A core stemness program in exhausted CD8+ T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1201764 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31802900_1.fastq.gz | Fastqsanger.gz | |||
| SRR31802900_2.fastq.gz | Fastqsanger.gz | |||
| SRR31802901_1.fastq.gz | Fastqsanger.gz | |||
| SRR31802901_2.fastq.gz | Fastqsanger.gz | |||
| SRR31802853_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Persistent antigen stimulation exposes CD8+ T cells to various metabolic stresses and induces a dysfunctional state termed T-cell exhaustion. Exhausted CD8+ T cells are continuously replenished by a recently discovered self-renewing stem-like CD8+ T-cell subset, which maintains long-term immunity and provides proliferative burst in response to immunotherapies. Although the redox system plays an important role in regulating T-cell activation, how cellular redox affects the differentiation of stem-like and exhausted CD8+ T cells is incompletely understood. Here, we showed that both antigen stimulation and terminal differentiation reduced mitochondrial oxidation and reactive oxygen species (ROS) in exhausted CD8+ T cells, which displayed a chromatin state primed for regulation by the redox sensing KEAP1-NRF2 pathway. During chronic viral infection, KEAP1 promoted expansion of antiviral CD8+ T cells and facilitated their differentiation into the stem-like subset in a cell autonomous manner. In addition, KEAP1 was required for establishing proper transcriptional programs of stem-like and exhausted CD8+ T cells. Mechanistically, KEAP1 maintained oxidation by upregulating genes involved in mitochondrial oxidation and repressing NRF2-driven transcription of antioxidant pathways. Deleting KEAP1 binding domain in NRF2 released NRF2 from regulation by KEAP1, impaired expansion and stemness of CD8+ T cells, and dysregulated multiple metabolic pathways including redox pathways. Thus, our study revealed a novel role of the redox pathway in regulating the molecular program and differentiation of stem-like and exhausted CD8+ T cells during chronic antigen stimulation.
2024-11-11 | GSE224756 | GEO
Project description:In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of approximately 216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.
2025-04-23 | GSE285181 | GEO
Project description:In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of approximately 216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.
2025-04-23 | GSE285178 | GEO
Project description:In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of approximately 216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.
2025-04-23 | GSE285186 | GEO
Project description:In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of approximately 216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.
2025-04-23 | GSE285184 | GEO
Project description:In chronic viral infections, sustained CD8+ T cell response relies on TCF1+ precursor exhausted T cells (TPEX) exhibiting stem-like properties. TPEX self-renew and respond to PD-1 blockade, underscoring their paramount importance. However, strategies for effectively augmenting TPEX remain limited. Here, we demonstrate that ZC3H12A deficiency initiates a stemness program in TPEX but also increases cell death, whereas BCOR deficiency predominantly promotes TPEX proliferation. Consequently, co-targeting of both BCOR and ZC3H12A imparts exceptional stemness and functionality to TPEX, thereby enhancing viral control. Mechanistically, BCOR and ZC3H12A collaboratively suppress a core stemness program in TPEX characterized by heightened expression of approximately 216 factors. While TCF1 plays a role, this core stemness program relies on novel factors, including PDZK1IP1, IFIT3, PIM2, LTB, and POU2F2. Crucially, overexpressing POU2F2 robustly boosts TPEX and enhances antiviral immunity. Thus, a core stemness program exists in exhausted T cells, jointly repressed by BCOR and ZC3H12A, robustly controlling TPEX differentiation and providing new targets for addressing T cell exhaustion.
2025-04-23 | GSE285183 | GEO
Project description:CD8 T cells normally differentiate from resting naïve T cells into function effector and then memory CD8 T cells following acute infections. During chronic viral infections, however, virus-specific CD8 T cells often become exhausted. We used microarrays to examine the gene expression differences between naive, effector, memory and exhausted virus-specific CD8 T cells following lymphocytic choriomeningitis virus infection. Experiment Overall Design: Three or four independent samples were sorted by flow cytometry for each cell type (naive, effector, memory and exhausted) virus-specific CD8 T cells. RNA was extracted and hybridized to Affymetrix microarrays.
2008-06-16 | E-GEOD-9650 | biostudies-arrayexpress
Project description:Exhausted T cells express multiple co-inhibitory molecules that impair their function and limit immunity to chronic viral infection. Defining novel markers of exhaustion is important both for identifying and potentially reversing T cell exhaustion. Herein, we show that the ectonucleotidse CD39 is a marker of exhausted CD8+ T cells. CD8+ T cells specific for HCV or HIV express high levels of CD39, but those specific for EBV and CMV do not. CD39 expressed by CD8+ T cells in chronic infection is enzymatically active, co-expressed with PD-1, marks cells with a transcriptional signature of T cell exhaustion and correlates with viral load in HIV and HCV. In the mouse model of chronic Lymphocytic Choriomeningitis Virus infection, virus-specific CD8+ T cells contain a population of CD39high CD8+ T cells that is absent in functional memory cells elicited by acute infection. This CD39high CD8+ T cell population is enriched for cells with the phenotypic and functional profile of terminal exhaustion. These findings provide a new marker of T cell exhaustion, and implicate the purinergic pathway in the regulation of T cell exhaustion. CD8+ T cells from subjects with HCV infection were sorted and pelleted and re-suspended in TRIzol (Invitrogen). RNA extraction was performed using the RNAdvance Tissue Isolation kit (Agencourt). Concentrations of total RNA were determined with a Nanodrop spectrophotometer or Ribogreen RNA quantification kits (Molecular Probes/Invitrogen). RNA purity was determined by Bioanalyzer 2100 traces (Agilent Technologies). Total RNA was amplified with the WT-Ovation Pico RNA Amplification system (NuGEN) according to the manufacturer's instructions. After fragmentation and biotinylation, cDNA was hybridized to HG-U133A 2.0 microarrays (Affymetrix).
2015-09-08 | E-GEOD-72752 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-04-23 | GSE285187 | GEO
Project description:Bryostatin-1, a pharmacological agent from marine organisms, has been studied for HIV and cancer therapies due to its modulation of protein kinase C. In our previous study (Zhao M et al. Pharmacological research. 2019;139:524-34.), we found that bryostatin-1 downregulated inhibitory receptor PD-1 on activated CD8+ T cells from people with HIV. Since HIV-specific CD8+ T cells become functionally exhausted during chronic HIV infection and PD-1 expression is known to be related to the exhaustion state of these cells, we hypothesized that bryostatin-1 may modulate CD8+ T cell exhaustion. To test this, we generated in vitro exhausted OT-I CD8+ T cells as previously described (Zhao M et al PLoS Pathog. 16(6): e1008555) by repeatedly stimulating cells with OVA(257-264) peptide. Then we treated both exhausted CD8+ T cells (repeat peptide stimulated cells) and non-exhausted CD8+ T cells (single peptide stimulated cells) with bryostatin-1 for 3 days. We found that bryostatin-1 decreased exhaustion-associated markers and improved the functionality of exhausted CD8+ T cells. To investigate the underlying mechanism of how bryostatin-1 exerts its effects on exhausted CD8+ T cells, we performed RNA-sequencing (RNA-seq) on in vitro exhausted OT- I CD8+ T cells which were treated with bryostatin-1 or DMSO, with single peptide stimulated cells as non-exhausted controls. Taken together, our study demonstrate bryostatin-1's effect on exhausted CD8+ T cells and bryostatin-1's potential in enhancing T cell immunity against chronic infection or cancer.
2025-01-06 | GSE284406 | GEO