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T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection
Open accessAbstract
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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“Consistently, a CD8 + Tcell transcriptional profile of exhaustion correlates with beneficial outcome in AID 35,59 and response to immunotherapies. 60”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [59]
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Radziszewska, A., Moulder, Z., Jury, E. C., & Ciurtin, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911431 · Cited by 20
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Increased attrition of memory T cells during sepsis requires 2B4
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“Likewise, CD8+ T-cell exhaustion, as exhibited by high expression of PD-1, acts as a positive predictor of recovery in autoimmune, but not viral, disease [84].”
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ResultAntigen-specific immune decoys intercept and exhaust autoimmunity to prevent disease
Griffin, J. D., Song, J. Y., Huang, A., Sedlacek, A. R., Flannagan, K., & Berkland, C. J. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119440 · Cited by 18
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Lessons From Transcriptome Analysis of Autoimmune Diseases
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“to also play an inhibitory role in long-term autoimmune disease pathology.(3) In a previous study, the PD-1 expression in PBMCs from patients with MS was lower than that in PBMCs from healthy controls.”
BackgroundRe-programming immunosurveillance in persistent non-infectious ocular inflammation
Epps, S. J., Boldison, J., Stimpson, M. L., Khera, T. K., Lait, P. J. P., Copland, D. A., Dick, A. D., & Nicholson, L. B. (2018) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2018.03.001 · Cited by 17
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“Second, as both ADAM10 and ADAM17 are highly expressed in RA [35, 36], cleavage of LAG-3 may drive the T cells to a less protective stage [8, 37].”
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Davidson, A., & Diamond, B. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-384929-8.00003-4 · Cited by 16
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“The T cell costimulation molecules are key regulators of T-cell activation, tolerance, and exhaustion.(17) Modification of these pathway alterations has been translated into effective strategies for cancer”
Slauenwhite, D., McAlpine, S. M., Hanly, J. G., Malik, A. E., Haidl, I. D., Marshall, J. S., & Issekutz, T. B. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41223 · Cited by 16
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WIEDEMAN, A. E., Speake, C., & Long, S. A. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12437 · Cited by 15
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Davidson, A., & Diamond, B. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812102-3.00003-8 · Cited by 16
Characterization of Antigen-Induced CD4+ T-Cell Senescence in Multiple Sclerosis
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Autoreactive CD8 T cells in NOD mice exhibit phenotypic heterogeneity but restricted TCR gene usage
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Kang, Q., Ren, J., Cong, J., & Yu, W. (2024) · BMC Pulmonary Medicine · doi:10.1186/s12890-024-02961-7 · Cited by 16
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Long, S. A., MUIR, V. S., Jones, B. E., Wall, V., Ylescupidez, A., Hocking, A. M., Pribitzer, S., Thorpe, J., Fuchs, B., WIEDEMAN, A. E., et al. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1383110 · Cited by 15
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Harnessing CD8+ T‐cell exhaustion to treat type 1 diabetes
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“Moreover, previous studies showed that T lymphocyte exhaustion were also a dependent risk factor of poor outcome.([33]) Numerous of preclinical studies showed that revised lymphocyte function could help to improve sepsis survival.”
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“The expression of the co-inhibitory programmed death-1 (PD-1) receptor is an essential mechanism for controlling homeostatic activation in the first months after auto-HSCT and keeping autoreactive T cell clones under control (105).”
BackgroundProtecting the kidney against autoimmunity and inflammation
Kurts, C., & Meyer‐Schwesinger, C. (2018) · Nature Reviews Nephrology · doi:10.1038/s41581-018-0097-0 · Cited by 15
PD-1/PD-L1 Combinations in Advanced Urothelial Cancer: Rationale and Current Clinical Trials
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Unbalanced Expression of ICOS and PD-1 in Patients with Neuromyelitis Optica Spectrum Disorder
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“T-cell T-cell exhaustion is a naturally occurring phenomenon in the human immune system, which likely evolved to protect the host from autoimmunity but also leads to limited control of pathogens and cancer [33,42].”
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“Of note, the exhaustion of T cells regularly impedes the ability to defeat viral infection [59] and promote the occurrence of cancer [60].”
Investigation of type I interferon responses in ANCA-associated vasculitis
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A key control point in the T cell response to chronic infection and neoplasia: FOXO1
Marcel, N., & Hedrick, S. Μ. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.02.001 · Cited by 16
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“Interestingly, in this case, rather than proper sepsis, patients experience the persisting presence of the infectious agent, still burdened by a negative prognosis [61] .”
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“T-cell exhaustion refers to an immunologic condition in which CD8+ T cells show a progressive loss of cytokine production and cytotoxic potential [206].”
