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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TIGIT as a Promising Therapeutic Target in Autoimmune Diseases
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Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice
Admin, A., Azoury, M. E., Tarayrah, M., Afonso, G., Pais, A., Colli, M. L., Maillard, C., Lavaud, C., Alexandre‐Heymann, L., Gonzalez-Duque, S., et al. (2020) · Diabetes · doi:10.2337/db20-0013 · Cited by 57
Regulation of activated T cell survival in rheumatic autoimmune diseases
Rosetti, F., Madera-Salcedo, I. K., Rodríguez‐Rodríguez, N., & Crispín, J. C. (2022) · Nature Reviews Rheumatology · doi:10.1038/s41584-021-00741-9 · Cited by 54
T Cell Transcriptomes Describe Patient Subtypes in Systemic Lupus Erythematosus
Bradley, S. J., Suárez‐Fueyo, A., Moss, D. R., Kyttaris, V. C., & Tsokos, G. C. (2015) · PLoS ONE · doi:10.1371/journal.pone.0141171 · Cited by 52
“The transcriptome of peripheral blood components show variation with circadian [37] and seasonal [38] periodicity and are growing in descriptive utility in autoimmunity [39] and other clinical settings including transplantation [40] heart failure [41] amyotrophic lateral sclerosis [42] and several cancers [43, 44] whe…”
Background
Expanding the B Cell-Centric View of Systemic Lupus Erythematosus
Morawski, P. A., & Bolland, S. M. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.02.001 · Cited by 52
“In the context of SLE, the exhausted T cell state could be reproduced in vitro and depended on signaling through the inhibitory receptor PD-1 [32], providing a potential target of therapeutic benefit.”
BackgroundInfluential
Drivers of the immunopathogenesis in systemic lupus erythematosus
Rose, T., & Dörner, T. (2017) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2017.09.007 · Cited by 50
Revealing the cellular degradome by mass spectrometry analysis of proteasome-cleaved peptides
Wolf-Levy, H., Javitt, A., Eisenberg-Lerner, A., Kacen, A., Ulman, A., Sheban, D., Dassa, B., Fishbain-Yoskovitz, V., Carmona-Rivera, C., Kramer, M. P., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4279 · Cited by 55
Integrated, multicohort analysis reveals unified signature of systemic lupus erythematosus
Haynes, W. A., Haddon, D. J., Diep, V. K., Khatri, A., Bongen, E., Yiu, G., Balboni, I., Bolen, C. R., Mao, R., Utz, P. J., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.122312 · Cited by 53
“signature, associated with decreased risk of flare, in CD8+ T cells from individuals who have SLE (12).”
Background
Understanding the molecular drivers of disease heterogeneity in Crohn's disease using multi-omic data integration and network analysis
Sudhakar, P., Verstockt, B., Cremer, J., Verstockt, S., Sabino, J., Ferrante, M., & Vermeire, S. (2021) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izaa281 · Cited by 49
Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset?
Carré, A., Richardson, S. J., Larger, É., & Mallone, R. (2020) · Diabetologia · doi:10.1007/s00125-020-05298-y · Cited by 53
The double-edged sword: Harnessing PD-1 blockade in tumor and autoimmunity
Kuchroo, J. R., Hafler, D. A., Sharpe, A. H., & Lucca, L. E. (2021) · Science Immunology · doi:10.1126/sciimmunol.abf4034 · Cited by 51
“Conversely, expression of a surrogate marker of costimulation predicted better viral clearance in hepatitis C and more protection after influenza vaccination (188).”
Background
Immune Profiling and Precision Medicine in Systemic Lupus Erythematosus
Nagafuchi, Y., Shoda, H., & Fujio, K. (2019) · Cells · doi:10.3390/cells8020140 · Cited by 49
“They found that CD8 T-cell exhaustion negatively correlated with CD4 T-cell co-stimulation and that it indicated a better prognosis in SLE and in ANCA-associated vasculitis patients [94,95].”
Background
Is There a Positive Side to T Cell Exhaustion?
