Cited by 692T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersDiabetes and associated disorders

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T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection

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McKinney, Eoin F., Lee, James C., Jayne, David R. W., Lyons, Paul A., Smith, Kenneth G. C.·2015·Nature

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Abstract

The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory 'help' signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cells in vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The 'non-exhausted' T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.

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Breiman, L. (2001) · Machine Learning · doi:10.1023/a:1010933404324 · Cited by 133,538
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
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
Emergence of Scaling in Random Networks
Barabási, A.-L., & Albert, R. (1999) · Science · doi:10.1126/science.286.5439.509 · Cited by 36,135
WGCNA: an R package for weighted correlation network analysis
Langfelder, P., & Horvath, S. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-559 · Cited by 27,252
Cluster analysis and display of genome-wide expression patterns
Eisen, M. B., Spellman, P. T., Brown, P. O., & Botstein, D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.25.14863 · Cited by 16,184
The 1982 revised criteria for the classification of systemic lupus erythematosus
Tan, E. M., Cohen, A. S., Fries, J. F., Masi, A. T., Mcshane, D. J., Rothfield, N. F., Schaller, J. G., Talal, N., & Winchester, R. J. (1982) · Arthritis & Rheumatism · doi:10.1002/art.1780251101 · Cited by 14,519
Bioconductor: open software development for computational biology and bioinformatics
Gentleman, R. C., Carey, V. J., Bates, D. M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 12,082
Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829
Adjusting batch effects in microarray expression data using empirical Bayes methods
Johnson, W. E., Li, C., & Rabinovic, A. (2007) · Biostatistics · doi:10.1093/biostatistics/kxj037 · Cited by 8,658
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Greisen, S. R., & Deleuran, B. W. (2021) · Current Rheumatology Reports · doi:10.1007/s11926-021-00991-2 · Cited by 6
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Schardey, J., Lü, C., Neumann, J. H. L., Wirth, U., Li, Q., Jiang, T., Zimmermann, P., Andrassy, J., Bazhin, A. V., Werner, J., et al. (2023) · Cancers · doi:10.3390/cancers15194743 · Cited by 6
“More-over, there has been increasing evidence that T-cell exhaustion in the mucosa of IBD patients is related to inﬂammatory disease progression [9–11].”
Abnormalities in CD57 + cytotoxic T cells and Vδ1 + γδT cells in subclinical celiac disease in childhood are affected by cytomegalovirus. The Generation R Study
Jansen, M. A. E., van den Heuvel, D., Jaddoe, V. W. V., van Zelm, M. C., & Moll, H. A. (2017) · Clinical Immunology · doi:10.1016/j.clim.2017.04.008 · Cited by 6
Co-inhibitory receptors, transcription factors and tolerance
Mohammadzadeh, A. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106572 · Cited by 6
Acute Conditioning of Antigen-Expanded CD8+ T Cells via the GSK3β-mTORC Axis Differentially Dictates Their Immediate and Distal Responses after Antigen Rechallenge
Táborská, P., Stakheev, D., Svobodová, H., Strizova, Z. O., Bartůňková, J., & Smrž, D. (2020) · Cancers · doi:10.3390/cancers12123766 · Cited by 6
The Role of Exhaustion in Tumor-Induced T-Cell Dysfunction in Cancer
Prado-Garcı́a, H., & Romero‐Garcia, S. (2020) · Springer eBooks · doi:10.1007/978-3-030-30845-2_8 · Cited by 6
Identification and immunoassay of biomarkers associated with T cell exhaustion in systemic lupus erythematosus
Zheng, Y., Li, H., Wang, Y., Huang, L., Chen, L., Lin, S., & Lin, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1476575 · Cited by 5
Identification of unanimous immune subtypes for different hormone receptor phenotypes of human breast cancer with potential prognostic significance
Yu, D. C. W., Zhou, L., & Zhang, Q. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.107473 · Cited by 5
Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing
Zhao, W., Shen, Y., Cai, G.-X., Li, Y., Liu, W., Wu, J., Xu, Y., Chen, S.-Q., & Zhou, Z. M. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.12.011 · Cited by 5
