The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
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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“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]
In the citing paper
“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]
In the citing paper
“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 the citing paper
“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]
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Restoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057
Self-citationPD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression
Day, C. L., Kaufmann, D. E., Kiepiela, P., Brown, J. A., Moodley, E. S., Reddy, S., Mackey, E. W., Miller, J. D., Leslie, A. J., DePierres, C., et al. (2006) · Nature · doi:10.1038/nature05115 · Cited by 2,680
Self-citationGreenwald, R. J., Freeman, G. J., & Sharpe, A. H. (2005) · Annual Review of Immunology · doi:10.1146/annurev.immunol.23.021704.115611 · Cited by 2,318
Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function
Zajac, A. J., Blattman, J. N., Murali-Krishna, K., Sourdive, D. J. D., Suresh, M., Altman, J. D., & Ahmed, R. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.12.2205 · Cited by 1,978
Self-citationCTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms
Parry, R. V., Chemnitz, J. M., Frauwirth, K. A., Lanfranco, A. R., Braunstein, I., Kobayashi, S. V., Linsley, P. S., Thompson, C. B., & Riley, J. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9543-9553.2005 · Cited by 1,931
Joshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861
Self-citationWherry, E. J., Blattman, J. N., Murali‐Krishna, K., der Most, R. G. V., & Ahmed, R. (2003) · Journal of Virology · doi:10.1128/jvi.77.8.4911-4927.2003 · Cited by 1,645
Self-citationLanier, L. L. (1998) · Annual Review of Immunology · doi:10.1146/annurev.immunol.16.1.359 · Cited by 1,641
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction
Trautmann, L., Janbazian, L., Chomont, N., Said, E. A., Gimmig, S., Bessette, B., Boulassel, M.-R., Delwart, E., Sepulveda, H., Balderas, R. S., et al. (2006) · Nature Medicine · doi:10.1038/nm1482 · Cited by 1,565
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Impact of Age-, Cancer- and Treatment-Driven Inflammation on T Cell Function and Immunotherapy
Quinn, K. M., Kartikasari, A. E. R., Cooke, R. E., Koldej, R. M., Ritchie, D. S., & Plebanski, M. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.5mr0520-466r · Cited by 31
Cai, G., Nie, X., Li, L., Hu, L., Wu, B., Lin, J., Jiang, C., Wang, H., Wang, X., & Shen, Q. (2013) · Journal of Gastroenterology · doi:10.1007/s00535-013-0762-9 · Cited by 27
Weber, E. W., Lynn, R. C., Parker, K. R., Anbunathan, H., Lattin, J., Sotillo, E., Good, Z., Malipatlolla, M., Xu, P., Vandris, P., et al. (2020) · doi:10.1101/2020.01.26.920496 · Cited by 18
“Consistent with murine models of viral infection wherein antigen clearance induces T cell memory rather than exhaustion (Joshi et al., 2007; Rutishauser et al., 2009; Wherry et al., 2007; Wherry et al., 2004), early cessation of tonic CAR signaling (RestedD7-11) redirected T cell differentiation away from exhaustion a…”
BackgroundResultInfluentialAmes, R. Y., Ting, L.-M., Gendlina, I., Kim, K., & Macian, F. (2017) · Infection and Immunity · doi:10.1128/iai.00364-17 · Cited by 16
Turano, P. S., Akbulut, E., Dewald, H. K., Vasilopoulos, T., Fitzgerald-Bocarsly, P., Herbig, U., & Martínez-Zamudio, R. I. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116795 · Cited by 16
Homeostasis and Durability of T-Cell Memory—The Resting and the Restless T-Cell Memory
Radbruch, A., McGrath, M. A., Siracusa, F., Hoffmann, U., Sercan-Alp, Ö., Hutloff, A., Tokoyoda, K., Chang, H.-D., & Dong, J. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a038083 · Cited by 16
Single-molecule imaging of transcription dynamics, RNA localization and fate in human T cells
Lattanzio, M. V., Šoštarić, N., Kanagasabesan, N., Popović, B., Bradarić, A., Wardak, L., Guislain, A., Savakis, P., Tutucci, E., & Wolkers, M. C. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00592-0 · Cited by 3
Metadata
- 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
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