Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Open accessAbstract
Chronic viral infections often result in T cell exhaustion. To determine the molecular signature of exhaustion, we compared the gene-expression profiles of dysfunctional lymphocytic choriomeningitis virus (LCMV)-specific CD8(+) T cells from chronic infection to functional LCMV-specific effector and memory CD8(+) T cells generated after acute infection. These data showed that exhausted CD8(+) T cells: (1) overexpressed several inhibitory receptors, including PD-1, (2) had major changes in T cell receptor and cytokine signaling pathways, (3) displayed altered expression of genes involved in chemotaxis, adhesion, and migration, (4) expressed a distinct set of transcription factors, and (5) had profound metabolic and bioenergetic deficiencies. T cell exhaustion was progressive, and gene-expression profiling indicated that T cell exhaustion and anergy were distinct processes. Thus, functional exhaustion is probably due to both active suppression and passive defects in signaling and metabolism. These results provide a framework for designing rational immunotherapies during chronic infections.
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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 [37]
Secretion of TNF-α in some populations of cells is reduced because of the contemporary arrest of p38-MAPK and PD-1 pathways.
“Secretion of TNF-α in some populations of cells is reduced because of the contemporary arrest of p38-MAPK and PD-1 pathways.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [194]
Telomerase activity in CD8+/CD45RA+ T cells is improved by blocking only the p38 pathway but not PD-1 signaling, indicating that non-overlapping signaling pathways are involved.
“However, the telomerase activity in CD8+/CD45RA+ T cells is improved by blocking only the p38 pathway but not the PD-1 signaling, indicating that non-overlapping signaling pathways are involved (193, 194).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [194]
In cells that present characteristics of immune senescence, simultaneous blockade of both p38-MAPK and PD-1 signaling supports their proliferation, both in young and older human beings.
“In these cells that present characteristics of immune senescence (decreased proliferation, lower telomerase activity, and increased presence of DNA damage), the simultaneous blockade of both p38-MAPK and PD-1 signaling supports their proliferation, both in young and in older human beings.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [194]
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Self-citation
- Authors
- Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R.
- Affiliations
- Emory University (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Wherry, E. John
- Ahmed, Rafi
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 27
- Issue
- 4
- Pages
- 670-684
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2040353461
- Cited by
- 2,103
- References
- 56
- Citations by year
- 2026: 110 · 2025: 148 · 2024: 140 · 2023: 144 · 2022: 139 · 2021: 180 · 2020: 161 · 2019: 138 · 2018: 119 · 2017: 102 · 2016: 112 · 2015: 116 · 2014: 88 · 2013: 83 · 2012: 80
- FWCI
- 19.12
- Type
- journal article
- Language
- en
- Update notices
- erratum (2007-11-26)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2116 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI071309, AI 30048, 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
- CD8+ T cell exhaustion, chronic viral infection, lymphocytic choriomeningitis virus, PD-1, inhibitory receptors, T cell receptor signaling, cytokine signaling, T cell metabolism, bioenergetics, T cell migration, transcription factors, T cell anergy, gene expression profiling, immunotherapy
- MeSH terms
- Animals, Cell Differentiation, Chronic Disease, Female, Flow Cytometry, Immunologic Memory, Lymphocyte Activation, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Molecular Sequence Data, Phenotype, Virus Diseases, Gene Expression, Clonal Anergy, CD8-Positive T-Lymphocytes, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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