cells. Biosensors were engineered from a circularly permuted luciferase, linked internally by either caspase 3/7 or granzyme B/caspase 8 cleavage sites, thus allowing activation upon proteolytic cleavage by the respective proteases. Coincubation of murine CTLs with target cells expressing either type of biosensor led to a robust luminescent signal within minutes of cell contact. The signal was modulated by the strength of TCR signaling, the ratio of CTL/target cells, and the type of biosensor used. Additionally, the luciferase signal at 30 min correlated with target cell death, as measured by a (51)Cr-release assay. The rate of caspase 3/7 biosensor activation was unexpectedly rapid following granzyme B- compared with Fas-mediated signal induction in murine CTLs; the latter appeared gradually after a 90-min delay in perforin- or granzyme B-deficient CTLs. Remarkably, the Fas-dependent, caspase 3/7 biosensor signal induced by perforin-deficient human CTLs was also detectable after a 90-min delay when measured by redirected killing. Thus, we have used a novel, real-time assay to demonstrate the distinct pattern of caspase activation induced by granzyme B versus Fas in human and murine CTLs.
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