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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
Schwartz, R. H. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141110 · Cited by 1,487
Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin
Intlekofer, A. M., Takemoto, N., Wherry, E. J., Longworth, S. A., Northrup, J. T., Palanivel, V., Mullen, A. C., Gasink, C. R., Kaech, S. M., Miller, J. D., et al. (2005) · Nature Immunology · doi:10.1038/ni1268 · Cited by 1,293
Self-citationMolecular and functional profiling of memory CD8 T cell differentiation.
Kaech, S., Hemby, S., Kersh, E., & Ahmed, R. (2002) · Cell · doi:10.1016/s0092-8674(02)01139-x · Cited by 1,081
Self-citationControl of Effector CD8 + T Cell Function by the Transcription Factor Eomesodermin
Pearce, E. L., Mullen, A. C., Martins, G. A., Krawczyk, C. M., Hutchins, A. S., Zediak, V. P., Banica, M., DiCioccio, C. B., Gross, D. A., Mao, C.-A., et al. (2003) · Science · doi:10.1126/science.1090148 · Cited by 1,014
Interleukin-10 determines viral clearance or persistence in vivo
Brooks, D. G., Trifilo, M. J., Edelmann, K. H., Teyton, L., McGavern, D. B., & Oldstone, M. B. A. (2006) · Nature Medicine · doi:10.1038/nm1492 · Cited by 937
Characterization of Hepatitis B Virus (HBV)-Specific T-Cell Dysfunction in Chronic HBV Infection
Boni, C., Fisicaro, P., Valdatta, C., Amadei, B., Di Vincenzo, P., Giuberti, T., Laccabue, D., Zerbini, A., Cavalli, A., Missale, G., et al. (2007) · Journal of Virology · doi:10.1128/jvi.02844-06 · Cited by 920
Memory CD8 T-Cell Differentiation during Viral Infection
Wherry, E. J., & Ahmed, R. (2004) · Journal of Virology · doi:10.1128/jvi.78.11.5535-5545.2004 · Cited by 889
Self-citationPD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection
Petrovas, C., Casazza, J. P., Brenchley, J. M., Price, D. A., Gostick, E., Adams, W. C., Precopio, M. L., Schacker, T., Roederer, M., Douek, D. C., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061496 · Cited by 889
BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1
Watanabe, N., Gavrieli, M., Sedy, J. R., Yang, J., Fallarino, F., Loftin, S. K., Hurchla, M. A., Zimmerman, N., Sim, J., Zang, X., et al. (2003) · Nature Immunology · doi:10.1038/ni944 · Cited by 883
Ahmed, R., Salmi, A. A., Butler, L. D., Chiller, J. M., & Oldstone, M. B. A. (1984) · The Journal of Experimental Medicine · doi:10.1084/jem.160.2.521 · Cited by 792
Self-citationTranscriptional Mechanisms Underlying Lymphocyte Tolerance
Macián, F., Garcia-Cozar, F. J., Im, S., Horton, H. F., Byrne, M. C., & Rao, A. (2002) · Cell · doi:10.1016/s0092-8674(02)00767-5 · Cited by 687
Kruppel-like factor 2 regulates thymocyte and T-cell migration
Carlson, C. M., Endrizzi, B. T., Wu, J., Ding, X., Weinreich, M. A., Walsh, E. R., Wani, M. A., Lingrel, J. B., Hogquist, K. A., & Jameson, S. C. (2006) · Nature · doi:10.1038/nature04882 · Cited by 603
Urbani, S., Amadei, B., Tola, D., Massari, M., Schivazappa, S., Missale, G., & Ferrari, C. I. (2006) · Journal of Virology · doi:10.1128/jvi.01177-06 · Cited by 599
Resolution of a chronic viral infection after interleukin-10 receptor blockade
Ejrnaes, M., Filippi, C. M., Martinic, M. M. A., Ling, E. M., Togher, L. M., Crotty, S., & von Herrath, M. G. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061462 · Cited by 556
Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins
Heissmeyer, V., Macián, F., Im, S., Varma, R., Feske, S., Venuprasad, K., Gu, H., Liu, Y., Dustin, M. L., & Rao, A. (2004) · Nature Immunology · doi:10.1038/ni1047 · Cited by 515
Antigen-independent memory CD8 T cells do not develop during chronic viral infection
Wherry, E. J., Barber, D. L., Kaech, S. M., Blattman, J. N., & Ahmed, R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407192101 · Cited by 495
Self-citationRadziewicz, H., Ibegbu, C., Fernandez, M. L., Workowski, K., Obideen, K. M., Wehbi, M. A., Hanson, H. L., Steinberg, J. P., Masopust, D., Wherry, E. J., et al. (2006) · Journal of Virology · doi:10.1128/jvi.02021-06 · Cited by 495
Self-citationRathmell, J. C., Heiden, M. G. V., Harris, M. H., Frauwirth, K. A., & Thompson, C. B. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00066-6 · Cited by 467
Egr-2 and Egr-3 are negative regulators of T cell activation
Safford, M., Collins, S. L., Lutz, M. A., Allen, A. N., Huang, C.-T., Kowalski, J., Blackford, A. L., Horton, M. R., Drake, C. G., Schwartz, R. H., et al. (2005) · Nature Immunology · doi:10.1038/ni1193 · Cited by 446
LKLF: A Transcriptional Regulator of Single-Positive T Cell Quiescence and Survival
Kuo, C. T., Veselits, M., & Leiden, J. M. (1997) · Science · doi:10.1126/science.277.5334.1986 · Cited by 419
The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut
Kabashima, K., Saji, T., Murata, T., Nagamachi, M., Matsuoka, T., Segi‐Nishida, E., Tsuboi, K., Sugimoto, Y., Kobayashi, T., Miyachi, Y., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214459 · Cited by 418
