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Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?
Abstract
Can the immune system be reactivated continuously throughout the lifetime of an organism or is there a finite point at which repeated antigenic challenge leads to the loss of lymphocyte function or the cells themselves or both? Replicative senescence and exhaustion are processes that control T cell proliferative activity and function; however, there is considerable confusion over the relationship between these two intrinsic cellular control mechanisms. In this Opinion article, we compare the molecular regulation of senescence and exhaustion in T cells. Available data suggest that both processes are regulated independently of each other and that it may be safer to block exhaustion than senescence to enhance immunity.
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“In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [53]
In the citing paper
“Based on phenotype and function, senescent T cells must not be confused with exhausted T cells induced by prolonged antigen stimulation [40–42].”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [42]
In the citing paper
“The restriction to the extent of proliferation of T cells, especially those that are specific for frequently encountered or persistent antigens may therefore compromise the maintenance of specific immunity in older humans as they may be driven towards senescence [1, 12].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [12]
In the citing paper
“Short telomeres are interpreted as DNA damage by cell sensing machinery that initiates a cascade of events that culminates in growth arrest (reviewed in Akbar and Henson 2011 [12]).”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [12]
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“Taken together, although infiltrating T cells display an advanced transitional(TTM) or even effector memory phenotype (TEM), the distinct PD-1þ KLRG1 , CD57 , CD39þ, Tim-3þ marker profile of CD8þ TILs indicate an inherent immune exhaustion signature, characteristic of impaired functionality due to continuous (tumor)–…”
BackgroundCellular senescence impact on immune cell fate and function
Vicente, R., Mausset-Bonnefont, A.-L., Jorgensen, C., Louis-Plence, P., & Brondello, J.-M. (2016) · Aging Cell · doi:10.1111/acel.12455 · Cited by 151
“Nevertheless, such alterations of the T-cell phenotype are not restricted to senescent T cells (for review, see Akbar & Henson, 2011; Wherry, 2011; Crespo et al., 2013).”
BackgroundDoes tuberculosis threaten our ageing populations?
Byng-Maddick, R., & Noursadeghi, M. (2016) · BMC Infectious Diseases · doi:10.1186/s12879-016-1451-0 · Cited by 149
“Reduced T cell output by the thymus, T cell immune senescence, defined by reduced capacity for cell proliferation, and immune exhaustion, defined by reduced capacity to produce cytokines and other effector molecules are the most consistent reported effects of ageing on the immune system [10, 11].”
Background3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells
Wang, Z., McWilliams‐Koeppen, H. P., Reza, H., Ostberg, J. R., Chen, W., Wang, X., Huynh, C., Vyas, V., Chang, W.-C., Starr, R., et al. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.02.009 · Cited by 148
The role of cellular senescence in skin aging and age-related skin pathologies
Chin, T., Lee, X. E., Ng, P. Y., Lee, Y., & Dreesen, O. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1297637 · Cited by 164
“T cell function also declines with age, and reduced numbers of CD4 + cytotoxic T cells are correlated with increased p16-positive cells in the dermis (Akbar and Henson, 2011; Hasegawa et al., 2023).”
BackgroundExhaustion of T lymphocytes in the tumor microenvironment: Significance and effective mechanisms
Gholami, M. D., Kardar, G. A., Saeedi, Y., Heidari, S., Garssen, J., & Falak, R. (2017) · Cellular Immunology · doi:10.1016/j.cellimm.2017.10.002 · Cited by 143
“Senescent T cells are dysfunctional and incapable of killing target cells, and may in fact inhibit normal T cell activity in the TME [42,43].”
InfluentialCD28 co-stimulation in T-cell homeostasis: a recent perspective
Hünig, T., Beyersdorf, N., & Kerkau, T. (2015) · ImmunoTargets and Therapy · doi:10.2147/itt.s61647 · Cited by 147
“While exhausted cells eventually undergo apoptosis, senescent T-cells usually are resistant to apoptosis and persist (reviewed in Akbar and Henson 46 ).”
Li, Y., Shen, Y., Hohensinner, P. J., Ju, J., Wen, Z., Goodman, S. B., Zhang, H., Goronzy, J. J., & Weyand, C. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.09.013 · Cited by 138
“, 2016) and continue to participate in clonal expansion, distinguishing lymphocyte aging from senescence (Akbar and Henson, 2011; Chou and Effros, 2013; Sharpless and Sherr, 2015).”