Soluble Immune Checkpoints Associated With Disease Activity and Treatment Response in GD and TED
Yin, Q., Zhu, T., Song, D., Fang, S., Zhou, H., & Guan, H. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae763 · Cited by 4
Immune checkpoint molecule expression is altered in the skin and peripheral blood in vasculitis
Miyabe, C., Dong, Y., Ikeda, T., Takahashi, K., Miyabe, Y., & Kawakami, T. (2021) · Scientific Reports · doi:10.1038/s41598-021-99558-5 · Cited by 5
Blood Transcriptome Profiling Links Immunity to Disease Severity in Myotonic Dystrophy Type 1 (DM1)
Nieuwenhuis, S., Widomska, J., Blom, P., Hoen, P. T., van Engelen, B. V., & Glennon, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063081 · Cited by 6
Computation of Transcriptional Networks of Circulating Immune Cells in Type 1 Diabetes
Ochsner, S. A., Pillich, R., Rawool, D., Grethe, J. S., & McKenna, N. J. (2022) · iScience · doi:10.1016/j.isci.2022.104581 · Cited by 5
“CD56 cells have been shown to promote CD8 T cell exhaustion, and this phenomenon has been linked to improved prognosis in autoimmune diseases (McKinney et al., 2015).”
Background
Bayesian clustering with uncertain data
Nicholls, K., Kirk, P., & Wallace, C. (2024) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1012301 · Cited by 6
Early allogeneic immune modulation after establishment of donor hematopoietic cell-induced mixed chimerism in a nonhuman primate kidney transplant model
Little, C. J., Kim, S. C., Fechner, J. H., Post, J., Coonen, J., Chlebeck, P. J., Winslow, M., Kobuzi, D., Strober, S., & Kaufman, D. B. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1343616 · Cited by 5
COVID-19 Modified mRNA “Vaccines”: Lessons Learned from Clinical Trials, Mass Vaccination, and the Bio-Pharmaceutical Complex, Part 2
Mead, M. N., Seneff, S., Rose, J., Wolfinger, R. D., Hulscher, N., & McCullough, P. A. (2024) · International Journal of Vaccine Theory Practice and Research · doi:10.56098/w66wjg87 · Cited by 13
Circulating levels of chemokines in patients with psoriasis vulgaris and their association with disease severity: A case–control study from North India
Chhabra, S., Joshi, N., Narang, T. K., & Dogra, S. (2019) · Indian Journal of Dermatology Venereology and Leprology · doi:10.4103/ijdvl.ijdvl_392_18 · Cited by 5
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Sahu, R., Mishra, R., & Majee, C. (2020) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2020.1797485 · Cited by 5
“cence may also be important; T-cell exhaustion has a central role in determining outcome in autoimmune disease [66].”
Background
Bystander Memory T Cells and IMiD/Checkpoint Therapy in Multiple Myeloma: A Dangerous Tango?
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“IKZF1 binds the IL-2 gene promoter and represses IL-2 production and proliferation in T cells (70, 71) thus controlling important steps in induction of effective immune responses, regulation of inflammation as well as prevention of autoimmunity.”
ResultInfluential
Spontaneous and Immune Checkpoint Inhibitor-Induced Autoimmune Diseases: Analysis of Temporal Information by Using the Japanese Adverse Drug Event Report Database
Ogawa, K., Kozuka, Y., Uno, H., Utsumi, K., Noyori, O., & Hosoki, R. (2021) · Clinical Drug Investigation · doi:10.1007/s40261-021-01042-5 · Cited by 6
CD2-negative lymphoma-associated T-cells: a potential mechanism of immune-evasion in diffuse large B-cell lymphoma
Ghosh, A., Marques-Piubelli, M. L., Wang, X., Sheu, T. G., Cheng, J., Khan, K. B., Lü, W., Manning, J., Tang, G., Solis, L. M., et al. (2022) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-022-03348-x · Cited by 5
“In situations of chronic T-cell activation, this interaction prevents the development of an exhausted T-cell phenotype [4, 6].”
Background
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“T cell exhaustion could improve the outcomes of autoimmune disease by limiting T cell activity [221–223].”
BackgroundInfluential
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Xu, Z., Huo, S., Zhang, Y., Lin, W., Liu, J., Wen, X., Liu, Y., Shi, C., & Xu, G. (2025) · Materials & Design · doi:10.1016/j.matdes.2025.114508 · Cited by 4
Reprogramming immunity: Emerging therapeutic frontiers and clinical trial advances of CAR-T cell therapy in autoimmune diseases
