In Vitro Modeling of CD8 T Cell Exhaustion [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA868692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21012521.fastq.gz | Fastqsanger.gz | |||
| SRR21012522.fastq.gz | Fastqsanger.gz | |||
| SRR21012523.fastq.gz | Fastqsanger.gz | |||
| SRR21012524.fastq.gz | Fastqsanger.gz | |||
| SRR21012525.fastq.gz | Fastqsanger.gz |
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Project description:In Vitro Modeling of CD8 T Cell Exhaustion
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Project description:RNA-seq was used to study the gene expression of Invitro CD8 T cell exhaustion cells
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Project description:ATAC-seq was used to study the chromatin landscape of Invitro CD8 T cell exhaustion cells
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Project description:Epigenetic scarring of terminally dysfunctional CD8 T cells hinders long-term protection and response to immune checkpoint blockade during chronic infections and cancer. We developed a faithful in vitro model for CD8 T cell terminal dysfunction as a platform to advance T cell immunotherapy. Using TCR-transgenic CD8 T cells, we found that 1-week peptide stimulation, mimicking conditions in previous models, failed to induce a stable exhaustion program. In contrast, prolonged stimulation for 2-3 weeks induced T cell dysfunction but triggered activation-induced cell death, precluding long-term investigation of exhaustion programs. To better mimic in vivo exhaustion, we provided post-effector, chronic TGFβ1 signals, enabling survival of chronically stimulated CD8 T cells for over 3 weeks. These conditions induced a stable state of terminal dysfunction (TDysf), marked by a stable loss of effector, cytotoxicity, and memory programs, along with mitochondrial stress and impaired protein translation. Importantly, transcriptomic and epigenetic analyses confirmed the development of terminal exhaustion-specific signatures in TDysf cells. Adoptive transfer of TDysf cells revealed their inability to recall effector functions or proliferate after acute LCMV rechallenge. This novel tractable model system enables investigation of molecular pathways driving T cell terminal dysfunction and discovery of new therapeutic targets for cancer or chronic infections.
2025-08-08 | GSE304671 | GEO
Project description:CD8+ T cells isolated from HCC tissue were divided into three groups: PD1-TIM3- CD8+ TILs, exhibiting full effector function; PD1-intTIM3+ CD8+ TILs, exhibiting partial exhaustion; and PD1-hiTIM3+ CD8+ TILs, exhibiting severe exhaustion, as reflected by the differences in their ability to produce effector cytokines respectively. Transcriptome sequence analysis was performed to investigate the gene expression profile was performed.
2019-12-31 | E-MTAB-7278 | biostudies-arrayexpress
Project description:Epigenetic scarring of terminally dysfunctional CD8 T cells hinders long-term protection and response to immune checkpoint blockade during chronic infections and cancer. We developed a faithful in vitro model for CD8 T cell terminal dysfunction as a platform to advance T cell immunotherapy. Using TCR-transgenic CD8 T cells, we found that 1-week peptide stimulation, mimicking conditions in previous models, failed to induce a stable exhaustion program. In contrast, prolonged stimulation for 2-3 weeks induced T cell dysfunction but triggered activation-induced cell death, precluding long-term investigation of exhaustion programs. To better mimic in vivo exhaustion, we provided post-effector, chronic TGFβ1 signals, enabling survival of chronically stimulated CD8 T cells for over 3 weeks. These conditions induced a stable state of terminal dysfunction (TDysf), marked by a stable loss of effector, cytotoxicity, and memory programs, along with mitochondrial stress and impaired protein translation. Importantly, transcriptomic and epigenetic analyses confirmed the development of terminal exhaustion-specific signatures in TDysf cells. Adoptive transfer of TDysf cells revealed their inability to recall effector functions or proliferate after acute LCMV rechallenge. This novel tractable model system enables investigation of molecular pathways driving T cell terminal dysfunction and discovery of new therapeutic targets for cancer or chronic infections.
2025-08-08 | GSE304670 | GEO
Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Determination of NFAT1 binding sites in CD8 T cells in vitro
2015-02-13 | E-GEOD-64407 | biostudies-arrayexpress
Project description:During persistent antigen stimulation, CD8+ cytolytic T cells (CTL) show a gradual decrease in effector function, or “exhaustion”, which impairs the immune response to tumors and infections. Here we show that NFAT, a transcription factor with an established role in T cell activation, in parallel controls a second transcriptional program conferring the characteristic features of CD8+ T cell exhaustion, including upregulation of genes encoding inhibitory cell surface receptors and diminished TCR signaling. Expression of an engineered NFAT1, which induces this negative regulatory program in the absence of the effector program, interferes with the ability of CD8+ T cells to protect against Listeria infection or attenuate tumor growth in vivo. NFAT elicits this second program of gene expression in large part by binding to a subset of the sites occupied by NFAT during a typical effector response, suggesting that a balance between the two pathways determines the outcome of TCR signaling. Understanding the role of CA-RIT-NFAT1 in T cells
2015-02-13 | E-GEOD-64408 | biostudies-arrayexpress
Project description:Exhausted CD8 T cells result from chronic antigen stimulation and have reduced ability to clear disease. The epigenetic regulation of the dysfunctional phenotype of exhausted CD8 T cells is a promising avenue for therapies aimed at reversing or preventing CD8 T cell exhaustion. Here, utilizing an in vitro model, we show global increase of the repressive histone modification H3K27me3 in CD8 T cell exhaustion as well as increased gene expression of the subunits of PRC2, the complex responsible for H3K27me3 deposition. H3K27me3 correlated with decreased gene expression and localized to naïve/memory T cell genes in CD8 T cell exhaustion. PRC2 inhibition increased expression of many of these naïve/memory genes while reducing expression of key exhaustion genes. Further, we identified potential enhancers and transcription factors predicted to promote expression of the PRC2 subunits. Our study highlights the importance of the repressive epigenetic landscape of exhausted CD8 T cells as well as a novel role for PRC2 in T cell biology.
2024-10-31 | GSE263885 | GEO