ArticlePLoS pathogens2020
Rapid in vitro generation of bona fide exhausted CD8+ T cells is accompanied by Tcf7 promotor methylation.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 71 citations in OpenAlex.
- Contrasting functions of CD73 and adenosine in CD8+ T-cell exhaustion during antitumor immunity.Oncoimmunology · 2026Article
- In Vitro Inhibition of STAT5 Signaling Limits CD8+ T-cell Exhaustion and Improves Outcomes in Adoptive T-cell Therapy.Cancer immunology research · 2026Article
- Article
- DUSP4 promotes anti-tumor CD8Nature communications · 2026Article
- A senescence-associated gene signature predicts radiotherapy prognosis in non-small cell lung cancer and identifies CSF1 as a target to potentiate radioimmunotherapy.Biology direct · 2026Article
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- CKS1B is a tumor-intrinsic factor driving CD8Science advances · 2026Article
- Intratumoral Virus-Like Particles Containing a TLR9 Agonist Combined with Systemic αPD-1 Activate Tumor-Specific CD8+ T Cells.Cancer research communications · 2026Article
- Article
- Nebivolol prevents exhausted T cells and enhances cytotoxicity against MCF-7 breast cancer cells in a β2-adrenergic receptor-dependent manner.Clinical and experimental immunology · 2026Article
- Reversing T cell dysfunction in a novelFrontiers in immunology · 2026Article
- Non-redundant functions of NFATc1 in survival and NFATc2 in generation of exhausted CD8Frontiers in immunology · 2026Article
- Genome scale CRISPR screens identify actin capping proteins as key modulators of therapeutic responses to radiation and immunotherapy.bioRxiv : the preprint server for biology · 2025Article
- TGFβ limits proximal CD8+ TCR signaling via PTPN22 following strong and moderate agonism.Journal of immunology (Baltimore, Md. : 1950) · 2025Article
- Chronic antigen stimulation in melanoma induces T cell exhaustion and limits efficacy of T cell bispecific therapies.Oncoimmunology · 2025Article
- Faithful modeling of terminal CD8+T cell dysfunction and epigenetic stabilization in vitro.JCI insight · 2025Article
- SPECIFIC: A systematic framework for engineering cell state-responsive synthetic promoters reveals key regulators of T cell exhaustion.Quantitative biology (Beijing, China) · 2025Article
- Immunometabolite L-2-HG promotes epigenetic modification of exhausted T cells and improves antitumor immunity.JCI insight · 2025Article
- IL-27 elicits a cytotoxic CD8Nature · 2025Article
- Transient EZH2 Suppression by Tazemetostat during In Vitro Expansion Maintains T-Cell Stemness and Improves Adoptive T-Cell Therapy.Cancer immunology research · 2025Article
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 2 countries.
Funding
Abstract
Exhaustion is a dysfunctional state of cytotoxic CD8+ T cells (CTL) observed in chronic infection and cancer. Current in vivo models of CTL exhaustion using chronic viral infections or cancer yield very few exhausted CTL, limiting the analysis that can be done on these cells. Establishing an in vitro system that rapidly induces CTL exhaustion would therefore greatly facilitate the study of this phenotype, identify the truly exhaustion-associated changes and allow the testing of novel approaches to reverse or prevent exhaustion. Here we show that repeat stimulation of purified TCR transgenic OT-I CTL with their specific peptide induces all the functional (reduced cytokine production and polyfunctionality, decreased in vivo expansion capacity) and phenotypic (increased inhibitory receptors expression and transcription factor changes) characteristics of exhaustion. Importantly, in vitro exhausted cells shared the transcriptomic characteristics of the gold standard of exhaustion, CTL from LCMV cl13 infections. Gene expression of both in vitro and in vivo exhausted CTL was distinct from T cell anergy. Using this system, we show that Tcf7 promoter DNA methylation contributes to TCF1 downregulation in exhausted CTL. Thus this novel in vitro system can be used to identify genes and signaling pathways involved in exhaustion and will facilitate the screening of reagents that prevent/reverse CTL exhaustion.
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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.