Mukherjee, A. M. (2025) · Clinical Immunology Communications · doi:10.1016/j.clicom.2025.09.003 · Cited by 4
CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence
Liu, F., Keane, J. T., Lewis, H.-G. S., King-Peoples, T. R., June, C. H., & Posey, A. D. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-013208 · Cited by 4
Miltefosine reinvigorates exhausted T cells by targeting their bioenergetic state
Zhang, X., Zhang, C., Lu, S., Dong, J., Tang, N., Wang, Y., Han, W., Pan, X., Zhang, X., Liu, D., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101869 · Cited by 4
NK cell exhaustion in Wilson’s disease revealed by single-cell RNA sequencing predicts the prognosis of cholecystitis
Jin, Y., Xing, J., Dai, C., Jin, L., Zhang, W., Tao, Q., Hou, M., Li, Z., Yang, W., Feng, Q., et al. (2024) · eLife · doi:10.7554/elife.98867.3 · Cited by 12
Beyond disease susceptibility—Leveraging genome‐wide association studies for new insights into complex disease biology
Lee, J. C. (2017) · HLA · doi:10.1111/tan.13170 · Cited by 4
“Early evidence suggests that these pathways may be shared between different diseases and thus have effects on prognosis that are independent of a specific diagnosis.(40,44) Further elucidation of the extent of this sharing, and the biology of disease prognosis in general, would therefore appear to be an important step…”
BackgroundSelf-citation
Systemic Lupus Erythematosus
Nijjar, J. S., & Smith, K. G. C. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812102-3.00030-0 · Cited by 4
Self-citation
Effects of Aire on perforin expression in BMDCs via TLR7/8 and its therapeutic effect on type 1 diabetes
Zhang, Y., Lu, Y., Gao, Y., Liang, X., Zhang, R., Wang, X., Zou, X., & Yang, W. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.109890 · Cited by 3
T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker?
Xu, Q., Li, L., & Zhu, R. (2025) · Current Allergy and Asthma Reports · doi:10.1007/s11882-025-01199-5 · Cited by 7
“Conversely, T cell exhaustion may serve as a therapeutic approach in autoimmunity and organ transplantation, correlating with enhanced therapeutic outcomes and improved prognosis [7, 8].”
Alterations in CD8+CD45RA+CCR7− T cells as a potential biomarker for primary Sjögren's syndrome
Pan, J., Wu, R., He, L., Bai, Y., Ding, J., Wang, Y., Shu, F., Zhang, Z., Zhang, P., & Qi, C. (2025) · Immunobiology · doi:10.1016/j.imbio.2025.152914 · Cited by 4
Assessment of PredictSURE IBD Assay in a Multinational Cohort of Patients With Inflammatory Bowel Disease
Alsoud, D., Noor, N. M., Chen, L. A., Abadom, V., Anderson, S. H. C., Ardolli, L., Axelrad, J. E., Bossuyt, P. J., Croitoru, K., Damas, O. M., et al. (2025) · United European Gastroenterology Journal · doi:10.1002/ueg2.70050 · Cited by 4
“Following prior discovery in other immune‐mediated diseases [13], a CD8 þ T‐ cell gene expression signature was identified that was associated with subsequent disease course in IBD patients [14], with later mechanistic work revealing a likely role for T‐cell exhaustion [15].”
InfluentialSelf-citation
EBV-dUTPase Modulates Host Immune Responses Potentially Altering the Tumor Microenvironment in EBV-associated Malignancies
Ariza, M. E., & Williams, M. V. (2016) · Current Research on HIV/AIDS · doi:10.29011/2575-7105.100001 · Cited by 4
Expression of CTLA-4 and CD86 Antigens and Epstein-Barr Virus Reactivation in Chronic Lymphocytic Leukemia—Any Link with Known Prognostic Factors?
Grywalska, E., Mielnik, M., Podgajna, M., Hymos, A., Ludian, J., Rolińska, A., Gosik, K., Kwaśniewski, W. M., Sosnowska‐Pasiarska, B., Smok-Kalwat, J., et al. (2022) · Cancers · doi:10.3390/cancers14030672 · Cited by 4
“It is very likely that EBV infection may have similar effects [13].”
Background
Age-related immunosenescence in Behçet’s disease
Cansu, D. Ü., & Korkmaz, C. (2022) · Rheumatology International · doi:10.1007/s00296-022-05144-x · Cited by 4
“As a result, T-cell exhaustion may be beneficial in autoimmune diseases [53].”
Background
Predicted Immune-Related Genes and Subtypes in Systemic Lupus Erythematosus Based on Immune Infiltration Analysis
Xu, L., Su, X., Liu, Z., & Zhou, A. (2022) · Disease Markers · doi:10.1155/2022/8911321 · Cited by 4
SARS-CoV-2-Vaccine-Related Endocrine Disorders: An Updated Narrative Review
Ishay, A., Oleinikov, K., & Shacham, E. C. (2024) · Vaccines · doi:10.3390/vaccines12070750 · Cited by 3

