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Early B Cell Factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells [ChIP-seq]

ABSTRACT: Apoptosis is a genetically regulated program of cell death that plays a key role in immune disease processes. We identified EBF4, a little-studied member of the early B cell factor (EBF) family of transcription factors, in a whole-genome CRISPR screen for regulators of Fas/APO-1/CD95-mediated T cell death. Loss of EBF4 increases the half-life of the c-FLIP protein and its presence in the Fas signaling complex impairs caspase-8 cleavage and apoptosis. Transcriptome analysis revealed that EBF4 regulates molecules such as TBX21, EOMES, granzyme, and perforin that are important for human natural killer (NK) and CD8+ T cell functions Bio-ID - mass spectrometry analyses showed EBF4 binding to STAT3, STAT5, and MAP kinase 3, and a strong pathway relationship to IL-2 regulated genes which are known to govern cytotoxicity pathways ChIP-seq analysis defined a canonical EBF4 binding motif 5'-CCCNNGG/AG-3' closely related to the EBF1 binding site and using a luciferase-based reporter, we found a dose-dependent transcriptional response of this motif to EBF4. We also conducted ATAC-seq in EBF4 overexpressing cells and found increased chromatin accessibility upstream of granzyme and perforin and in topologically associated domains in human lymphocytes. Finally, we discovered that the EBF4 has basal expression in human but not mouse NK cells and CD8+ T cells and vanishes following activating stimulation. Together our data reveal key features of a previously unknown transcriptional regulator of human cytotoxic immune function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206219 | GEO | 2022/07/27

REPOSITORIES: GEO

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Early B Cell Factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells [RNA-seq]

Project description:Apoptosis is a genetically regulated program of cell death that plays a key role in immune disease processes. We identified EBF4, a little-studied member of the early B cell factor (EBF) family of transcription factors, in a whole-genome CRISPR screen for regulators of Fas/APO-1/CD95-mediated T cell death. Loss of EBF4 increases the half-life of the c-FLIP protein and its presence in the Fas signaling complex impairs caspase-8 cleavage and apoptosis. Transcriptome analysis revealed that EBF4 regulates molecules such as TBX21, EOMES, granzyme, and perforin that are important for human natural killer (NK) and CD8+ T cell functions. Bio-ID - mass spectrometry analyses showed EBF4 binding to STAT3, STAT5, and MAP kinase 3, and a strong pathway relationship to IL-2 regulated genes which are known to govern cytotoxicity pathways. ChIP-seq analysis defined a canonical EBF4 binding motif 5’-CCCNNGG/AG-3’ closely related to the EBF1 binding site and using a luciferase-based reporter, we found a dose-dependent transcriptional response of this motif to EBF4. We also conducted ATAC-seq in EBF4 overexpressing cells and found increased chromatin accessibility upstream of granzyme and perforin and in topologically associated domains in human lymphocytes. Finally, we discovered that the EBF4 has basal expression in human but not mouse NK cells and CD8+ T cells and vanishes following activating stimulation. Together our data reveal key features of a previously unknown transcriptional regulator of human cytotoxic immune function.

2022-07-27 | GSE206221 | GEO

Early B Cell Factor 4 modulates FAS-mediated apoptosis and promotes cytotoxic function in human immune cells [ATAC-seq]

2022-07-27 | GSE206220 | GEO

Cytokine-enhanced cytolytic activity of Exosomes from NK Cells

Project description:Natural killer (NK) cells are a type of innate lymphocytes that play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell-cell interaction with cell surface proteins and then attack target cells via multiple mechanisms involving TRAIL, Fas Ligand, cytokine secretion, perforin, and granzymes. In addition, extracellular vesicles (EVs), including exosomes derived from NK cells (NK-EVs), possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells in a granzyme B independent manner. In addition, small RNA-seq and mass spectrometry analyses indicate that miRNA and protein profiles in EVs are altered by cytokine stimulation. We also show NK-EVs are taken up by target cells via macropinocytosis. Collectively, our findings reveal novel characteristics of NK-EVs and the mechanism of their incorporation into target cells.

2021-09-09 | PXD018982 | Pride

Cytokine-enhanced cytolytic activity of Exosomes from NK Cells [small RNA seq]

2021-05-01 | GSE150342 | GEO

CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy

Project description:CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. Although it was mechanistically illuminated in vitro, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.

2019-03-16 | GSE128392 | GEO

Transcription profiling of human Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis patients blister cells from skin lesions reveals these consist of cytotoxic T cells annd NK cells

Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis; (TEN) are life-threatening adverse drug reactions characterized; by massive epidermal necrosis, in which the specific danger; signals involved remain unclear. Here we show that blister; cells from skin lesions of SJS-TEN primarily consist of cytotoxic; T lymphocytes (CTLs) and natural killer (NK) cells, and both; blister fluids and cells were cytotoxic. Gene expression profiling; identified granulysin as the most highly expressed cytotoxic; molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids; were two to four orders of magnitude higher than perforin,; granzyme B or soluble Fas ligand concentrations, and depleting; granulysin reduced the cytotoxicity. Granulysin in the blister; fluids was a 15-kDa secretory form, and injection of it into; mouse skin resulted in features mimicking SJS-TEN. Our; findings demonstrate that secretory granulysin is a key molecule; responsible for the disseminated keratinocyte death in SJS-TEN; and highlight a mechanism for CTL- or NK cellâmediated; cytotoxicity that does not require direct cellular contact. Experiment Overall Design: Blood samples were obtained from 5 different patients with SJS/TEN. The peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood samples by Ficoll-Isopaque (Pharmacia Fine Chemicals) density gradient centrifugation. Total RNA from PBMC was isolated using the RNeasy kit (Qiagen). The 28S and 18S ribosomal RNA peak ratios were determined using microfluidics technology (Agilent). RNA was subjected to reverse transcription using the Superscript II kit (Invitrogen), and the cleaned cRNA was then hybridized to an Affymetrix human genome U133 plus 2.0 array.

2009-01-13 | E-GEOD-13727 | biostudies-arrayexpress

The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [ChIP-Seq]

Project description:The transcription factor Tcf1 plays an essential role for the development of NK cells, however, its precise role for NK cell development, maturation and function is poorly understood. Here we show that distinct domains of Tcf1 direct bone marrow progenitors towards the NK cell lineage and mediate lineage commitment and NK cell expansion, and that Tcf1 downregulation is required for terminal NK cell maturation. Impaired NK cell development in the absence of Tcf1 is explained by increased cell death due to excessive expression of Granzyme family proteins, which results in NK cell self-destruction. In addition, excessive Granzyme B expression leads to target cell induced NK cell death and consequently reduced target cell killing by NK cells lacking Tcf1. Mechanistically, Tcf1 prevents excessive Granzyme B expression by binding to a newly identified enhancer element upstream of the Granzyme B locus. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for lymphocyte development.

2017-08-23 | GSE92710 | GEO

The transcription factor Tcf1 ensures the development and cytotoxic function of NK cells by limiting the expression of Granzymes [Affymetrix]

2017-08-23 | GSE92709 | GEO

PBMS cells from SJS/TEN

Project description:Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell—mediated cytotoxicity that does not require direct cellular contact.

2008-12-04 | GSE13727 | GEO

SJS blister cells

2008-12-04 | GSE13726 | GEO

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