Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A post-translational regulatory map of chronic antigen-driven human T cell dysfunction

ABSTRACT: T cells exposed to persistent antigen, either in the context of chronic viral infections or tumors, iteratively lose both self-renewal and cytotoxic capacity. Several transcriptional, epigenetic, and metabolic drivers of this process have been identified. However, the post-transcriptional regulatory mechanisms influencing the proteome of dysfunctional T cells are not well understood. Here we present a time-resolved cysteine reactivity landscape of human T cells during the development of chronic antigen-driven dysfunction. Persistent T cell receptor stimulation of human T cells following activation significantly remodeled the T cell proteome compared with cytokine-mediated expansion, including changes in canonical T cell exhaustion-associated proteins as well as proteins related to mitochondrial function, redox homeostasis, nucleotide metabolism, and cell cycle progression. Exhausted T cells displayed frequent reactivity changes in nucleotide-binding domains across several protein classes that were associated with progressive loss of mitochondrial ATP production and activation of nucleotide salvage. Our comprehensive proteomic resource thus reveals a unique set of post-transcriptional changes as part of an exhausted T cell program and lays the groundwork for novel cysteine-directed therapeutics to enhance cancer immunotherapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE294111 | GEO | 2026/04/15

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcriptomic analysis of antigen-specific CD4 T cells infiltrating the liver (Figure 6)

Project description:Antigen-specific CD4 T cells immuno-exhausted transcriptional profile after local antigen reactivity in the liver.

2024-12-19 | GSE269525 | GEO

Strength of CD28 costimulation directs self-renewal or differentiation of TCF-1+ PD-1+ CD8 T cells through metabolic regulation

Project description:During persistent antigen stimulation, such as in chronic infections and cancer, T cells differentiate into a hypofunctional exhausted state to survive. Exhausted PD-1+ CD8 T cell responses are sustained by TCF-1+ precursors (Tpex) that self-renew or differentiate into exhausted T cells (Tex) that retain some effector function. Tpex have high expression of the costimulatory molecule CD28 and are the cells that respond to PD-1 targeted immunotherapy. Here, we demonstrate that abrogation of CD28 signaling impairs maintenance of anti-viral T cell responses during chronic infection. Low-level CD28 signaling was required to preserve mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation. Our findings show that CD28 signaling is essential for long-term maintenance of antigen-specific T cells during chronic stimulation, and suggest that the activation status of antigen presenting cells determines Tpex differentiation into more functional effector-like Tex cells.

2023-07-01 | GSE200506 | GEO

Redox sensor KEAP1 promotes stemness and prevents reductive stress in exhausted CD8+ T cells via inhibiting NRF2

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

Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours

Project description:Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours

| PRJNA1336097 | ENA

Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours.

Project description:Antigen reactivity defines tissue-resident memory and exhausted T cells in tumours.

| PRJNA1336637 | ENA

Endoplasmic reticulum proteostasis in senescent cells is a vulnerability to senolytic vanadyl sulfate

Project description:Lifestyles including dietary choices have a major impact on shaping of human physiology and health, including aging. However, the underlying mechanisms remain largely unknown. Here, we use a blood nutrient compound library-based screening approach to demonstrate that vanadyl sulfate (VS), a mineral dietary supplement, selectively induces cell death in senescent cells, thus extends lifespan and ameliorates phenotypes of aging and age-related disorders in vivo. Integrated functional omics strategies including activity-based protein profiling reveal that senescent cells accumulate glutathione disulfide, leading to overall reduced cysteine reactivity of the proteome but elevated cysteine reactivity of proteins that are crucial for endoplasmic reticulum (ER) proteostasis, which licenses VS to effectuate senolysis. VS inactivates reactive cysteines on proteins to form incorrect disulfide bonds, causing aberrant protein misfolding and aggregation that sabotage ER proteostasis, leading to senescent cell death. Our findings uncover a unique vulnerability of senescent cells for therapeutic exploration to treat aging and age-related disorders.

