Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection
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T cell exhaustion often occurs during chronic infection and prevents optimal viral control. The molecular pathways involved in T cell exhaustion remain poorly understood. Here we show that exhausted CD8+ T cells are subject to complex layers of negative regulation resulting from the coexpression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to seven inhibitory receptors. Coexpression of multiple distinct inhibitory receptors was associated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by various inhibitory pathways was nonredundant, as blockade of the T cell inhibitory receptors PD-1 and LAG-3 simultaneously and synergistically improved T cell responses and diminished viral load in vivo. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of coexpressed inhibitory receptors.
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In persistent disease settings such as chronic infection and malignancies, T cells acquire multiple inhibitory surface molecules that effectively prevent T cell activation.
“T cells acquiring multiple inhibitory surface molecules in persistent disease settings such as chronic infection [37,38] and malignancies [30,**39,40], which effectively prevent T cell activation.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [38]
Tim-3, LAG-3, and BTLA are co-expressed with PD-1, and this co-expression strongly correlates with immune dysfunction in cancer patients.
“In the course of defining exhausted PD-1+ T cells, T cell immunoglobulin and mucin-domain-containing molecule-3 (Tim-3) [39,41], lymphocyte-activation gene (LAG)-3 [38], and the B and T-cell lymphocyte attenuator (BTLA, CD272) [42,43] were found to be co-expressed with PD-1, and the co-expression has been strongly correlated with immune dysfunction in patients with cancer.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [38]
Exhausted T cells may highly express multiple inhibitory receptors, including PD-1, 2B4, BTLA, CTLA-4, CD160, LAG-3, and Tim-3.
“Notably, exhausted T cells may highly express multiple “inhibitory” receptors, including PD-1, 2B4 (CD244), BTLA, CTLA-4, CD160, LAG-3 and Tim-3 [38,42,43,45].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [38]
T cells co-expressing these surface molecules show significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.
“In these studies, T cells co-expressing these surface molecules show a significant decrease in IL-2, IFNγ, and TNFα expression as well as cell cycle arrest, which defines T cell exhaustion.”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [38]
During chronic inflammation, T cells become exhausted and upregulate non-redundant inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT that limit their effectiveness.
“During chronic inflammation in particular, T cells are known to become exhausted and to upregulate a wide range of non-redundant inhibitory receptors that limit their effectiveness, such as PD-1, CTLA-4, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), or T-Cell immunoreceptor with Ig And ITIM domains (TIGIT) [See Table 1 (9–11)].”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [10]
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- Authors
- Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J.
- Affiliations
- The Wistar Institute (US)
- Boston Children's Hospital (US)
- St. Jude Children's Research Hospital (US)
- University of Pennsylvania (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Wherry, E John
- ORCID
- Venue
- Nature Immunology
- Published
- 2008-11-30
- Volume
- 10
- Issue
- 1
- Pages
- 29-37
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC2605166
- OpenAlex
- W2104966044
- Cited by
- 2,062
- References
- 56
- Citations by year
- 2026: 84 · 2025: 83 · 2024: 116 · 2023: 112 · 2022: 141 · 2021: 164 · 2020: 190 · 2019: 159 · 2018: 152 · 2017: 120 · 2016: 123 · 2015: 128 · 2014: 86 · 2013: 88 · 2012: 91
- FWCI
- 31.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI071309, R01AI071309)
- 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 › Immune Cell Function and Interaction
- Keywords
- T cell exhaustion, CD8+ T cells, inhibitory receptors, chronic viral infection, PD-1, LAG-3, receptor co-expression, viral load, T cell response
- MeSH terms
- Lymphocyte Activation Gene 3 Protein, Animals, Antigens, Surface, Chronic Disease, Disease Models, Animal, Immunologic Memory, Lymphocyte Activation, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Receptors, Immunologic, Down-Regulation, Antigens, CD, CD8-Positive T-Lymphocytes, Apoptosis Regulatory Proteins, Mice, Programmed Cell Death 1 Receptor
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