Pawelec, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00111 · Cited by 50
“Thus, for example, transcriptional signatures characteristic of CD8+ T-cells were reported to be associated with better prognosis in several different autoimmune diseases including type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis a…”
Background
Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease
Cashman, K. S., Jenks, S. A., Woodruff, M. C., Tomar, D., Tipton, C. M., Scharer, C. D., Lee, F. E.-H., Boss, J. M., & Sanz, I. (2019) · Immunological Reviews · doi:10.1111/imr.12820 · Cited by 55
A LAG-3–Specific Agonist Antibody for the Treatment of T Cell–Induced Autoimmune Diseases
Angin, M., Brignone, C., & Triebel, F. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900823 · Cited by 48
T Cell Memory in Infection, Cancer, and Autoimmunity
Barnaba, V. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.811968 · Cited by 49
“Consistent with this hypothesis, recent data in both experimental and human T1D showed that self- or non-self-reactive T cells shared common phenotypic, transcriptional and epigenetic program features of exhaustion, those autoreactive displayed a wider level of heterogenicity, depending on the TCR affinity for self-an…”
Result
Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression
Xhonneux, L.-P., Knight, O., Lernmark, Å., Bonifacio, E. E., Hagopian, W., Rewers, M., She, J., Toppari, J., Parikh, H. M., Smith, K. G. C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abd5666 · Cited by 48
Self-citation
Pro‐inflammatory self‐reactive T cells are found within murine TCR‐αβ+CD4−CD8−PD‐1+ cells
Rodríguez‐Rodríguez, N., Apostolidis, S. A., Fitzgerald, L., Meehan, B. S., Corbett, A. J., Martín‐Villa, J. M., McCluskey, J., Tsokos, G. C., & Crispín, J. C. (2016) · European Journal of Immunology · doi:10.1002/eji.201546056 · Cited by 48
Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans
Fan, L., Liu, J., Hu, W., Chen, Z., Lan, J., Zhang, T., Zhang, Y., Wu, X., Zhong, Z., Zhang, D., et al. (2024) · Cell Research · doi:10.1038/s41422-024-00945-0 · Cited by 47
“We prospectively recruited 171 tumor patients who received anti-tumor chemotherapy combined with ( n = 83) or without ( n = 88) anti-PD-1 treatment at SAHZU between 16th Sep 2022 and 24th Feb 2023 (Supplementary information, Fig.”
Tolerogenic Dendritic Cells from Poorly Compensated Type 1 Diabetes Patients Have Decreased Ability To Induce Stable Antigen-Specific T Cell Hyporesponsiveness and Generation of Suppressive Regulatory T Cells
Dáňová, K., Grohová, A., Strnadová, P., Funda, D. P., Šumnı́k, Z., Lebl, J., Cinek, O., Průhová, Š., Koloušková, S., Obermannová, B., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600676 · Cited by 46
“IL-10–producing Tregs induced by GAD65-loaded tolDCs are thus functional and are able to suppress proliferation of responder T cells.”
BackgroundInfluential
Strength in Numbers: Opportunities for Enhancing the Development of Effective Treatments for Type 1 Diabetes—The TrialNet Experience
Greenbaum, C. J., Speake, C., Krischer, J. P., Buckner, J. H., Gottlieb, P. A., Schatz, D., Herold, K. C., & Atkinson, M. A. (2018) · Diabetes · doi:10.2337/db18-0065 · Cited by 49
“(72) of chronic viral infections and other autoimmune diseases.”
Background
T Cells in Systemic Lupus Erythematosus
Paredes, J. L., Fernandez‐Ruiz, R., & Niewold, T. B. (2021) · Rheumatic Disease Clinics of North America · doi:10.1016/j.rdc.2021.04.005 · Cited by 46
Antigen discrimination by T cells relies on size-constrained microvillar contact
Jenkins, E. M., Körbel, M., O’Brien‐Ball, C., McColl, J. T., Chen, K. Y., Kotowski, M., Humphrey, J., Lippert, A. H., Brouwer, H., Santos, A. M., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36855-9 · Cited by 43
Disrupting B and T-cell collaboration in autoimmune disease: T-cell engagers versus CAR T-cell therapy?
Shah, K., Leandro, M. J., Cragg, M. S., Kollert, F., Schuler, F., Klein, C., & Reddy, V. R. (2024) · Clinical & Experimental Immunology · doi:10.1093/cei/uxae031 · Cited by 48
“In AID, regulatory and exhausted T cells are associated with disease remission and improved prognosis [107].”
Background
Extracellular Vesicles Transfer the Receptor Programmed Death-1 in Rheumatoid Arthritis
Greisen, S. R., Yan, Y., Hansen, A. S., Venø, M. T., Nyengaard, J. R., Moestrup, S. K., Hvid, M., Freeman, G. J., Kjems, J., & Deleuran, B. W. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00851 · Cited by 45
“However, these cells have recently been suggested to be associated with a better prognosis (4).”
Regulatory Immune Mechanisms beyond Regulatory T Cells
Christoffersson, G., & von Herrath, M. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.04.005 · Cited by 46
Revisiting T Cell Tolerance as a Checkpoint Target for Cancer Immunotherapy
Nüssing, S., Trapani, J. A., & Parish, I. A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.589641 · Cited by 48
T-Cell Aging-Associated Phenotypes in Autoimmune Disease
Zhao, T. V., Sato, Y., Goronzy, J. J., & Weyand, C. M. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.867950 · Cited by 50
“Similarly, a previous study showed that a transcriptional signature of CD8 T cell exhaustion is associated with a good prognosis in patients with other autoimmune diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis and SLE (McKinney et al., 2015).”
