Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity
Open accessAbstract
CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.
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T cell exhaustion is characterized by progressive loss of cytokine expression, proliferative potential, and upregulation of inhibitory receptors.
“Other situations of chronic antigen stimulation, such as cancer or chronic viral infections, result in T cell exhaustion, characterized by the progressive loss of cytokine expression, proliferative potential, and upregulation of inhibitory receptors (immune checkpoints).”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [33]
Exhaustion can be partially reversed by immune checkpoint inhibitors.
“Exhaustion can be partially reversed by immune checkpoint inhibitors, providing the basis for successful therapies against cancer. 32,33”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [33]
Tumor-infiltrating T cell terminal exhaustion resulting from chronic and continuous tumor antigen stimulation is the primary factor contributing to immune evasion and resistance to cancer immunotherapy.
“Tumor-infiltrating T cell terminal exhaustion resulting from chronic and continuous tumor antigen stimulation is the primary factor contributing to immune evasion and resistance to cancer immunotherapy25.”
Hypoxia treatment resulted in substantial transcriptional changes in T cells, including marked downregulation of a cohort of cytokines and upregulation of genes enriched in the hypoxia pathway.
“The data analysis showed that hypoxia treatment resulted in substantial transcriptional changes in T cells. These included marked downregulation of a cohort of cytokines expression, one of the critical hallmark features of T cell exhaustion25, accompanied by upregulation of genes enriched in the hypoxia pathway (Fig. 2d, e; twofold change, p < 0.01 as cutoffs).”
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The Immunology of Psoriasis-Current Concepts in Pathogenesis
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Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
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Neuregulin 4 suppresses NASH-HCC development by restraining tumor-prone liver microenvironment
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SPP1 + macrophages cause exhaustion of tumor-specific T cells in liver metastases
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- Authors
- Collier, J. L., Weiss, S. A., Pauken, K. E., Sen, D. R., & Sharpe, A. H.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Sharpe, Arlene H.
- Venue
- Nature Immunology
- Published
- 2021-06-17
- Volume
- 22
- Issue
- 7
- Pages
- 809-819
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC9197228
- OpenAlex
- W3169670703
- Cited by
- 237
- References
- 190
- Citations by year
- 2026: 33 · 2025: 52 · 2024: 50 · 2023: 47 · 2022: 45 · 2021: 9 · 2020: 1
- FWCI
- 3.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AI108545)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Allergy and Infectious Diseases (P01AI056299, P01AI039671, P01AI108545)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD8+ T cells, T cell exhaustion, chronic viral infection, cancer immunotherapy, autoimmunity, autoreactive T cells, T cell dysfunction, cytokine production, cytotoxicity, epigenetic programming, transcriptional programming, chronic antigen exposure
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Autoimmune Diseases, Chronic Disease, Communicable Diseases, Humans, Neoplasms, Phenotype, Receptors, Antigen, T-Cell, Signal Transduction, Autoimmunity, Cytokines, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Epigenesis, Genetic, B7-H1 Antigen, Programmed Cell Death 1 Receptor
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