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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Background
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Chen, J., Qian, X., He, Y., Han, X., & Pan, Y. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28948 · Cited by 29
Integrated relationship of nasopharyngeal airway host response and microbiome associates with bronchiolitis severity
Fujiogi, M., Raita, Y., Pérez‐Losada, M., Freishtat, R. J., Celedon, J. C., Mansbach, J. M., Piedra, P. A., Zhu, Z., Camargo, C. A., & Hasegawa, K. (2022) · Nature Communications · doi:10.1038/s41467-022-32323-y · Cited by 31
“Lifetime history of systemic antibiotic use 79 (32)”
Background
Neuro faces of beneficial T cells: essential in brain, impaired in aging and neurological diseases, and activated functionally by neurotransmitters and neuropeptides
Levite, M. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.357903 · Cited by 29
“…poor memory recall; homeostatic self-renewal and proliferation; and distinct transcriptional and epigenetic programs (Crespo et al., 2013; McKinney et al., 2015; McKinney and Smith, 2016; Hashimoto et al., 2018; Saeidi et al., 2018; Stelekati et al., 2018; Kurachi, 2019; McLane et al.,…”
BackgroundInfluential
Transcriptional Dysregulation Study Reveals a Core Network Involving the Progression of Alzheimer's Disease
Meng, G., & Mei, H. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00101 · Cited by 28
“Another way is to associate the subnetwork expression to disease progresses or clinical traits, which can uncover the regulatory components involved in the dysregulation of diseases (McKinney et al., 2015).”
Background
Prolidase deficiency, a rare inborn error of immunity, clinical phenotypes, immunological features, and proposed treatments in twins
AlRumayyan, N., Slauenwhite, D., McAlpine, S. M., Roberts, S., Issekutz, T. B., Huber, A. M., Liu, Z., & Dérfalvi, B. (2022) · Allergy Asthma and Clinical Immunology · doi:10.1186/s13223-022-00658-2 · Cited by 28
“T cell cytokine responses in both patients were normal with the exception of elevated proportions of IL-17+ CD8+ TEM cells [35].”
Background
Multiomic profiling of chronically activated CD4+ T cells identifies drivers of exhaustion and metabolic reprogramming
Lawton, M. L., Inge, M. M., Blum, B. C., Smith-Mahoney, E. L., Bolzan, D., Lin, W., McConney, C., Porter, J., Moore, J., Youssef, A., et al. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002943 · Cited by 25
“…opted to probe both KAT2B, a histone acetyltransferase known to associate with p300 that has been implicated as a marker in T-cell exhaustion [109,110], and a mixture of class I HDACs (HDAC1/2/3), which have also been linked to T-cell exhaustion [111–113] and were connected in our p300-centered…”
Exhaustion of CD39-Expressing CD8+ T Cells in Crohn’s Disease Is Linked to Clinical Outcome
Globig, A.-M., Mayer, L., Heeg, M., Andrieux, G., Ku, M., Otto-Mora, P., Hipp, A. V., Zoldan, K., Pattekar, A., Rana, N., et al. (2022) · Gastroenterology · doi:10.1053/j.gastro.2022.06.045 · Cited by 30
Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming
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Cytotoxic Tph subset with low B-cell helper functions and its involvement in systemic lupus erythematosus
Seki, N., Tsujimoto, H., Tanemura, S., Kojima, S., Miyoshi, F., Kikuchi, J., Saito, S., Akiyama, M., Sugahara, K., Yoshimoto, K., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-05989-x · Cited by 29
“Furthermore, it has been shown that in chronic infections, cancer and autoimmune diseases, persistent antigen stimulation under suboptimal conditions can lead to the induction of T-cell exhaustion 30 – 33 .”
Decreased Protein Kinase C-β Type II Associated with the Prominent Endotoxin Exhaustion in the Macrophage of FcGRIIb−/− Lupus Prone Mice is Revealed by Phosphoproteomic Analysis
Ondee, T., Jaroonwitchawan, T., Pisitkun, T., Gillen, J., Nita‐Lazar, A., Leelahavanichkul, A., & Somparn, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061354 · Cited by 26
“Indeed, the immune exhaustion after repeatedor high-stimulation by pathogens in chronic infection or sepsis, respectively, is well-known [5,6].”
