Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A novel purine salvage pathway protects CD8 T cells from metabolic stress

ABSTRACT: Chronic metabolic stress impacts the immune cell function, increasing the incidence of autoimmune diseases and cancers. Whether past history of a high fat diet (HFD) leads to immune dysfunction is less understood. Moreover, whether factors other than persistent epigenetic changes would impact on the immune function remain unknown. We find that even a transient exposure to HFD causes persistent metabolome changes and long-term vulnerability of CD8 T cells to oxidative stress. The past HFD signature of CD8 T cells includes enrichment of lipid species highly susceptible to ferroptosis, and depletion of metabolites with anti-oxidant function. We find that xanthine, through the salvage purine pathway fuels the GTP, which is subsequently converted to tetrahydrobiopterin (BH4) and dihydrobiopterin (BH2). Xanthine-derived biopterins serve as ROS scavengers, rescuing CD8 T cells from activation-induced ferroptosis. Administration of xanthine or BH2 markedly reduces tumor growth in mice transiently fed HFD. Our data uncover that metabolic stress remains tattooed on membrane lipids, generating vulnerability to oxidative stress and ferroptosis, that can be mitigated by purine salvage pathway through the replenishment of guanines and biopterins pools.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Sidonia Fagarasan

PROVIDER: PXD063309 | JPOST Repository | Mon Feb 09 00:00:00 GMT 2026

REPOSITORIES: jPOST

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20231116_2406-2420_SidoniaLab_re_DIA-NN_output.zip	Other
	231116_480_DIA_CB_MM_23_2406.raw	Raw
	231116_480_DIA_CB_MM_23_2407.raw	Raw
	231116_480_DIA_CB_MM_23_2408.raw	Raw
	231116_480_DIA_CB_MM_23_2409.raw	Raw

Items per page:

1 - 5 of 17

Similar Datasets

A defective pentose phosphate pathway reduces inflammatory macrophage responses during hypercholesterolemia

Project description:Metabolic reprogramming has emerged as a crucial regulator of immune cell activation but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function.

2018-10-31 | GSE107412 | GEO

Taldo1 Knockdown impaired NADPH production in CD8+ T cells

Project description:Transaldolase (TALDO1), is a key enzyme in the non-oxidative pentose phosphate pathway. However, the impact of Taldo1 disruption on CD8+ T cell differentiation and function remains undefined. Here, we found that knockdown of Taldo1 in CD8+ T cells impairs NADPH production, causes ribose-5-phosphate accumulation, elevates oxidative stress, reduces lipid synthesis, induces mitochondrial dysfunction, and compromises effector cell proliferation, cytokine production, and antitumor efficacy, whereas enhancing Taldo1 promotes memory T cell differentiation, persistence, and recall responses during immune challenges.

2026-02-08 | GSE315519 | GEO

Tkt knockdown impaired NADPH production in CD8+ T cells

Project description:Transketolase (TKT) is a key enzyme in the non-oxidative pentose phosphate pathway. However, the impact of Taldo1 disruption on CD8+ T cell differentiation and function remains undefined. Here, we found that knockdown of Taldo1 in CD8+ T cells impairs NADPH production, causes ribose-5-phosphate accumulation, elevates oxidative stress, reduces lipid synthesis, induces mitochondrial dysfunction, and compromises effector cell proliferation, cytokine production, and antitumor efficacy, whereas enhancing Taldo1 promotes memory T cell differentiation, persistence, and recall responses during immune challenges.

2026-02-08 | GSE315826 | GEO

The Tumor Microenvironment Imposes Persistent ATF4 in CD8+ TILs to Obstruct Cancer Control

Project description:The T cell-intrinsic element that responds to tumor microenvironment (TME) stress to shape CD8+ tumor infiltrating lymphocyte (TIL) fate and function in solid cancers remains elusive. Here we report that the hypoxic TME imprints persistent activity of the central transcriptional node of the integrated stress response (ISR), activating transcription factor 4 (ATF4), in CD8+ TILs that results in metabolic polarity, mitochondrial oxidative stress, and cell death. Chronic ATF4 expression replicated the terminal exhaustion cell state in CD8+ T cells and high Atf4 expression in bulk tumor or peripheral T cells of patients with melanoma predicted poor response to PD-1 inhibition. Genetic or pharmacologic attenuation of ATF4 reduced mitochondrial oxidative stress and promoted viability among CD8+ TILs, enabling complete responses to PD-1 inhibition and conferring protection from re-emergent disease. Our multidisciplinary approach identifies chronic ATF4 activity as a barrier to immune checkpoint inhibitors, positioning ISR therapeutics as novel treatment strategies to improve efficacy of immunotherapy combinations.

2025-06-23 | GSE300172 | GEO

Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics

Project description:Regulatory T cells (Tregs) are critical for maintaining immune homeostasis and preventing autoimmunity. Here, we show that the non-oxidative pentose phosphate pathway (PPP) regulates Treg function to prevent autoimmunity. Deletion of transketolase (TKT), an indispensable enzyme of non-oxidative PPP, in Tregs causes a fatal autoimmune disease in mice, with impaired Treg suppressive capability despite regular Treg numbers and normal Foxp3 expression levels. Mechanistically, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced -KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient Tregs. We also find that TKT levels are frequently downregulated in Tregs of patients with autoimmune disorders. Our study identifies the non-oxidative PPP as an integrator of metabolic and epigenetic processes that control Treg function.