Result
Cytotoxic CD161−CD8+ TEMRA cells contribute to the pathogenesis of systemic lupus erythematosus
Xiong, H., Cui, M., Kong, N., Jing, J., Xu, Y., Liu, X., Yang, F., Xu, Z., Yan, Y., Zhao, D., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104507 · Cited by 43
Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities
Brunell, A. E., Lahesmaa, R., Autio, A. K., & Thotakura, A. K. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1151632 · Cited by 46
Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis
Aarslev, K., Dige, A., Greisen, S., Kreutzfeldt, M., Jessen, N., Vilstrup, H., Deleuran, B., & Grønbæk, H. (2017) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365521.2016.1233576 · Cited by 42
Exhausted T cells in systemic lupus erythematosus patients in long-standing remission
Lima, G., Treviño-Tello, F., Atisha‐Fregoso, Y., Llorente, L., Fragoso-Loyo, H. E., & Jakez‐Ocampo, J. (2021) · Clinical & Experimental Immunology · doi:10.1111/cei.13577 · Cited by 46
Dynamic Adoption of Anergy by Antigen-Exhausted CD4 + T Cells
Trefzer, A., Kadam, P., Wang, S.-H., Pennavaria, S., Lober, B., Akçabozan, B., Kranich, J., Brocker, T., Nakano, N., Irmler, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2021.108748 · Cited by 47
Smoking activates cytotoxic CD8+ T cells and causes survivin release in rheumatoid arthritis
Wasén, C., Turkkila, M., Bossios, A., Erlandsson, M. C., Andersson, K., Ekerljung, L., Malmhäll, C., Brisslert, M., Silfverswärd, S. T., Lundbäck, B., et al. (2017) · Journal of Autoimmunity · doi:10.1016/j.jaut.2016.12.009 · Cited by 43
Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again
Bucktrout, S. L., Bluestone, J. A., & Ramsdell, F. (2018) · Genome Medicine · doi:10.1186/s13073-018-0588-4 · Cited by 47
Immunomodulatory activity of humanized anti–IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes
Herold, K. C., Bucktrout, S. L., Wang, X., Bode, B. W., Gitelman, S. E., Gottlieb, P. A., Hughes, J. W., Joh, T., McGill, J. B., Pettus, J., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.126054 · Cited by 43
“Indeed, improved prognoses were associated with reduced expression of IL-7RA in patients with systemic lupus erythematosus, type 1 diabetes (T1D), antineutrophil cytoplasmic antibody vasculitis, and idiopathic pulmonary fibrosis (14).”
Background
Autoantibody-positive healthy individuals with lower lupus risk display a unique immune endotype
Slight-Webb, S. R., Smith, M. C., Bylinska, A., Macwana, S., Guthridge, C. J., Lu, R., Merrill, J. T., Chakravarty, E. F., Arriens, C., Munroe, M. E., et al. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.04.047 · Cited by 43
Aberrant expression of USF2 in refractory rheumatoid arthritis and its regulation of proinflammatory cytokines in Th17 cells
Hu, D., Tjon, E. C., Andersson, K., Molica, G. M., Pham, M. C., Healy, B. C., Murugaiyan, G., Pochet, N. L. M. M., Kuchroo, V. K., Bokarewa, M. I., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007935117 · Cited by 43
Pathogenic T-Cell Responses in Immune-Mediated Glomerulonephritis
Linke, A., Tiegs, G., & Neumann, K. (2022) · Cells · doi:10.3390/cells11101625 · Cited by 46
“In addition, transcriptional profiling of blood CD8+ T cells from AAV patients provided evidence for a correlation of an activated, non-exhausted phenotype of CD8+ T cells with a poor prognosis of the disease [144,145].”
Background
Suppression of diabetes by accumulation of non–islet-specific CD8 + effector T cells in pancreatic islets
Christoffersson, G., Chodaczek, G., Ratliff, S. S., Coppieters, K. T., & von Herrath, M. G. (2018) · Science Immunology · doi:10.1126/sciimmunol.aam6533 · Cited by 42
Homeostatic proliferation leads to telomere attrition and increased PD-1 expression after autologous hematopoietic SCT for systemic sclerosis
Arruda, L. C. M., Lima-Júnior, J. R., Clave, E., Moraes, D. A., Douay, C., Fournier, I., Moins‐Teisserenc, H., Covas, D. T., Simões, B. P., Farge, D., et al. (2018) · Bone Marrow Transplantation · doi:10.1038/s41409-018-0162-0 · Cited by 42
Single-cell transcriptome analysis of CAR T-cell products reveals subpopulations, stimulation, and exhaustion signatures
Wang, X., Peticone, C., Kotsopoulou, E., Göttgens, B., & Calero‐Nieto, F. J. (2021) · OncoImmunology · doi:10.1080/2162402x.2020.1866287 · Cited by 43
“cells, which showed specific upregulation of genes that matched previously described exhaustion signatures.(13,15) Only few cells showed an exhaustion signature, corroborating previous reports of low incidence of exhaustion following acute stimulation in CAR-activated cells.”
MethodResult

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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