Background
4‐1BB costimulation promotes bystander activation of human CD8 T cells
Reithofer, M., Rosskopf, S., Leitner, J. M., Battin, C., Bohle, B., Steinberger, P., & Jahn‐Schmid, B. (2020) · European Journal of Immunology · doi:10.1002/eji.202048762 · Cited by 26
L-type amino acid transporter 1 as a target for inflammatory disease and cancer immunotherapy
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Rheumatic Manifestations and Diseases From Immune Checkpoint Inhibitors in Cancer Immunotherapy
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Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission
Gamerith, G., Mildner, F., Merkel, P. A., Harris, K. M., Cooney, L., Lim, N., Spiera, R., Seo, P., Langford, C. A., Hoffman, G. S., et al. (2022) · Annals of the Rheumatic Diseases · doi:10.1136/ard-2022-222479 · Cited by 26
Effector Memory–Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor–Dependent Proinflammatory and Migratory Responses
Doan-Ngoc, T.-M., Tilly, G., Danger, R., Bonizec, O., Masset, C., Guérif, P., Bruneau, S., Glémain, A., Harb, J., Cadoux, M., et al. (2022) · Journal of the American Society of Nephrology · doi:10.1681/asn.2022030286 · Cited by 26
Time-spatial analysis of T cell receptor repertoire in esophageal squamous cell carcinoma patients treated with combined radiotherapy and PD-1 blockade
Yan, C., Ma, X., Guo, Z., Wei, X., Han, D., Zhang, T., Chen, X., Cao, F., Dong, J., Zhao, G., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2025668 · Cited by 25
Readapting the adaptive immune response – therapeutic strategies for atherosclerosis
Sage, A. P., & Mallat, Z. (2017) · British Journal of Pharmacology · doi:10.1111/bph.13700 · Cited by 24
“High PD-1 expression on T cells can also be associated with anergic or exhausted T cells in chronic inflammation in humans (McKinney et al., 2015) and may mark a pathogenic subset of T cells refractory to normal inhibitory signals.”
Background
Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations
Schrezenmeier, E. V., Weißenberg, S. Y., Stefanski, A., Szelinski, F., Wiedemann, A., Lino, A. C., & Dörner, T. (2018) · Current Opinion in Rheumatology · doi:10.1097/bor.0000000000000576 · Cited by 26
Treatment of natalizumab‐associated PML with filgrastim
Stefoski, D., Balabanov, R. D., Waheed, R., Ko, M., Koralnik, I. J., & Morales, F. S. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.776 · Cited by 25
Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance
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Heterogeneity and clonality of kidney-infiltrating T cells in murine lupus nephritis
Smita, S., Chikina, M. D., Shlomchik, M. J., & Tilstra, J. S. (2022) · JCI Insight · doi:10.1172/jci.insight.156048 · Cited by 24
Single-cell RNA sequencing shows the immune cell landscape in the kidneys of patients with idiopathic membranous nephropathy
Shi, M., Wang, Y., Zhang, H., Ling, Z., Chen, X., Wang, C., Liu, J., & Ma, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1203062 · Cited by 24
“CD8+ T cells might present with exhaustion markers in some patients with autoimmune-related kidney diseases, like SLE and IgAN (19, 20).”
New Therapeutic Targets in Antineutrophil Cytoplasm Antibody–Associated Vasculitis
Prendecki, M. F., & McAdoo, S. P. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41407 · Cited by 25
“cell phenotype has been shown to correlate with a reduced risk of disease relapse (30).”
Background
Immune Modulation in Lung Cancer: Current Concepts and Future Strategies
Gaissmaier, L., & Christopoulos, P. (2020) · Respiration · doi:10.1159/000510385 · Cited by 24
Hobit and human effector T‐cell differentiation: The beginning of a long journey
Braun, J., Frentsch, M., & Thiel, A. (2015) · European Journal of Immunology · doi:10.1002/eji.201545959 · Cited by 24
Emerging therapeutic biomarkers of autoimmune hepatitis and their impact on current and future management
Czaja, A. J. (2018) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2018.1453356 · Cited by 25
“tion [115], and manipulations that suppress the activation and proliferation of CD4 T cells, block CD2 signaling, and inhibit”
Background
Vasculitis Pathogenesis: Can We Talk About Precision Medicine?
