Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection
Open accessAbstract
Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain–containing molecule–3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus–specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-γ, TNF-α, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Blockade of Tim-3 and PD-1 rescues effector functions, shown by cell cycle progression and acquired effector cytokine expression and cytotoxicity.
“blockade of these surface molecules allows rescue of their effector functions as shown by cell cycle progression and acquired effector cytokine expression and cytotoxicity [40,43,44].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [44]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PD-1 and Its Ligands in Tolerance and Immunity
Keir, M. E., Butte, M. J., Freeman, G. J., & Sharpe, A. H. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090331 · Cited by 5,378 · see citing works
Self-citationMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
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. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 25
- [1]Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004;78:5535–5545. doi: 10.1128/JVI.78.11.5535-5545.2004. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [2]Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol. 2007;19:408–415. doi: 10.1016/j.coi.2007.06.004. [DOI] [PubMed] [Google Scholar] · DOI
- [3]Barber DL, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–687. doi: 10.1038/nature04444. [DOI] [PubMed] [Google Scholar] · DOI
- [5]Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–245. doi: 10.1038/ni1443. [DOI] [PubMed] [Google Scholar] · DOI
- [6]Velu V, et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature. 2009;458:206–210. doi: 10.1038/nature07662. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [7]Crawford A, Wherry EJ. The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses. Curr Opin Immunol. 2009;21:179–186. doi: 10.1016/j.coi.2009.01.010. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [9]Blackburn SD, et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37. doi: 10.1038/ni.1679. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- [10]Monney L, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–541. doi: 10.1038/415536a. [DOI] [PubMed] [Google Scholar] · DOI
- [11]Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK, Umetsu DT. The costimulatory role of TIM molecules. Immunol Rev. 2009;229:259–270. doi: 10.1111/j.1600-065X.2009.00772.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [12]Jones RB, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205:2763–2779. doi: 10.1084/jem.20081398. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [13]Golden-Mason L, et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol. 2009;83:9122–9130. doi: 10.1128/JVI.00639-09. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [14]Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003;77:4911–4927. doi: 10.1128/JVI.77.8.4911-4927.2003. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [15]Elrefaei M, Barugahare B, Ssali F, Mugyenyi P, Cao H. HIV-specific IL-10-positive CD8+ T cells are increased in advanced disease and are associated with decreased HIV-specific cytolysis. J Immunol. 2006;176:1274–1280. doi: 10.4049/jimmunol.176.2.1274. [DOI] [PubMed] [Google Scholar] · DOI
- [16]Elrefaei M, et al. HIV-specific IL-10-positive CD8+ T cells suppress cytolysis and IL-2 production by CD8+ T cells. J Immunol. 2007;178:3265–3271. doi: 10.4049/jimmunol.178.5.3265. [DOI] [PubMed] [Google Scholar] · DOI
- [17]Workman CJ, et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol. 2004;172:5450–5455. doi: 10.4049/jimmunol.172.9.5450. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- [18]Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223) J Immunol. 2005;174:688–695. doi: 10.4049/jimmunol.174.2.688. [DOI] [PubMed] [Google Scholar] · DOI
- [19]Streeck H, et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med. 2008;5:e100. doi: 10.1371/journal.pmed.0050100. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [20]Wherry EJ, Blattman JN, Ahmed R. Low CD8 T-cell proliferative potential and high viral load limit the effectiveness of therapeutic vaccination. J Virol. 2005;79:8960–8968. doi: 10.1128/JVI.79.14.8960-8968.2005. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
- [21]Blackburn SD, et al. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: Implications for CD8 T-cell exhaustion. J Virol. 2010;84:2078–2089. doi: 10.1128/JVI.01579-09. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [22]Said EA, et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med. 2010;16:452–459. doi: 10.1038/nm.2106. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [23]Zhu C, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–1252. doi: 10.1038/ni1271. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
