PD-1 Protects Bystander-Activated T Cells from Activation-Induced Cell Death
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ABSTRACT:
PROVIDER: PRJNA820849 | ENA |
REPOSITORIES: ENA
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Project description:PD-1 is a critical T-cell checkpoint that suppresses nonantigen-specific bystander memory T-cell activation and proliferation but also protects them from apoptotic activation-induced cell death.
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Project description:Background: Binding of the programmed death-1 (PD-1) receptor to its ligands (PD-L1/2) transduces inhibitory signals that promote exhaustion of activated T cells. Blockade of the PD 1 pathway is widely used for cancer treatment, yet the inhibitory signals transduced by PD-1 in T cells remain elusive. Methods: Expression profiles of human CD8+ T cells in resting, activated (CD3+CD28) and PD-1-stimulated cells (CD3+CD28+PD-L1-Fc) conditions were evaluated by RNA-seq. Bioinformatic analyses were used to identify signaling pathways differentially regulated in PD 1-stimulated cells.
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Project description:Enfortumab vedotin is a Nectin-4-directed antibody–drug conjugate designed to deliver the microtubule-disrupting agent monomethyl auristatin E (MMAE) in tumor cells. Using preclinical models of urothelial cancer (UC), we expand the understanding of the multifaceted mechanism of action for enfortumab vedotin that includes direct cytotoxicity on Nectin-4–positive tumor cells, indirect bystander effect on neighboring Nectin-4–negative tumor cells, and MMAE-mediated induction of immunogenic cell death (ICD) and associated increase in activated immune cells in the tumor microenvironment. Importantly, vaccination with enfortumab vedotin-treated tumor cells drives antitumor immunity and provides protection against rechallenge in mice. MMAE-mediated ICD induction modulates the tumor microenvironment in a complementary manner to immune checkpoint inhibition. Accordingly, enfortumab vedotin plus PD-1 inhibitor shows enhanced antitumor activity in vivo. These preclinical results demonstrate the underlying mechanisms consistent with the significantly improved clinical outcomes observed for enfortumab vedotin plus pembrolizumab relative to chemotherapy in the first-line treatment of la/mUC.
2024-04-19 | GSE264352 | GEO
Project description:There is much evidence that T cells may be activated via mechanisms which act independently of direct TCR ligation. Despite this, the question of whether such forms of ‘bystander’ T cell activation occur during immune responses is hotly debated. To address some outstanding questions, we set up an in vitro system within which to analyse bystander T cell activation in human T cells, in the absence of the possibility for TCR cross-reactivity. In addition, we have investigated the genetic, phenotypic, and functional characteristics of bystander activated T cells. Here, we show that bystander T cell activation is, indeed, observed during a specific immune response, and that it occurs preferentially amongst CD4+ memory T cells. Furthermore, bystander activated T cells display a distinct gene expression profile. The mechanism for bystander T cell activation involves soluble factors, and the outcome is an elevated level of apoptosis. This may provide an explanation for the attrition of T cell memory pools of heterologous specificity during immune responses to pathogens such as viruses.
2009-02-11 | GSE13738 | GEO
Project description:There is much evidence that T cells may be activated via mechanisms which act independently of direct TCR ligation. Despite this, the question of whether such forms of âbystanderâ T cell activation occur during immune responses is hotly debated. To address some outstanding questions, we set up an in vitro system within which to analyse bystander T cell activation in human T cells, in the absence of the possibility for TCR cross-reactivity. In addition, we have investigated the genetic, phenotypic, and functional characteristics of bystander activated T cells. Here, we show that bystander T cell activation is, indeed, observed during a specific immune response, and that it occurs preferentially amongst CD4+ memory T cells. Furthermore, bystander activated T cells display a distinct gene expression profile. The mechanism for bystander T cell activation involves soluble factors, and the outcome is an elevated level of apoptosis. This may provide an explanation for the attrition of T cell memory pools of heterologous specificity during immune responses to pathogens such as viruses. Experiment Overall Design: Three conditions tested with 4 biological repilicates in each: Experiment Overall Design: Resting cells - cells expressing a TCR which does not specifically recognize SEB (Vβ13.1 T cells) and did not upregulate the activation marker CD25 in response to transwell SEB-stimulated co-culture over a 5 day period. Experiment Overall Design: Bystander activated cells - cells expressing a TCR which does not specifically recognize SEB (Vβ13.1 T cells), but which did upregulate the activation marker CD25 in response to transwell SEB-stimulated co-culture over a 5 day period. Experiment Overall Design: Directly activated cells - cells expressing a TCR which is known to specifically recognize SEB (Vβ17 T cells), and which did upregulate the activation marker CD25 in response to direct SEB stimulation over a 5 day period.