BackgroundRetractedTemporal Alterations in CD8+ T Cells During the Progression From Stage 1 to Stage 3 Type 1 Diabetes
Schroderus, A., Pitkänen, V., Ekman, I., Stevens, D., Rytkönen-Nissinen, M. A., Rintamäki, R. M., Pihlajamäki, J., Knip, M., Veijola, R., Toppari, J., et al. (2024) · Diabetes · doi:10.2337/db24-0159 · Cited by 14
T cell dysregulation in rheumatoid arthritis: Recent advances and natural product interventions
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The next innovations in chimeric antigen receptor T cell immunotherapies for cancer
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Nectin Family Ligands Trigger Immune Effector Functions in Health and Autoimmunity
Hermans, D., van Beers, L., & Broux, B. (2023) · Biology · doi:10.3390/biology12030452 · Cited by 13
“Controversially, exhaustion of CD8+ T cells has been shown to predict a more positive outcome for autoimmunity [106,108].”
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A unique CD8+ T lymphocyte signature in pediatric type 1 diabetes
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“Maybe more significant from a clinical point of view, recent data indicate that inhibitory receptor–mediated pathways, which negatively interfere with T cell activation and function, specifically protect against a relapsing course in multiple autoimmune diseases (14).”
BackgroundT cell exhaustion implications during transplantation
Shahbazi, M., Soltanzadeh-Yamchi, M., & Mohammadnia‐Afrouzi, M. (2018) · Immunology Letters · doi:10.1016/j.imlet.2018.08.003 · Cited by 13
Prolidase Deficiency Causes Spontaneous T Cell Activation and Lupus-like Autoimmunity
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“In immune mediated inflammatory diseases such as systemic erythematosus lupus, type I diabetes mellitus and ANCA-associated vasculitis, their presence is often associated with improved disease prognosis [ 34–36].”
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Odler, B., Bruchfeld, A. N., Scott, J., Geetha, D., Little, M. A., Jayne, D. R. W., & Kronbichler, A. (2023) · Clinical Kidney Journal · doi:10.1093/ckj/sfad009 · Cited by 12
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“Cells expressing an exhaustion phenotype have been associated with improved outcomes in T1D (46, 48).”
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“In contrast, transcriptional analysis of blood pathological CD8 + T cells from patients with autoimmune disease indicated a correlation between an activated, non-exhausted CD8 + T cell phenotype and a poor prognosis [49, 50].”
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Epigenetics behind CD8+ T cell activation and exhaustion
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Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets
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Plasma checkpoint protein levels and galectin-9 in juvenile systemic lupus erythematosus
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“suppression of the Tcells; inhibiting them for cancer treatment may result in autoimmune rheumatic manifestations.(11) However, the profile of these checkpointproteins in rheumatic diseases, per se have not been studied in detail.”
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Monitoring immunomodulation strategies in type 1 diabetes
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“Transcriptomic profiling of T cells from patients with autoimmunity showed that a T cell exhaustion signature correlated with a more benign form of autoimmune disease, indicating that mechanisms associated with T cell exhaustion may be important in controlling autoimmunity (74).”
BackgroundMetabolic programming in chronically stimulated T cells: Lessons from cancer and viral infections
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“In that vein, a genetic signature of CD8 T cell exhaustion has been reported to predict clinical progression (11), suggesting a role for CD8 T cells in lupus pathophysiology.”
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“However, a recent study suggests that the transcriptional profile of exhausted CD8+ T cells during chronic infections may actually predict favorable clinical outcome in autoimmune and inflammatory diseases (40).”
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“All rights rese generalized T-cell exhaustion in autoimmune disease may serve as a predictive biomarker as well as a correlate for therapeutic efficacy in the wake of immunomodulatory interventions [23,24].”
BackgroundTo Remember or to Forget: The Role of Good and Bad Memories in Adoptive T Cell Therapy for Tumors
Mondino, A., & Manzo, T. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01915 · Cited by 11
“Although CD8 T cell exhaustion was first described in LCMV chronic infection, (58, 59) it is now clear that it occurs in several other chronic infections, (60–62) in autoimmune disorders (63, 64) as well as in cancer (56, 65).”
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“While exhaustion poses an obstacle to the treatment of chronic infections and malignancy, it may also serve a protective role in limiting immunopathology (14, 15).”
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Immune Checkpoints in Solid Organ Transplantation
Bello, A. D., & Treiner, E. (2023) · Biology · doi:10.3390/biology12101358 · Cited by 10
“Finally, IC expression is often dysregulated in AIDs, and increased, sustained, IC expression may be associated with a more favorable evolution, at least in specific diseases [17,18].”
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“Second, “T cell depletion” was recently proposed as the exhaustion of T cells gradually after long-term exposure to persistent antigens and inflammation.([24-26]) Bhat et al also observed that the mouse model of COPD combined with Haemophilus influenzae infection has increased number of inflammatory cells in the lung…”
Background
Metadata
- 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.
- Venue
- Nature
- Published
- 2015-06-29
- Volume
- 523
- Issue
- 7562
- Pages
- 612-616
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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