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3 results on '"Astrid Cleven"'

1. RhoB Mediates Phosphoantigen Recognition by Vγ9Vδ2 T Cell Receptor

Author

Zsolt Sebestyen, Wouter Scheper, Anna Vyborova, Siyi Gu, Zuzana Rychnavska, Marleen Schiffler, Astrid Cleven, Coraline Chéneau, Martje van Noorden, Cassie-Marie Peigné, Daniel Olive, Robert Jan Lebbink, Rimke Oostvogels, Tuna Mutis, Gerrit Jan Schuurhuis, Erin J. Adams, Emmanuel Scotet, and Jürgen Kuball

Subjects
Biology (General), QH301-705.5
Abstract

Human Vγ9Vδ2 T cells respond to tumor cells by sensing elevated levels of phosphorylated intermediates of the dysregulated mevalonate pathway, which is translated into activating signals by the ubiquitously expressed butyrophilin A1 (BTN3A1) through yet unknown mechanisms. Here, we developed an unbiased, genome-wide screening method that identified RhoB as a critical mediator of Vγ9Vδ2 TCR activation in tumor cells. Our results show that Vγ9Vδ2 TCR activation is modulated by the GTPase activity of RhoB and its redistribution to BTN3A1. This is associated with cytoskeletal changes that directly stabilize BTN3A1 in the membrane, and the subsequent dissociation of RhoB from BTN3A1. Furthermore, phosphoantigen accumulation induces a conformational change in BTN3A1, rendering its extracellular domains recognizable by Vγ9Vδ2 TCRs. These complementary events provide further evidence for inside-out signaling as an essential step in the recognition of tumor cells by a Vγ9Vδ2 TCR.

Published
2016
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2. Uncovering the mode of action of engineered T cells in patient cancer organoids

Author

Johanna F. Dekkers, Maria Alieva, Astrid Cleven, Farid Keramati, Amber K. L. Wezenaar, Esmée J. van Vliet, Jens Puschhof, Peter Brazda, Inez Johanna, Angelo D. Meringa, Heggert G. Rebel, Maj-Britt Buchholz, Mario Barrera Román, Amber L. Zeeman, Sam de Blank, Domenico Fasci, Maarten H. Geurts, Annelisa M. Cornel, Else Driehuis, Rosemary Millen, Trudy Straetemans, Mara J. T. Nicolasen, Tineke Aarts-Riemens, Hendrikus C. R. Ariese, Hannah R. Johnson, Ravian L. van Ineveld, Froso Karaiskaki, Oded Kopper, Yotam E. Bar-Ephraim, Kai Kretzschmar, Alexander M. M. Eggermont, Stefan Nierkens, Ellen J. Wehrens, Henk G. Stunnenberg, Hans Clevers, Jürgen Kuball, Zsolt Sebestyen, Anne C. Rios, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Biomedical Engineering, Molecular Medicine, Bioengineering, Applied Microbiology and Biotechnology, Biotechnology
Abstract

Extending the success of cellular immunotherapies against blood cancers to the realm of solid tumors will require improved in vitro models that reveal therapeutic modes of action at the molecular level. Here we describe a system, called BEHAV3D, developed to study the dynamic interactions of immune cells and patient cancer organoids by means of imaging and transcriptomics. We apply BEHAV3D to live-track >150,000 engineered T cells cultured with patient-derived, solid-tumor organoids, identifying a ‘super engager’ behavioral cluster comprising T cells with potent serial killing capacity. Among other T cell concepts we also study cancer metabolome-sensing engineered T cells (TEGs) and detect behavior-specific gene signatures that include a group of 27 genes with no previously described T cell function that are expressed by super engager killer TEGs. We further show that type I interferon can prime resistant organoids for TEG-mediated killing. BEHAV3D is a promising tool for the characterization of behavioral-phenotypic heterogeneity of cellular immunotherapies and may support the optimization of personalized solid-tumor-targeting cell therapies.

Published
2022

3. Androgen-inducible gene 1 increases the ER Ca(2+) content and cell death susceptibility against oxidative stress

Author

Axel Methner, Dmitrij Lisak, Astrid Cleven, Lars Schneider, Vitalij Enders, and Nadine Nickel

Subjects
0301 basic medicine, Male, Programmed cell death, Gene Expression, Biology, Endoplasmic Reticulum, 03 medical and health sciences, Mice, Protein Domains, Gene expression, Genetics, Animals, Sex Characteristics, Cell Death, Endoplasmic reticulum, Membrane Proteins, General Medicine, Embryo, Mammalian, Molecular biology, Transmembrane protein, Cell biology, Mice, Inbred C57BL, Transmembrane domain, Cytosol, Alternative Splicing, Oxidative Stress, 030104 developmental biology, Membrane protein, Organ Specificity, Membrane topology, Calcium, Female
Abstract

Androgen-induced gene 1 (AIG1) is a transmembrane protein implicated with survival (its expression level was shown to correlate with the survival of patients suffering from hepatocellular carcinoma) and Ca(2+) signaling (over-expression of AIG1 increased transcription mediated by the Ca(2+)-dependent nuclear factor of activated T cells). We aimed to shed light on this less-studied protein and investigated its tissue expression, genomic organization, intracellular localization and membrane topology as well as its effects on cell death susceptibility and the Ca(2+) content of the endoplasmic reticulum. Immunoblotting of mouse tissues demonstrated highest expression of AIG1 in the liver, lung and heart. AIG1 has a complex genomic organization and expresses several splice variants in a tissue-dependent manner. Analyzing the topology of AIG1 in the ER membrane using a protease-protection assay suggested that AIG has five transmembrane domains with a luminal N- and cytosolic C-terminus and a hydrophobic stretch between the third and fourth membrane domain that does not cross the membrane. AIG1 over-expression slightly increased susceptibility to oxidative stress, which correlated with an increased ER Ca(2+) concentration in two different cell lines. Together, these results indicate that AIG1 plays a role in the control of the intracellular Ca(2+) concentration and cell death susceptibility.

Published
2015

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