Özen, S., & Batu, E. D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01892 · Cited by 24
“In another study of the same group on gene-expression biomarkers, they demonstrated an association between T cell exhaustion and poor prognosis in AAV and suggested that this process could be targeted in AAV treatment (100).”
Prognosis of immune checkpoint inhibitor-induced myasthenia gravis: a single center experience and systematic review
Qin, Y., Chen, S., Gui, Q., Zhang, T., Li, Y., Du, Z., Lv, Y., Du, X., Hu, Y., & Liu, Z. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1372861 · Cited by 24
Disease-associated B cells and immune endotypes shape adaptive immune responses to SARS-CoV-2 mRNA vaccination in human SLE
Faliti, C. E., Van, T. T. P., Anam, F. A., Cheedarla, N., Williams, M. E., Mishra, A. K., Usman, S. Y., Woodruff, M. C., Kraker, G., Runnstrom, M. C., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-02010-9 · Cited by 23
Dysregulated T cells in multiple sclerosis
Chihara, N. (2018) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12438 · Cited by 23
“might be largely distinct from the initial factors predisposing to broken self tolerance.(1) MS is an autoimmune disorder characterized by”
Background
Novel Diagnostic and Therapeutic Strategies in Juvenile Autoimmune Hepatitis
Sciveres, M., Nastasio, S., & Maggiore, G. (2019) · Frontiers in Pediatrics · doi:10.3389/fped.2019.00382 · Cited by 24
“PD-1 is also found to be increased in exhausted T cells (51).”
Background
T Cells Plead for Rejuvenation and Amplification; With the Brain’s Neurotransmitters and Neuropeptides We Can Make It Happen
Levite, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.617658 · Cited by 23
Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future
Pan, M., Zhao, H., Jin, R., Leung, P. S. C., & Shuai, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1156212 · Cited by 24
The role of MDA5 in the development of autoimmune disease
Sadler, A. J. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.4mr0617-223r · Cited by 23
“However, the presence of exhausted T cells in patients with autoimmune diseases correlates with a more favorable prognosis [68].”
T-Cell Compartmentalization and Functional Adaptation in Autoimmune Inflammation: Lessons From Pediatric Rheumatic Diseases
Mijnheer, G., & van Wijk, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00940 · Cited by 24
“Previous observations from peripheral blood derived CD8 Tcells show that the transcriptional signature reflecting exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple auto-immune diseases, including SLE (49).”
Background
Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients
Hu, X., Shen, C., Meng, T., Ooi, J. D., Eggenhuizen, P. J., Zhou, Y.-O., Luo, H., Chen, J.-B., Lin, W., Gong, Y., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.991469 · Cited by 22
“We assume that one probable reason is that patients with lower lymphocyte count might have higher proportions of nonexhausted autoreactive T cells which drive kidney injury in patients with DPPs, as a previous study has shown that CD8 T cell exhaustion could predict a favorable outcome in multisystem autoimmune and in…”
Result
Transcriptomic studies of systemic lupus erythematosus
Nakano, M., Iwasaki, Y., & Fujio, K. (2021) · Inflammation and Regeneration · doi:10.1186/s41232-021-00161-y · Cited by 20
“[39] 2015 23 adults CD4+ T cells, CD8+ T cells Microarray The exhaustion signature in CD8 T cells, which was associated with poor outcomes in patients with viral infections, was correlated with a lower risk of disease relapse in AAV and SLE patients.”
Background
Stromal Cells Underlining the Paths From Autoimmunity, Inflammation to Cancer With Roles Beyond Structural and Nutritional Support
Honan, A. M., & Chen, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.658984 · Cited by 21
“This was seen in antibody associated vasculitis (AAV), IBD, and systemic lupus erythematosus (SLE) (McKinney et al., 2015).”
Background
Uncovering the flip side of immune checkpoint inhibitors: a comprehensive review of immune-related adverse events and predictive biomarkers
Miao, Y., Quan, W., Tang, X., Shi, W., Li, Q., Li, R. J., Wang, J., Gan, J., Dong, X., Liang, H., et al. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.89376 · Cited by 23
“Disease activity in antinuclear cytoplasmic antibody (ANCA)-related vasculitis and SLE could be linked to T-cell exhaustion, as an instance [209].”

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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