Goronzy, J. J., Li, G., Yu, M., & Weyand, C. M. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.003 · Cited by 134
Prattichizzo, F., De Nigris, V., La Sala, L., Procopio, A. D., Olivieri, F., & Ceriello, A. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1810327 · Cited by 129
“These findings clearly point at the endothelium as a key organ in the pathophysiology of aging and in diabetes complications.”
BackgroundZhang, Z., Chen, L., Chen, H., Zhao, J., Li, K., Sun, J., & Zhou, M. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104207 · Cited by 135
Gough, D. J., Koetz, L., & Levy, D. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083395 · Cited by 137
Aging disturbs the balance between effector and regulatory CD4+ T cells
van der Geest, K. S. M., Abdulahad, W. H., Tete, S. M., Lorencetti, P. G., Horst, G., Bos, N. A., Kroesen, B., Brouwer, E., & Boots, A. M. H. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.11.005 · Cited by 131
“The latter finding could reflect a minor increase of CD45RA re-expressing memory cells in the aged individuals (Akbar and Henson, 2011).”
BackgroundThe role of the T cell in age-related inflammation
Macaulay, R., Akbar, A. N., & Henson, S. M. (2012) · AGE · doi:10.1007/s11357-012-9381-2 · Cited by 130
“When telomeres reach a critically short length, they initiate a DNA damage response that can induce apoptosis or growth arrest termed replicative senescence, an increasingly recognised important factor in T-cell immunosenescence (reviewed in Akbar and Henson 2011).”
BackgroundSelf-citationDNA methylation: a promising landscape for immune system-related diseases
Suárez-Álvarez, B., Rodríguez, R. M. A., Fraga, M. F., & López‐Larrea, C. (2012) · Trends in Genetics · doi:10.1016/j.tig.2012.06.005 · Cited by 133
Highly differentiated cytotoxic T cells in inclusion body myositis
Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher‐Allan, C., Amato, A. A., & Dorfman, D. M. (2019) · Brain · doi:10.1093/brain/awz207 · Cited by 125
Salminen, A. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-021-02123-w · Cited by 127
“Studies on senescent T cells have revealed a state called T cell exhaustion which have many different properties compared to those of senescent T cells [18, 19].”
BackgroundType 2 diabetes is associated with the accumulation of senescent T cells
Lau, E. Y. M., Carroll, E. C., Callender, L. A., Hood, G., Berryman, V., Pattrick, M., Finer, S., Hitman, G. A., Ackland, G. L., & Henson, S. M. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13344 · Cited by 118
Self-citationLiu, X., Hoft, D. F., & Peng, G. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133679 · Cited by 116
Immune Regulatory Processes of the Tumor Microenvironment under Malignant Conditions
Pansy, K., Uhl, B., Krstić, J., Szmyra, M., Fechter, K., Santiso, A., Thüminger, L., Greinix, H., Kargl, J., Prochazka, K. T., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413311 · Cited by 113
T-cell exhaustion in immune-mediated inflammatory diseases: New implications for immunotherapy
Gao, Z., Feng, Y., Xu, J., & Liang, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.977394 · Cited by 118
“In other words, the dysfunctional and exhausted states of T-cells cannot be classified as identical concepts (90, 91).”
BackgroundThe Single-Cell Phenotypic Identity of Human CD8+ and CD4+ T Cells
Brummelman, J., Pilipow, K., & Lugli, E. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.05.007 · Cited by 113
The aged tumor microenvironment limits T cell control of cancer
Chen, C.-Y., Jaiswal, S., Martínez, D., Yerinde, C., Ji, K. Y., Miranda, V., Fung, M. E., Weiss, S. A., Zschummel, M., Taguchi, K., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01828-7 · Cited by 114
“Therefore, the relative importance of age-associated CD8 + T cell dysfunction versus chronic stimulation-driven CD8 + T cell exhaustion in the aged TME remains unclear 16 .”