2022-03-31 | GSE198995 | GEO

Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in epididymal adipose tissue of diet-induced obese mice

Project description:We examined the effect of quercetin on the gene expression and function of epididymal adipose tissue (EAT) in Western diet-induced obese mice. Quercetin suppressed the increase in the number of macrophages and the decrease in the ratio of CD4+ to CD8+ T cells in EAT, and the elevation of plasma leptin and TNFÎ± levels in mice fed the Western diet. Comprehensive gene expression analysis revealed that quercetin suppressed gene expression associated with the accumulation and activation of immune cells, including macrophages and lymphocytes in EAT. It also improved the expression of the oxidative stress-sensitive transcription factor NFÎºB, NADPH oxidases, and antioxidant enzymes. Quercetin markedly increased gene expression associated with mitochondrial oxidative phosphorylation and mitochondrial DNA Quercetin most likely universally suppresses the accumulation and activation of immune cells, including anti-inflammatory cells, whereas it specifically increased gene expression associated with mitochondrial oxidative phosphorylation. Suppression of oxidative stress and NFÎºB activity likely contributed to the prevention of the accumulation and activation of immune cells and resulting chronic inflammation. Quercetin most likely universally suppresses the accumulation and activation of immune cells, including anti-inflammatory cells, whereas it specifically increased gene expression associated with mitochondrial oxidative phosphorylation. Suppression of oxidative stress and NFÎºB activity likely contributed to the prevention of the accumulation and activation of immune cells and resulting chronic inflammation. C57BL/6J mice were fed a control diet; a Western diet high in fat, cholesterol, and sucrose; or the same Western diet containing 0.05% quercetin for 18 weeks.

2016-02-25 | E-GEOD-71367 | biostudies-arrayexpress

Ketolysis is a metabolic driver of CD8+ T cell effector function through histone acetylation

Project description:Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. However, the metabolic pathways critical for optimal T cell responses remain poorly understood. Here, we identify ketone bodies (KBs) – including -hydroxybutyrate (OHB) and acetoacetate (AcAc) – as essential fuels supporting CD8+ T cell metabolism and effector function. Ketolysis is an intrinsic feature of highly functional CD8+ T effector (Teff) cells and OHB directly increases CD8+ Teff cell IFN- production and cytolytic activity. Using metabolic tracers, we establish that CD8+ Teff cells preferentially use KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boost the respiratory capacity of CD8+ T cells and TCA cycle-dependent metabolic pathways that fuel T cell growth. Mechanistically, we find that OHB is a major substrate for acetyl-CoA production in CD8+ T cells and regulates effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

2023-10-11 | PXD036292 | Pride

Pereira2020 - NRF2–p53 integrated-systems model of oxidative stress

Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2. The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).

2021-10-29 | MODEL2110270001 | BioModels

PTMA Safeguards Mitochondrial Integrity to Sustain Metabolic Function and Antitumor Persistence of CD8+ T Cells

Project description:While immune checkpoint blockade (ICB) has revolutionized cancer treatment, its clinical efficacy remains constrained by the progressive exhaustion of tumor-reactive CD8+ T cells - a dysfunctional state intimately linked to mitochondrial impairment. This underscores the urgent need to identify and target molecular regulators that govern mitochondrial metabolic fitness in CD8+ T cells, thereby preserving their effector function within the immunosuppressive tumor microenvironment (TME) to improve therapeutic outcomes. Through integrative single-cell TCR-seq and longitudinal transcriptomic profiling of reactive CD8+ T cell clones during clinical ICB treatment, we found PTMA levels in CD8+ T cells showed significant positive correlation with clinical ICB efficacy, establishing its potential as a predictive biomarker for immunotherapy outcomes. Importantly, we demostrated that Ptma expression is directly regulated by T cell factor 1 (TCF1), a transcription factor essential for T cell stemness. Moreover, genetic ablation of Ptma severely compromises the persistent effector function of CD8+ T cells and completely abrogates the in vivo efficacy of ICB. Mechanistically, we reveal that PTMA physically interacts with TFAM to safeguard mitochondrial DNA (mtDNA) integrity in CD8+ T cells under metabolic stress, thereby maintaining electron transport chain (ETC) function and oxidative phosphorylation (OXPHOS) capacity. Collectively, our findings delineate the TCF1-PTMA axis as a critical molecular nexus connecting mitochondrial metabolic competence to the stem-like properties of CD8+ T cells. This discovery provides both fundamental insights into the metabolic regulation of antitumor immunity and clinically actionable strategies to overcome ICB resistance.

2026-02-13 | GSE307982 | GEO

PPARβ/δ-orchestrated metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells [scRNA-seq]

Project description:The formation of antigen-specific memory CD8+ T cells is one of the most important features of the adaptative immune system, allowing the establishment of long-term protection against secondary infections. Although emerging evidence suggests that metabolic reprogramming is crucial for memory T cell differentiation and survival, the underlying mechanisms that drive metabolic rewiring needed for memory T cells remain unclear. Here, we found that the nuclear receptor peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) was upregulated to instruct the metabolic reprogramming, including downregulation of aerobic glycolysis and the promotion of oxidative metabolism and fatty acid oxidation, that occurs during the transition toward the establishment of central memory CD8+ T cells. Mechanistically, the exposure to interleukin-15 (IL-15) and expression of T cell factor 1 (TCF1) could coordinately activated the PPARβ/δ pathway during acute viral infection and chronic antigen exposure contexts, counteracting apoptosis induced by antigen clearance and metabolic stress. Together, our work indicates that PPARβ/δ is a master metabolic regulator orchestrating the metabolic reprogramming required for the establishment of a metabolic profile favorable for T cells longevity.

2024-08-23 | GSE268419 | GEO