Authors: McKinney, E. F., Lee, J. C., Jayne, D. R. W., Lyons, P. A., & Smith, K. G. C.
Affiliations: University of Cambridge (GB)
Corresponding author: McKinney, Eoin F.
Smith, Kenneth G. C.
ORCID: McKinney, Eoin F.
Lee, James C.
Jayne, David R. W.
Lyons, Paul A.
Smith, Kenneth G. C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2015-06-29
Volume: 523
Issue: 7562
Pages: 612-616
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature14468
PMC: PMC4623162
OpenAlex: W2103056503
Cited by: 685
References: 56
Citations by year: 2026: 45 · 2025: 54 · 2024: 82 · 2023: 45 · 2022: 81 · 2021: 65 · 2020: 73 · 2019: 74 · 2018: 65 · 2017: 48 · 2016: 40 · 2015: 10
FWCI: 26.79
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Apollo (University of Cambridge) (submittedVersion)
Apollo
Funders: Wellcome Trust (083650/Z/07/Z, 104064, 104064/Z/14/Z, 100140, 079895/Z/06/Z, 083650, 079895, 100140/Z/12/Z, 094227, 094227/Z/10/Z, 079895/Z/06/B)
Medical Research Council (MR/L019027/1)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords: T cell exhaustion, CD8+ T cells, PD-1, chronic viral infection, autoimmune disease, inflammatory diseases, prognosis, hepatitis C virus, vaccine response, type 1 diabetes, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, idiopathic pulmonary fibrosis, dengue hemorrhagic fever, gene expression signatures, autoreactivity
MeSH terms: Animals, Autoimmune Diseases, Humans, Infections, Inflammation, Lupus Erythematosus, Systemic, Phenotype, Receptors, Antigen, T-Cell, Inflammatory Bowel Diseases, CD4-Positive T-Lymphocytes, Autoimmunity, CD8-Positive T-Lymphocytes, CD2 Antigens, Receptors, Interleukin-7, Mice, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Transcriptome, Programmed Cell Death 1 Receptor

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T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection

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