- [24]Sehrawat S, Suryawanshi A, Hirashima M, Rouse BT. Role of Tim-3/galectin-9 inhibitory interaction in viral-induced immunopathology: Shifting the balance toward regulators. J Immunol. 2009;182:3191–3201. doi: 10.4049/jimmunol.0803673. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [25]Zhu J, et al. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med. 2007;204:595–603. doi: 10.1084/jem.20061792. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
- [26]Sabatos CA, et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003;4:1102–1110. doi: 10.1038/ni988. [DOI] [PubMed] [Google Scholar] · DOI
- [27]Ahmed R, Salmi A, Butler LD, Chiller JM, Oldstone MB. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J Exp Med. 1984;160:521–540. doi: 10.1084/jem.160.2.521. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
Cited by
Sorted by citations
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652 · see citing works
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · see citing works
Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., et al. (2016) · Nature · doi:10.1038/nature19330 · Cited by 2,070 · see citing works
Self-citationLag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation
Anderson, A. C., Joller, N., & Kuchroo, V. K. (2016) · Immunity · doi:10.1016/j.immuni.2016.05.001 · Cited by 2,096 · see citing works
Self-citationKoyama, S., Akbay, E. A., Li, Y. Y., Herter-Sprie, G. S., Buczkowski, K. A., Richards, W. G., Gandhi, L., Redig, A. J., Rodig, S. J., Asahina, H., et al. (2016) · Nature Communications · doi:10.1038/ncomms10501 · Cited by 1,580 · see citing works
Self-citationPathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients
Zhou, Y., Fu, B., Zheng, X., Wang, D., Zhao, C., Qi, Y., Sun, R., Tian, Z., Xu, X., & Wei, H. (2020) · National Science Review · doi:10.1093/nsr/nwaa041 · Cited by 1,295 · see citing works
Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing
Yadav, M., Jhunjhunwala, S., Phung, Q. T., Lupardus, P., Tanguay, J., Bumbaca, S., Franci, C., Cheung, T. K., Fritsche, J., Weinschenk, T., et al. (2014) · Nature · doi:10.1038/nature14001 · Cited by 1,186 · see citing works
TIM3 comes of age as an inhibitory receptor
Wolf, Y., Anderson, A. C., & Kuchroo, V. K. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0224-6 · Cited by 959 · see citing works
Self-citationThe Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells
Martinez, G. J., Pereira, R. M., Äijö, T., Kim, E. Y., Marangoni, F., Pipkin, M. E., Togher, S., Heissmeyer, V., Zhang, Y. C., Crotty, S., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.006 · Cited by 857 · see citing works
“…its versatility, NFAT forms dimers on palindromic kB-like sequence elements and can bind DNA as a monomer (Chen et al., 1998; Giffin et al., 2003; Jin et al., 2010; Stroud et al., 2002); it also forms cooperative complexes with FOXP3, a transcription factor central to T cell regulatory function…”
InfluentialTim‐3 and its role in regulating anti‐tumor immunity
Das, M., Zhu, C., & Kuchroo, V. K. (2017) · Immunological Reviews · doi:10.1111/imr.12520 · Cited by 856 · see citing works
Self-citationT cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment
Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.003 · Cited by 752 · see citing works
Zhou, Q., Munger, M. E., Veenstra, R. G., Weigel, B. J., Hirashima, M., Munn, D. H., Murphy, W. J., Azuma, M., Anderson, A. C., Kuchroo, V. K., et al. (2011) · Blood · doi:10.1182/blood-2010-10-310425 · Cited by 675 · see citing works
Self-citationHypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen
Doedens, A. L., Phan, A. T., Stradner, M. H., Fujimoto, J. K., Nguyen, J. V., Yang, E., Johnson, R. S., & Goldrath, A. W. (2013) · Nature Immunology · doi:10.1038/ni.2714 · Cited by 660 · see citing works
Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure)
Kim, J. M., & Chen, D. S. (2016) · Annals of Oncology · doi:10.1093/annonc/mdw217 · Cited by 648 · see citing works
Li, H., Wu, K., Tao, K., Chen, L., Zheng, Q., Lu, X., Liu, J., Shi, L., Liu, C., Wang, G., et al. (2012) · Hepatology · doi:10.1002/hep.25777 · Cited by 496 · see citing works
Rangachari, M., Zhu, C., Sakuishi, K., Xiao, S., Karman, J., Chen, A., Angin, M., Wakeham, A., Greenfield, E. A., Sobel, R. A., et al. (2012) · Nature Medicine · doi:10.1038/nm.2871 · Cited by 394 · see citing works
Self-citationTIM-3 regulates CD103+ dendritic cell function and response to chemotherapy in breast cancer
de Mingo Pulido, Á., Gardner, A., Hiebler, S., Soliman, H., Rugo, H. S., Krummel, M. F., Coussens, L. M., & Ruffell, B. (2018) · Cancer Cell · doi:10.1016/j.ccell.2017.11.019 · Cited by 388 · see citing works
Baessler, A., & Vignali, D. A. A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-090222-110914 · Cited by 420 · see citing works
Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses
Liu, J., Yuan, Y., Chen, W., Putra, J., Suriawinata, A. A., Schenk, A. D., Miller, H. E., Guleria, I., Barth, R. J., Huang, Y. H., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1420370112 · Cited by 374 · see citing works
Phosphotyrosine-Dependent Coupling of Tim-3 to T-Cell Receptor Signaling Pathways
Lee, J., Su, E. W., Zhu, C., Hainline, S., Phuah, J., Moroco, J. A., Smithgall, T. E., Kuchroo, V. K., & Kane, L. P. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.05297-11 · Cited by 285 · see citing works
Self-citationHypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
Vignali, P. D. A., DePeaux, K., Watson, M. J., Ye, C., Ford, B. R., Lontos, K., McGaa, N. K., Scharping, N. E., Menk, A. V., Robson, S. C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-022-01379-9 · Cited by 269 · see citing works
VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy
Lines, J. L., Sempere, L. F., Broughton, T., Wang, L., & Noelle, R. (2014) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-14-0072 · Cited by 236 · see citing works
Viral acute lower respiratory infections impair CD8+ T cells through PD-1
Erickson, J. J., Gilchuk, P., Hastings, A. K., Tollefson, S. J., Johnson, M., Downing, M. B., Boyd, K. L., Johnson, J. E., Kim, A. S., Joyce, S., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62860 · Cited by 203 · see citing works
Gut microbiome modulates efficacy of immune checkpoint inhibitors
Yi, M., Yu, S., Qin, S., Liu, Q., Xu, H., Zhao, W., Chu, Q., & Wu, K. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-018-0592-6 · Cited by 179 · see citing works
Immunosuppressive Effects of Multiple Myeloma Are Overcome by PD-L1 Blockade
Hallett, W. H. D., Jing, W., Drobyski, W. R., & Johnson, B. D. (2011) · Biology of Blood and Marrow Transplantation · doi:10.1016/j.bbmt.2011.03.011 · Cited by 152 · see citing works
The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia
Koh, H. S., Chang, C. Y., Jeon, S.-B., Yoon, H. J., Ahn, Y.-H., Kim, H.-S., Kim, I.-H., Jeon, S. H., Johnson, R. S., & Park, E. J. (2015) · Nature Communications · doi:10.1038/ncomms7340 · Cited by 141 · see citing works
Clayton, K. L., Haaland, M. S., Douglas-Vail, M. B., Mujib, S., Chew, G. M., Ndhlovu, L. C., & Ostrowski, M. A. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302663 · Cited by 134 · see citing works
Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs
Gupta, S., Thornley, T. B., Gao, W., Larocca, R., Turka, L. A., Kuchroo, V. K., & Strom, T. B. (2012) · Journal of Clinical Investigation · doi:10.1172/jci45138 · Cited by 139 · see citing works
Self-citationLee, K., Shin, K., Kim, G., Song, Y. C., Bae, E., Kim, I., Koh, C., & Kang, C. (2016) · Aging Cell · doi:10.1111/acel.12435 · Cited by 125 · see citing works
Phosphatidylserine binding directly regulates TIM-3 function
Smith, C. M., Li, A., Krishnamurthy, N., & Lemmon, M. A. (2021) · Biochemical Journal · doi:10.1042/bcj20210425 · Cited by 61 · see citing works
Zhu, C., Dixon, K. O., Newcomer, K., Gu, G., Xiao, S., Zaghouani, S., Schramm, M. A., Wang, C., Zhang, H., Goto, K., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd2710 · Cited by 40 · see citing works
Self-citation
- Authors
- Jin, H.-T., Anderson, A. C., Tan, W. G., West, E. E., Ha, S.-J., Araki, K., Freeman, G. J., Kuchroo, V. K., & Ahmed, R.
- Affiliations
- Emory University (US)
- Brigham and Women's Hospital (US)
- Yonsei University (KR)
- Harvard University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-08-02
- Volume
- 107
- Issue
- 33
- Pages
- 14733-14738
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2930455
- OpenAlex
- W1994257755
- Cited by
- 858
- References
- 2
- Citations by year
- 2026: 29 · 2025: 74 · 2024: 48 · 2023: 66 · 2022: 42 · 2021: 61 · 2020: 62 · 2019: 42 · 2018: 61 · 2017: 47 · 2016: 60 · 2015: 73 · 2014: 48 · 2013: 53 · 2012: 54
- FWCI
- 19.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (P01AI054456, R01AI139675, R01AI089955, AI 056299, P01AI073748, AI054456, AI73748, P01AI056299, AI08080192)
- National Institute of Neurological Disorders and Stroke (K01NS054096, R01NS030843, NS038037, R29NS030843, NS030843, NS045937, P01NS038037, R37NS030843, NS054096, R01NS045937)
- 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 › Virology › HIV Research and Treatment
- Keywords
- TIM-3, PD-1, CD8+ T cell exhaustion, chronic viral infection, lymphocytic choriomeningitis virus, inhibitory receptors, IL-10, T cell co-inhibition, dual blockade, virus control, effector cytokines, T cell proliferation
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Antigens, Surface, Antigens, Viral, Chronic Disease, Female, Flow Cytometry, Interferon-gamma, Interleukin-2, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Receptors, Virus, Tumor Necrosis Factor-alpha, Interleukin-10, CD8-Positive T-Lymphocytes, Antibodies, Blocking, Apoptosis Regulatory Proteins, Mice, Programmed Cell Death 1 Receptor
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 ›
Are you an author, or do you see a problem with this page? Request a review
