Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The TET2 methylcytosine dioxygenase regulates early and late transitions in exhausted CD8+ T-cell differentiation

ABSTRACT: Epigenetic reprogramming of CAR T-cells by targeting TET2, a methylcytosine deoxygenase that mediates active DNA demethylation, has shown therapeutic potential; however, the role of TET2 in TEX development is unclear. In both CAR T-cell exhaustion models in vitro and chronic LCMV infection in vivo, TET2 drove the conversion from memory-like, self-renewing TEX progenitors towards effector (TEFF)-like and terminally differentiated TEX. TET2-deficient terminally differentiated TEX retained aspects of TEX progenitor biology, including decreased expression of the transcription factor TOX, suggesting that TET2 is required for terminal exhaustion.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE261093 | GEO | 2025/04/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate [coassay_TOXKO_LCMV_Arm_rechalle]

Project description:CD8 T cell exhaustion is a major barrier limiting anti-tumor therapy. Though checkpoint blockade temporarily improves exhausted CD8 T cell (Tex) function, the underlying epigenetic landscape of Tex remains largely unchanged, preventing their durable “reinvigoration.” Whereas the HMG-box transcription factor TOX has been identified as a critical initiator of Tex epigenetic programming, it remains unclear whether TOX plays an ongoing role in preserving Tex biology after cells commit to exhaustion. Here, we decoupled the role of TOX in the initiation versus maintenance of CD8 T cell exhaustion by temporally deleting TOX in established Tex cells. Induced TOX ablation in committed Tex resulted in apoptotic-driven loss of Tex, reduced expression of inhibitory receptors including PD-1, and a pronounced decrease in terminally differentiated subsets of Tex cells. Simultaneous gene expression and epigenetic profiling revealed a critical role for TOX in ensuring ongoing chromatin accessibility and transcriptional patterns for key Tex gene modules in committed Tex cells. Moreover, when exposed to strong effector-differentiation signals, established Tex in which TOX had been deleted acquired an altered chromatin landscape with increased accessibility at cytotoxic genes typically accessible in Teff cells, undergoing partial reprogramming into a more functional state. Together, these findings suggest that continuous TOX expression in established Tex functions as a durable epigenetic barrier to reinforce the Tex developmental fate by simultaneously maintaining Tex epigenetic commitment while restraining effector reprogramming. Manipulation of TOX even after Tex establishment could therefore provide a therapeutic opportunity to rewire Tex biology in settings of chronic infection or cancer

2025-03-01 | GSE255043 | GEO

Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate [coassay_TOXKO]

2025-03-01 | GSE255042 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [CITE-seq_PostInfection]

2023-05-31 | GSE214114 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [scRNA-seq_PostInfection]

2023-05-31 | GSE214113 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-Seq]

Project description:Here, we discovered a reciprocal antagonism between Stat5a and Tox in TEX cells. Stat5a antagonized the Tox-mediated exhaustion program to achieve a durable and protective hybrid effector/NK-like differentiation state in settings that typically drive exhaustion. Stat5 also drove TEX progenitors to differentiate into the effector-like TEXint subset, a key developmental step for PD-1 blockade responsiveness. Therapeutic enhancement of Stat5 activity in TEX cells using an orthogonal IL-2/IL2Rb pair system fostered TEXint cell accumulation and synergized with PD-L1 blockade. Finally, targeted delivery of Stat5-signals in TEX progenitors achieved partial epigenetic rewiring of these cells towards the effector/memory lineage and revived polyfunctionality. Together, these data highlight therapeutic opportunities of targeting Stat5 to antagonize the Tox-dependent epigenetic programming of TEX and provoke a hybrid program that exploits effector biology and durability for optimal therapeutic potential

2023-08-31 | GSE240431 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postChallenge]

2023-05-31 | GSE214112 | GEO

Enhanced STAT5a activation opposes Tox and rewires exhausted CD8 T cells towards a hybrid durable effector-like state during chronic stimulation [ATAC-postInfection]

2023-05-31 | GSE214111 | GEO

Distinct SWI/SNF chromatin remodelling complexes act differentially to maintain stem-like exhausted CD8 T cells [RNA-seq]

Project description:Exhausted CD8 T cells (TEX) arise during chronic viral infections and cancer and limit disease control. Three major sequential epigenetic remodeling events occur as naïve CD8 T cells (TN) differentiate into TEX: initial activation, early bifurcation between effector (TEFF) and TEX precursors, and later differentiation of effector-like and terminal TEX subsets from progenitor TEX. The epigenetic factors mediating these transitions remain poorly understood. Here, we uncovered distinct roles for two versions of the SWI/SNF chromatin remodeling complex, BAF and PBAF, in TEX differentiation using in vivo CRISPR screening. Disruption of BAF ablated antigen-specific CD8 T cells early in chronic infection, suggesting a requirement for BAF-mediated remodeling in the early epigenetic remodeling events. In contrast, depletion of PBAF subunits enhanced TEX formation and promoted progenitor TEX differentiation into more differentiated TEX subsets by limiting accessibility of TCF-1 binding sites. Loss of PBAF improved tumor control alone and in combination with anti-PD-L1. Simultaneous depletion of BAF- and PBAF-specific subunits revealed that BAF is required for the beneficial impact of loss of PBAF on TEX differentiation. Thus, BAF and PBAF regulate epigenetic transitions in CD8 T cell differentiation, with PBAF acting at a later stage in exhaustion as a guardian to limit full TEX differentiation and preserve TEX progenitor populations with implications for cancer immunotherapy.

2023-05-31 | GSE211410 | GEO

Distinct SWI/SNF chromatin remodelling complexes act differentially to maintain stem-like exhausted CD8 T cells [ATAC-seq]

2023-05-31 | GSE211409 | GEO

The Prostacyclin Receptor is a NRF2-regulated Immune Checkpoint in CD8 T cells

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data