T‐cell Immunoglobulin and ITIM Domain Contributes to CD 8+ T‐cell Immunosenescence
Song, Y., Wang, B., Song, R., Yu, H., Wang, D., Li, Y., Jiang, Y. Y., Xu, L., Ma, Y., Zheng, H., et al. (2018) · Aging Cell · doi:10.1111/acel.12716 · Cited by 109
“Exhausted T cells are derived from activated T cells that progressively lose function because of persistent antigen stimulation, whereas senescence is cell cycle arrest due to aging (Akbar & Henson, 2011; Crespo, Sun, Welling, Tian, & Zou, 2013).”
BackgroundReverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection
Schober, K., Voit, F., Grassmann, S. A., Müller, T. R., Eggert, J., Jarosch, S., Weißbrich, B., Hoffmann, P., Borkner, L., Nio, E., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0628-2 · Cited by 112
Convergence of Innate and Adaptive Immunity during Human Aging
Pereira, B. I., & Akbar, A. N. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00445 · Cited by 110
“On the contrary, these cells are polyfunctional, reflecting their ability to simultaneously carry out multiple functions, including secretion of IFN-γ and TNF-α and cytotoxicity (35, 38, 40), and this is an important observation that distinguishes senescent from exhausted T cells (41).”
BackgroundSelf-citationMaternal and fetal T cells in term pregnancy and preterm labor
Miller, D., Gershater, M., Slutsky, R., Romero, R. J., & Gomez‐Lopez, N. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0471-2 · Cited by 107
A second chance for telomerase reverse transcriptase in anticancer immunotherapy
Zanetti, M. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.67 · Cited by 106
T-cell senescence contributes to abnormal glucose homeostasis in humans and mice
Yi, H., Kim, S. Y., Kim, J. T., Lee, Y., Moon, J. S., Kim, M., Kang, Y. E., Joung, K. H., Lee, J. H., Kim, H. J., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1494-4 · Cited by 102
CCR8 Expression Defines Tissue-Resident Memory T Cells in Human Skin
McCully, M. L., Ladell, K., Andrews, R., Jones, R. E., Miners, K. L., Roger, L., Baird, D. M., Cameron, M. J., Jessop, Z. M., Whitaker, I. S., et al. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701377 · Cited by 103
Increased systemic inflammation and altered distribution of T-cell subsets in postmenopausal women
Abildgaard, J., Tingstedt, J. L., Zhao, Y., Hartling, H. J., Pedersen, A. T., Lindegaard, B., & Nielsen, S. D. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235174 · Cited by 98
“Increased transition from memory- to exhausted- and senescent T-cells leads to a loss of function necessary for adequate immune protection and replicative capacity [29].”
BackgroundVölkl, S., Rensing‐Ehl, A., Allgäuer, A., Schreiner, E., Lorenz, M. R., Rohr, J., Klemann, C., Fuchs, I., Schuster, V. H., von Bueren, A. O., et al. (2016) · Blood · doi:10.1182/blood-2015-11-685024 · Cited by 100
“Such cells show reduced proliferative capacity and defective memory formation.(19,39) The relevance of mTOR hyperactivation in terminal differentiation has been reinforced by the recent description of patients with PIK3CD gain-of-function mutations.”
BackgroundExtremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging
Soto‐Heredero, G., Heras, M. M. G. D. L., Escrig-Larena, J. I., & Mittelbrunn, M. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-064501 · Cited by 96
Metadata
- Authors
- Akbar, A. N., & Henson, S. M.
- Affiliations
- University College London (GB)
- Corresponding author
- Akbar, Arne N.
- ORCID
- Akbar, Arne N.
- Venue
- Nature Reviews Immunology
- Published
- 2011-03-25
- Volume
- 11
- Issue
- 4
- Pages
- 289-295
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- OpenAlex
- W2068367301
- Cited by
- 474
- References
- 96
- Citations by year
- 2026: 36 · 2025: 41 · 2024: 28 · 2023: 28 · 2022: 38 · 2021: 36 · 2020: 33 · 2019: 32 · 2018: 31 · 2017: 20 · 2016: 33 · 2015: 32 · 2014: 26 · 2013: 29 · 2012: 20
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- T cell senescence, T cell exhaustion, replicative senescence, viral persistence, aging, immune reactivation, T cell proliferation, immunosenescence
- MeSH terms
- Animals, Fatigue, Humans, Immunity, Cellular, Lymphocyte Activation, T-Lymphocytes, Virus Diseases, Cellular Senescence, Mice
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