He, X.-S., Rehermann, B., López‐Labrador, F. X., Boisvert, J., Cheung, R. C., Mumm, J. B., Wedemeyer, H. H., Berenguer, M., Wright, T. L., Davis, M. M., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.10.5692 · Cited by 416
Cutting Edge: Molecular Analysis of the Negative Regulatory Function of Lymphocyte Activation Gene-3
Workman, C. J., Dugger, K. J., & Vignali, D. A. A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.10.5392 · Cited by 389
Transcriptional repressor Blimp-1 regulates T cell homeostasis and function
Martins, G. A., Cimmino, L., Shelef, M. A., Szabolcs, M. J., Herron, A. J., Magnúsdóttir, E., & Calame, K. L. (2006) · Nature Immunology · doi:10.1038/ni1320 · Cited by 372
CD8 T cell dysfunction during chronic viral infection
Shin, H., & Wherry, E. J. (2007) · Current Opinion in Immunology · doi:10.1016/j.coi.2007.06.004 · Cited by 346
Self-citationTranscriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance
Kallies, A., Hawkins, E. D., Belz, G. T., Metcalf, D., Hommel, M., Corcoran, L. M., Hodgkin, P. D., & Nutt, S. L. (2006) · Nature Immunology · doi:10.1038/ni1321 · Cited by 320
Stimulation History Dictates Memory CD8 T Cell Phenotype: Implications for Prime-Boost Vaccination
Masopust, D., Ha, S., Vezys, V., & Ahmed, R. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.2.831 · Cited by 313
Self-citationZhang, J., Zhang, Z., Wang, X., Fu, J., Yao, J., Jiao, Y., Chen, L., Zhang, H., Wei, J., Jin, L., et al. (2007) · Blood · doi:10.1182/blood-2006-09-044826 · Cited by 309
Human CD8+ T-cell differentiation in response to viruses
van Lier, R. A. W., ten Berge, I. J. M., & Gamadia, L. E. (2003) · Nature Reviews Immunology · doi:10.1038/nri1254 · Cited by 297
Surh, C. D., Boyman, O., Purton, J. F., & Sprent, J. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00401.x · Cited by 277
Ablation of CD8 and CD4 T Cell Responses by High Viral Loads
Fuller, M. J., & Zajac, A. J. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.1.477 · Cited by 276
Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection
Shin, H., Blackburn, S. D., Blattman, J. N., & Wherry, E. J. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061937 · Cited by 273
Self-citationViral infections induce abundant numbers of senescent CD8 T cells
Voehringer, D., Blaser, C., Brawand, P., Raulet, D. H., Hanke, T., & Pircher, H. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.4838 · Cited by 246
E3 ubiquitin ligases as T cell anergy factors
Mueller, D. L. (2004) · Nature Immunology · doi:10.1038/ni1106 · Cited by 224
Ou, R., Zhou, S., Huang, L., & Moskophidis, D. (2001) · Journal of Virology · doi:10.1128/jvi.75.18.8407-8423.2001 · Cited by 175
Petrovas, C., Price, D. A., Mattapallil, J. J., Ambrozak, D. R., Geldmacher, C., Cecchinato, V., Vaccari, M., Tryniszewska, E. A., Emma Gostick, D., Roederer, M., et al. (2007) · Blood · doi:10.1182/blood-2007-01-069112 · Cited by 172
Katz, H. R., Vivier, E., Castells, M. C., McCormick, M. J., Chambers, J. M., & Austen, K. F. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.20.10809 · Cited by 155
Harris, J. E., Bishop, K. D., Phillips, N. E., Mordes, J. P., Greiner, D. L., Rossini, A. A., & Czech, M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.12.7331 · Cited by 137
Velu, V., Kannanganat, S., Ibegbu, C., Chennareddi, L. S., Villinger, F. J., Freeman, G. J., Ahmed, R., & Amara, R. R. (2007) · Journal of Virology · doi:10.1128/jvi.00024-07 · Cited by 133
Self-citationWherry, E. J., Blattman, J. N., & Ahmed, R. (2005) · Journal of Virology · doi:10.1128/jvi.79.14.8960-8968.2005 · Cited by 113
Self-citationMaeda, M., Carpenito, C., Russell, R. C., Dasanjh, J., Veinotte, L. L., Ohta, H., Yamamura, T., Tan, R., & Takei, F. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.7.4426 · Cited by 92
Type I transmembrane receptor with inhibitory function in mouse mast cells and NK cells
Rojo, S., Burshtyn, D. N., Long, E. O., & Wagtmann, N. R. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.1.9 · Cited by 90
Serine protease inhibitor 2A is a protective factor for memory T cell development
Liu, N., Phillips, T., Zhang, M., Wang, Y., Opferman, J. T., Shah, R., & Ashton‐Rickardt, P. G. (2004) · Nature Immunology · doi:10.1038/ni1107 · Cited by 86
2B4/CD48-Mediated Regulation of Lymphocyte Activation and Function
Assarsson, E., Kambayashi, T., Persson, C. M., Chambers, B. J., & Ljunggren, H. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.4.2045 · Cited by 42
Sagerström, C. G. (2004) · Developmental Cell · doi:10.1016/j.devcel.2004.05.015 · Cited by 40
Transcription factors that regulate memory in humoral responses
Calame, K. L. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00377.x · Cited by 36
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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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