ArticlePLoS pathogens2011
Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections.
Article in PLoS pathogens, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 55 citations in OpenAlex.
- Interleukin-18 armours antitumour immune effectors.Nature reviews. Immunology · 2026Review
- Combined administration of interleukin-2 and 18 with anti-PD-L1 antibody induces CCL5-positive CD8 T cells to suppress liver tumors.PNAS nexus · 2026Article
- CD226 identifies effector CD8Cell reports · 2025Article
- Cytotoxic T Cells: Kill, Memorize, and Mask to Maintain Immune Homeostasis.International journal of molecular sciences · 2025Review
- Mucosal tissue NK cells tune their function between optimal anti-pathogen activity and tissue protection.bioRxiv : the preprint server for biology · 2025Article
- Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness.Translational psychiatry · 2024Article
- Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Biological and clinical roles of IL-18 in inflammatory diseases.Nature reviews. Rheumatology · 2024Review
- Single-cell RNA sequencing reveals Immune Education promotes T cell survival in mice subjected to the cecal ligation and puncture sepsis model.Frontiers in immunology · 2024Article
- Complementary HLH susceptibility factors converge on CD8 T-cell hyperactivation.Blood advances · 2023Article
- Review
- Impaired muscle strength is associated with ultrastructure damage in myositis.Scientific reports · 2022Article
- Tissue-based IL-10 signalling in helminth infection limits IFNγ expression and promotes the intestinal Th2 response.Mucosal immunology · 2022Article
- Developmentally distinct CD4Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Expression of Cytokine Profiles and Related Receptors in Idiopathic Inflammatory Myopathies.Frontiers in pharmacology · 2022Article
- Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18RαNature communications · 2021Article
- Gene modification strategies for next-generation CAR T cells against solid cancers.Journal of hematology & oncology · 2020Review
- The Clinical Features of Co-circulating Dengue Viruses and the Absence of Dengue Hemorrhagic Fever in Pakistan.Frontiers in public health · 2020Observational
- Ablation of interferon regulatory factor 4 in T cells induces "memory" of transplant tolerance that is irreversible by immune checkpoint blockade.American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons · 2019Article
- Immune Exhaustion: Past Lessons and New Insights from Lymphocytic Choriomeningitis Virus.Viruses · 2019Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rα(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rα(hi) memory cells upregulated CD25 and produced IFN-γ, the IL-18Rα(lo) exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.
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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.