2025-12-15 | GSE284342 | GEO

Reversible mitochondrial dysfunction drives terminal T-cell exhaustion

Project description:The failure of T-cells to control tumor growth has been associated with several functional defects that collectively lead to T-cell “exhaustion.” This phenotype results from chronic antigen stimulation within the tumor microenvironment, but how repetitive antigenic stimulation leads to T-cell exhaustion remains poorly defined. Here we show that persistent antigen stimulation induces mitochondrial oxidative stress that reduces tricarboxylic acid (TCA) cycle activity. The resultant bioenergetic compromise impairs nucleotide triphosphate synthesis, induces endoplasmic reticulum (ER) stress, and activates an exhaustion-associated gene expression program. Reversal of oxidative stress with N-acetylcysteine effectively restores T-cell proliferation, effector function, and memory-associated gene expression and enhances anti-tumor T-cell efficacy in vivo. These data reveal that induction of mitochondrial oxidative stress is a critical component of terminal T-cell dysfunction. Furthermore, treatments that restore mitochondrial redox are sufficient to prevent T-cell exhaustion and enhance anti-tumor immunity.

2020-05-21 | GSE138459 | GEO

Single cell analysis of CD45+ immune cells from the islets of non-obese diabetic (NOD) mice

Project description:Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear if and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using non-obese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs. More IGRP-specific T cells resided in the peripheral lymphoid organs than in islets. To examine the impact of extra-islet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen presenting cells. Antigen exposure in the extra-islet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce IFNγ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.

2024-03-05 | GSE247956 | GEO

ZFP148 is a transcriptional regulator of effector CD8+ T cell differentiation [single-cell_multiome]

Project description:Chronic antigen exposure, as seen in persistent viral infections and cancer, drives CD8⁺ T cells to differentiate into diverse subsets: progenitor/stem-like, effector, and exhausted/dysfunctional cells. While genetic and epigenetic factors influencing these subsets are known, the mechanisms regulating their dynamic balance remain unclear. We identified Zinc-Finger Protein 148 (ZFP148) as a novel transcriptional checkpoint in CD8⁺ T cell effector differentiation. Using a genetic approach that deletes ZFP148 specifically in CD8+ T cells, we performed matched single cell RNA-seq and ATAC-seq on antigen-specific CD8+ T cells.

2026-02-02 | GSE297040 | GEO

The immune profile of circulating autoreactive CD4 T cells is imprinted through tissue activation during autoimmune liver diseases (TTm)

Project description:Autoimmune liver diseases (AILD) are immune-mediated disorders in which CD4 T cells play a central role. However, the link between circulating self-antigen-specific CD4 T cells and the targeted tissue has not been extensively studied in AILD. We hypothesized that circulating autoreactive CD4 T cells were clonally and functionally related to dominant intra-hepatic pathogenic CD4 T cell clones. Single cell transcriptomic analysis of circulating self-antigen-specific CD4 T cells revealed a specific B-helper and immuno-exhausted transcriptional profile, which was conserved for different autoantigens, but distinct from several other types of foreign antigen specificities. In the blood, the dominant hepatic CD4 T cell clones had a similar transcriptomic signature and were enriched in the PD-1+ TIGIT+ HLA-DR+ CD4 T cell subset. In a mouse model, antigen-specific CD4 T cells acquired the immuno-exhausted transcriptional profile when they accumulated in the liver after local antigen reactivity. Locally, immune checkpoint molecules controlled the response of antigen-specific CD4 T cells responsible for liver damage. Our study reveals the origin and biology of liver-derived autoreactive CD4 T cells in the blood of AILD patients that are imprinted by the liver environment, and suggest a dysregulation of the immune checkpoint molecules pathways. Our study enables tracking and isolating circulating autoreactive CD4 T cells for future diagnostic and therapeutic purposes.

2024-12-19 | GSE270738 | GEO

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