ArticleThe Journal of clinical investigation2023
mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed.
- Article
- Functional heterogeneity and plasticity in naïve CD8 T cells drive superior effector and memory responses.The Journal of experimental medicine · 2026Article
- RAD001-Adjuvanted Influenza Vaccine Synergizes With Anti-Programmed Cell Death Protein 1 Therapy to Enhance Antitumor Immunity in Programmed Cell Death Ligand 1-Low Murine Lung Cancer.World journal of oncology · 2026Article
- T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.Signal transduction and targeted therapy · 2026Review
- Loss of Kmt2c/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition.The Journal of clinical investigation · 2026Article
- Multifunctional Role of Mitochondrial Fatty Acid Oxidation in Cancer Immunotherapy and Aging.Cancer science · 2026Review
- Aberrant amino acid-sensing promotes immunotherapy resistance via the inflammatory cytokine-ZBTB5-mTORC1 axis.Nature cell biology · 2026Article
- Immunomodulatory Strategies for Managing Viral Infections in Solid Organ Transplantation: Progress and Challenges.Current microbiology · 2026Review
- Metabolic dysregulation reshapes the immune landscape: The gut microbiota-mTOR axis in respiratory viral infection immunity.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- TP53 Loss Fuels mTORC1 Activation and Autophagy Suppression to Drive Immune-Cold Colorectal Cancer.World journal of oncology · 2026Article
- Viral-host interactions mediated by the mTOR signaling pathway.Cell insight · 2026Review
- Regulators of CD8Nature reviews. Immunology · 2026Review
- T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy.Journal of cellular and molecular medicine · 2026Review
- Clonally expanded HSP-specific T cells contribute to glaucomatous neurodegeneration via the mTORC1 pathway.Journal of neuroinflammation · 2026Article
- Onatasertib re-sensitizes refractory nasopharyngeal carcinoma to immunotherapy: a Case Report.Frontiers in pharmacology · 2026Article
- The role of programmed cell death 1 in autoimmune diseases: mechanisms and therapeutic implications.Frontiers in immunology · 2026Review
- Aminoacyl-tRNA synthetases in tumor immunity: canonical translation, source-resolved immune circuits and therapeutic opportunities.Frontiers in immunology · 2026Review
- HPV-driven metabolic reprogramming promotes T cell exhaustion: targeting immunometabolic barriers with natural products.Frontiers in immunology · 2026Review
- Translational Downregulation of 5' TOP mRNAs During T Cell Exhaustion.bioRxiv : the preprint server for biology · 2025Article
- OGG1 activation improves T cell resilience to oxidative stress after allo-SCT and T cell engager exposure.Leukemia · 2025Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors.
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Abstract
T cell exhaustion is a state of T cell dysfunction associated with expression of programmed death 1 (PD-1). Exhausted CD8+ T cells are maintained by self-renewing stem-like T cells that provide differentiated TIM3+ cells, a part of which possesses effector-like properties. PD-1-targeted therapies enhance T cell response by promoting differentiation of stem-like T cells toward TIM3+ cells, but the role of mTOR during T cell exhaustion remains elusive. Here, we showed that mTOR inhibition has distinct outcomes during the beginning of and after the establishment of chronic viral infection. Blocking mTOR during the T cell expansion phase enhanced the T cell response by causing accumulation of stem-like T cells, leading to improved efficacy of PD-1 immunotherapy; whereas, after exhaustion progressed, mTOR inhibition caused immunosuppression, characterized by decreased TIM3+ cells and increased viral load with minimal changes in stem-like T cells. Mechanistically, a cell-intrinsic mTOR signal was vital for differentiation of stem-like T cells into the TIM3+ state in the early and late phases of chronic infection as well as during PD-1 immunotherapy. Thus, PD-1 blockade worked after cessation of mTOR inhibition, but simultaneous treatment failed to induce functional TIM3+ cells, reducing efficacy of PD-1 immunotherapy. Our data demonstrate that mTOR regulates T cell exhaustion and have important implications for combination cancer therapies with PD-1 blockade.
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