2009-02-21 | E-GEOD-13738 | biostudies-arrayexpress
Project description:Follicular T-helper (TFH) cells highly express the programmed cell death-1 (PD-1) molecule. Whereas inhibition of T cell receptor (TCR) signaling and CD28 co-stimulation is thought to be the primary mode of PD-1 functions, how PD-1 regulates TFH development and function remains unclear. Here we show that, when engaged by the ensemble of bystander B cells constitutively expressing PD-1 ligand 1 (PD-L1), PD-1 inhibits T-cell recruitment into follicles. This inhibition involves suppression of PI3K activities downstream of follicle-guidance receptor CXCR5, is independent from co-signaling with the TCR, and necessitates ICOS signaling to overcome. PD-1 further restricts CXCR3 upregulation on TFH cells, serving to concentrate these cells toward the GC territory, where PD-L1-PD-1 interactions between individual TFH and B cells optimize B-cell competition and affinity maturation. Therefore, operating in both costimulation-independent and -dependent manners, PD-1 plays an integral role in orchestrating tissue positioning and function of TFH cells.
2018-08-30 | GSE112066 | GEO
Project description:The radiation bystander effect is an important component of the overall biological response of tissues and organisms to ionizing radiation. Little is known about the contribution of genome level changes in neighboring bystander cells to tissue and organ stress after irradiation. The timing of these changes is critical in the physiological context and these questions can only be answered by studying signaling and global transcriptomics in a chronological way. Here, we present a strategy to identify different biologically important signaling modules that act in concert in the radiation and bystander responses. We used time series gene expression analysis of normal human fibroblast cells measured at 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after exposure to radiation coupled with a novel clustering method targeted to short time series, Feature Based Partitioning around medoids Algorithm (FBPA), to look for genes that were potentially co-regulated. This method uses biologically meaningful features of the expression profile and dimension augmentation to address the analysis of sparse data sets such as ours. We applied FBPA and Short Time series Expression Miner (STEM) to the same datasets and present the results of our comparisons using computational metrics as well as biological enrichment. Enrichment showed that gene expression in irradiated cells fell into broad categories of signal transduction, cell cycle/cell death and inflammation/immunity; but only FBPA clustered functions well. In bystander cells, the gene expression response was also broadly categorized into functions associated with cell communication and motility, signal transduction and inflammation; but neither STEM nor FBPA separated biological functions as well as in irradiated samples. Network analysis revealed that p53 and NF-kappaB were central players in gene expression in both irradiated and bystander gene clusters. Analysis of individual clusters also suggested new regulators of gene expression in the radiation and bystander response that may act at the epigenetic level such as histone deacetylases (HDAC1 and HDAC2) and methylases (KDM5B) that can act as strong transcription repressors. Based on these results, we propose a novel time series clustering method, FBPA, as a powerful approach that can be applied to sparse data sets (including genomic profiling data), where the choice of features selected for clustering and stringent statistical outcome analysis can augment our knowledge of the underlying cellular mechanisms in biological processes. There are 72 total samples, 4 corresponding biological replicates of IMR90 cells that were not irradiated (control=C), irradiated (alpha=A) and bystander (B), cells were harvested at 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after treatment
2011-01-14 | E-GEOD-21059 | biostudies-arrayexpress
Project description:The radiation bystander effect has been documented with multiple endpoints in various models. While many of the factors regulating this response are known, the mechanisms are still not well understood, and even less is known about signaling of bystander responses in 3-dimensional (3D) tissues. We have used the EPI-200 3D epidermal tissue model to measure global gene expression changes in bystander tissue in order to gain insight into the molecular pathways involved. We identified 187 genes with significantly altered expression in the region between 250 μm and 1 mm from the site of irradiation four hours after exposure. Gene expression at 250-500 μm and 500-750 μm was similar to that within the first 250 μm, the region that also included the directly irradiated tissue. Gene expression, although still significantly altered, began to return toward control levels in the region between 750 μm and 1 mm, however, suggesting a spatial limit to the bystander signal. The 3D bystander genes were concentrated in gene ontology classifications associated with direct irradiation, such as regulation of cell cycle progression and cell death, as well as categories previously associated with bystander responses, such as extracellular signaling, inflammatory processes, and terminal differentiation.
2016-09-10 | GSE32541 | GEO
Project description:Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation
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