ArticlePLoS biology2024
Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming.
Article in PLoS biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Article
- Targeting PKM2 Enhances the Anti-Tumor Function of CD8International journal of molecular sciences · 2026Article
- Persistent CD4Cellular immunology · 2026Article
- Single-cell transcriptomic analysis identifies a tumor-enriched GIMAP7⁺ CD4⁺ naïve T cell population with a unique immunoregulatory state in lung adenocarcinoma.Functional & integrative genomics · 2026Article
- Lactylation: a promising target for musculoskeletal disorders via interactions with chronic inflammation.Journal of advanced research · 2026Review
- From guardians to traitors: molecular mechanisms of tumor-induced T cell betrayal.Molecular cancer · 2026Review
- Oxidative-Stress-Associated Molecular Signatures in Immune-Mediated Diseases: A Systematic Review Integrating Machine Learning and Systems Biology Approaches.Antioxidants (Basel, Switzerland) · 2026Review
- Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy.Acta biochimica et biophysica Sinica · 2026Review
- Enhanced mortality prediction in pneumonia-associated acute respiratory distress syndrome: a model integrating lymphocyte subsets with clinical parameters in non-immunosuppressed adults.Frontiers in medicine · 2026Article
- Reversing T cell dysfunction in a novelFrontiers in immunology · 2026Article
- Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.bioRxiv : the preprint server for biology · 2025Article
- Multimodal analysis definesbioRxiv : the preprint server for biology · 2025Article
- EomesoderminImmunity · 2025Article
- Repeated COVID-19 Vaccination as a Poor Prognostic Factor in Pancreatic Cancer: A Retrospective, Single-Center Cohort Study.Cancers · 2025Article
- Article
- Role of Bioinformatics in Identifying Novel Biomarkers for Immune Cell Exhaustion and Tumor Microenvironment.Technology in cancer research & treatmentReview
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
Repeated antigen exposure leads to T-cell exhaustion, a transcriptionally and epigenetically distinct cellular state marked by loss of effector functions (e.g., cytotoxicity, cytokine production/release), up-regulation of inhibitory receptors (e.g., PD-1), and reduced proliferative capacity. Molecular pathways underlying T-cell exhaustion have been defined for CD8+ cytotoxic T cells, but which factors drive exhaustion in CD4+ T cells, that are also required for an effective immune response against a tumor or infection, remains unclear. Here, we utilize quantitative proteomic, phosphoproteomic, and metabolomic analyses to characterize the molecular basis of the dysfunctional cell state induced by chronic stimulation of CD4+ memory T cells. We identified a dynamic response encompassing both known and novel up-regulated cell surface receptors, as well as dozens of unexpected transcriptional regulators. Integrated causal network analysis of our combined data predicts the histone acetyltransferase p300 as a driver of aspects of this phenotype following chronic stimulation, which we confirmed via targeted small molecule inhibition. While our integrative analysis also revealed large-scale metabolic reprogramming, our independent investigation confirmed a global remodeling away from glycolysis to a dysfunctional fatty acid oxidation-based metabolism coincident with oxidative stress. Overall, these data provide both insights into the mechanistic basis of CD4+ T-cell exhaustion and serve as a valuable resource for future interventional studies aimed at modulating T-cell dysfunction.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.