The prostacyclin receptor PTGIR is a NRF2-dependent regulator of CD8 T cell exhaustion
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ABSTRACT:
PROVIDER: PRJNA1231109 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32558744_1.fastq.gz | Fastqsanger.gz | |||
| SRR32558744_2.fastq.gz | Fastqsanger.gz | |||
| SRR32558745_1.fastq.gz | Fastqsanger.gz | |||
| SRR32558745_2.fastq.gz | Fastqsanger.gz | |||
| SRR32558746_1.fastq.gz | Fastqsanger.gz |
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Project description:The progressive decline of CD8 T cell effector function, also known as T cell “exhaustion” (Tex), is a major contributor to immune evasion in cancer, yet the molecular mechanisms that promote this decline remain poorly understood. Here, we identify the prostaglandin I2 receptor (PTGIR) as a cell-intrinsic driver of CD8 T cell dysfunction. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, in terminally exhausted (Tex-term) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+/TIM-3+) CD8 Tex cells in response to chronic infection or tumor challenge. NRF2 promotes the increased expression of PTGIR, a receptor for the circulating eicosanoid prostacyclin, in CD8 T cells. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient CD8 T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-gamma and granzyme production) to chronic infection and cancer. Mechanistically, PTGIR signaling blunts both bioenergetic metabolism and effector cytokine production in CD8 T cells and promotes a Tex cell signature marked by high expression of interferon-stimulated genes (ISGs). Together, these results identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.
2025-04-24 | GSE290976 | GEO
Project description:Immune checkpoint inhibitor (ICI) therapies revitalize anti-cancer responses by intercepting protein-protein interactions between exhausted CD8 T (Tex) cells and cancer cells (e.g. PD-1:PD-L1). However, up to 50% of patients receiving ICIs relapse, warranting further interrogation of the underpinnings of Tex. We conducted RNA-seq meta-analysis of Tex versus effector (Teff) mouse CD8 T cells, and highlighted NRF2 transcriptional targets as the most upregulated gene set in Tex cells. LCMV or cancer inoculation of mice bearing NRF2 hyperactive—or Keap1-/- (NRF2 negative regulator)—T cells demonstrated that NRF2 drives Tex; evidenced by increased co-inhibitory marker (PD-1/TIM-3) expression and reduced cytokine (IFN-g/Granzyme-B) production. RNA-seq of Keap1-/- highlight Ptgir—which encodes the prostacyclin lipid receptor— as the most upregulated gene versus WT T cells. Accordingly, PTGIR knockout in NRF2-hyperactive/ Tex cells decreased PD-1/TIM-3 expression, increased cytokine production, and attenuated tumor growth. Our data underscore PTGIR as a NRF2-regulated Tex driver and illuminate an unconventional immune checkpoint class potentially based on protein-lipid interactions
2025-04-25 | PXD052688 | Pride
Project description:Understanding how circulating metabolites enforce pathways in dysfunctional immune cells may illuminate modes of intervention directed at reviving immune function. The NRF2 pathway is the most widely documented cytoprotective axis in land-dwelling eukaryotes. However, the role of this pathway in CD8+ T cells—which seek and destroy tumors and pathogen infected cells—has yet to be elucidated. Our lab has conducted a RNAseq meta-analysis of CD8+ T cells upon tumor, viral and bacterial inoculation. Curiously, the NRF2 pathway was robustly upregulated in dysfunctional CD8+T cells. To further investigate the role of NRF2 in these contexts we developed a mouse model whereby the NRF2 axis is permanently hyperactivated in CD8+ T cells, hereafter referred to as NRF2Hi. Our in vivo data demonstrate that NRF2Hi CD8+ T cells offer little overall cytoprotection and poorly control tumors and pathogens versus wildtype (WT) control CD8+ T cells. To understand why upregulation of the NRF2 axis could be unfavorable to CD8+ T cell function we conducted RNAseq on NRF2Hi versus WT cells upon viral infection of mice. We found that NRF2Hi cells massively upregulate the prostacyclin receptor (PTGIR), which binds to prostacyclin—a circulating metabolite of arachidonic acid that has only been investigated in vasodilation and is seemingly benign to CD8+ T cells. To decipher the role of PTGIR in CD8+ T cells, we silenced its expression and observed a revival of CD8+ T cell function, significantly reducing tumor and pathogen burden. Collectively, our data illuminate a NRF2-regulated immune checkpoint, PTGIR. Interventions that suppress the interaction between PTGIR and prostacyclin may serve therapeutic benefit in clinical contexts such as cancer and chronic pathogen infections.
2024-07-17 | GSE244465 | GEO
Project description:The Prostacyclin Receptor is a Nrf2-regulated Immune Checkpoint in CD8+ T cells
| PRJNA1023228 | ENA
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:The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.
| S-EPMC11230227 | biostudies-literature
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:Dapl1 is a critical regulator of CD8 T cell function and exhaustion in cancer immunity
| PRJNA733194 | ENA
Project description:CAFs, ascTAMs and M1- and TAM-like-MDMs were treated with 1 μM of the Prostacyclin analoga MRE and DMSO (as solvent control). The aim of this experiment is to see which effect MRE (Prostacyclinanaloga) has on RNA expression (activation of signaling pathways). Background: Prostacyclin receptor expression is elevated in TAMs. Prostacyclinsynthase expression was detected mainly in CAFs. (
2022-12-16 | E-MTAB-12437 | biostudies-arrayexpress
Project description:To identify unique chromatin regions predicting the anti-tumor efficacy of Nrf2-deleted smart CD8+ T cell therapy, we performed an assay for transposase-accessible chromatin sequencing (ATAC-seq) using tumor-infiltrating CD8+ T cells from tumor-bearing mice transferred Nrf2-deficient CD8+ T cells. From the analysis of ATAC-seq data, we identified quantitatively distinct open regions of chromatin that distinguish Nrf2-deficient CD8+ T cells or WT CD8+ T cells.
2024-04-01 | GSE229990 | GEO