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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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Torrance, B. L., & Haynes, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1006710 · Cited by 28
“TEMRA cells do not highly express PD-1 and they retain their effector function upon reactivation (91).”
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“Accordingly, there is an accumulation of these so‐called “exhausted T cells,” who lose their essential functional activity (A. N. Akbar & Henson, 2011).”
BackgroundTargeting Aging: Lessons Learned From Immunometabolism and Cellular Senescence
Martin, D. E., Torrance, B. L., Haynes, L., & Bartley, J. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.714742 · Cited by 29
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“Immunosenescence is a term that refers to the gradual change of the immune system resulting from ageing, persistent inflammatory states and chronic antigenic stimulation [17,18].”
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“Notably, the CD57hiCD39hiCD28low ‘exhausted’ phenotype in CD8+ CAR T cells corresponded with a higher expression of checkpoint markers such as PD-1 and LAG-3 (Figure 2B), known to be expressed on terminally exhausted T cells [15].”
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Cellular Senescence in Hepatocellular Carcinoma: The Passenger or the Driver?
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“Consequently, T cell cytotoxicity is compromised with the relevant immune responses [61,62].”
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Magatti, M., Pischiutta, F., Ortolano, F., Pasotti, A., Caruso, E., Cargnoni, A., Papait, A., Capuzzi, F., Zoerle, T., Carbonara, M., et al. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00369-1 · Cited by 30
“…and cytokine production observed in elderly TBI patients could be indicative of a progressive loss of effector function known as cell exhaustion, we evaluated also the expression of IL-2 considering that IL-2 production is one of the first functions to be lost in exhausted CD8 T cells [36].”
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“We precluded that CD45RA+CD25dimCD4+ T cells are late-stage memory CD4+ T cells that re-express CD45RA (Akbar & Henson, 2011; Di Mitri et al., 2011) and also confirmed their naive phenotype by analyzing differentiation markers, homing receptors, and intracellular cytokine production.”
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The Impact of Ageing on the CNS Immune Response in Alzheimer’s Disease
Chee, S. E. J., & Solito, E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.738511 · Cited by 29
“Cellular senescence is characterized by the inability of cells to proliferate, this process being related to the erosion of telomere (107).”
BackgroundMapping CAR T-Cell Design Space Using Agent-Based Models
Prybutok, A. N., Yu, J. S., Leonard, J. N., & Bagheri, N. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.849363 · Cited by 28
“The input files used to generate dish simulations are described in the Supplementary Material ( Supplementary Data 1 and Supplementary Table 4 for monoculture and Supplementary Data 2 and Supplementary Table 5 for co-culture).”
Mairhofer, D. G., Ortner, D., Tripp, C. H., Schaffenrath, S., Fleming, V., Heger, L., Komenda, K., Reider, D., Dudziak, D., Chen, S., et al. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.241 · Cited by 28
“However, we cannot exclude that aging has some effect due to similar fi ndings in old C57BL/6 mice and reports that showed an activated phenotype in T cells of aged mice (Akbar and Henson, 2011).”
Immunosenescence and gender: a study in healthy Cubans
Verdecia, B. G., Hernández, D. S., Lorenzo-Luaces, P., Badia, T., Rupalé, I. L., Mazorra, Z., Crombet, T., & Dávila, A. L. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-16 · Cited by 27
“[17].”
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“Single colour tubes were also used in each assay to adjust for overlapping emission spectra (see text for details)”
MethodTumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner
Etxebeste-Mitxeltorena, M., del Rincón-Loza, I., & Martín-Antonio, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.717850 · Cited by 26
T Cell Subpopulations in Healthy Elderly and Lung Cancer Patients: Insights from Cuban Studies
Saavedra, D., Verdecia, B. G., & Lage, A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00146 · Cited by 26
“The progressive decrease of T cell function as a consequence of a chronically high antigen load is described as part of the phenomenon of exhaustion (14).”
BackgroundImplication of Apoptosis for the Pathogenesis of Trypanosoma cruzi Infection
Decotè-Ricardo, D., Nunes, M. P., Morrot, A., & Freire-de-Lima, C. G. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00518 · Cited by 27
Toxicity of Cancer Therapies in Older Patients
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“Immunosenescence is a multifactorial condition observed in the elderly, consisting of a decreased capacity to respond to vaccination and invading pathogens, and an increased proinflammatory response owing to the accumulation of memory/effector cells [2, 4, 7, 8].”
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“TEMRA cells share the same characteristics as senescent cells, such as possessing short telomeres, DNA damage foci, and a secretome of senescenceassociated secretory phenotype (36).”
Backgroundvan der Geest, K. S. M., Wang, Q., Eijsvogels, T. M. H., Koenen, H. J. P. M., Joosten, I., Brouwer, E., Hopman, M. T. E., Jacobs, J. F. M., & Boots, A. M. H. (2017) · Immunity & Ageing · doi:10.1186/s12979-017-0087-2 · Cited by 25
“(a) Percentages of PD-1 expressing cells in CD4 (left panel) and CD8 (right panel) effector memory T cells (TEM) and terminally differentiated T cells (TTD) pre- (white) and post-walking (grey).”
BackgroundInfluentialSenescence and Aging: Does It Impact Cancer Immunotherapies?
Maggiorani, D., & Beausejour, C. M. (2021) · Cells · doi:10.3390/cells10071568 · Cited by 25
Tavenier, J., Langkilde, A., Haupt, T. H., Henriksen, J. H., Jensen, F. K., Petersen, J., & Andersen, O. (2015) · BMC Immunology · doi:10.1186/s12865-015-0136-6 · Cited by 22
“However, they are able to produce elevated amounts of pro-inflammatory cytokines [7–9].”
Aging promotes acquisition of naive-like CD8+ memory T cell traits and enhanced functionalities
Eberlein, J., Davenport, B., Nguyen, T. T., Victorino, F., Haist, K. C., Jhun, K., Karimpour‐Fard, A., Hunter, L., Kedl, R. M., Clambey, E. T., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci88546 · Cited by 23
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“The notion that aging can improve CD8T cell memory [1-5] stands in apparent contrast to much of the literature documenting numerous and often deleterious consequences of T cell aging [6-9].”
ResultDynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma
Beck, B. H., Kim, H., O’Brien, R. L., Jadus, M. R., Gillespie, G. Y., Cloud, G. A., Hoa, N. T., Langford, C. P., Lopez, R. D., Harkins, L. E., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122387 · Cited by 23
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“The deleterious cytokine responses can be curbed by decreasing unproductive inflammation [33].”
BackgroundCo-Expression of TIGIT and Helios Marks Immunosenescent CD8+ T Cells During Aging
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“Moreover, our findings warrant exploration of TIGITHelios CD8 T cells with respect to other known markers of aging and immunosenescence in CD8 T cells, such as NK cell-related receptors, and low telomerase expression (10, 36).”
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“Depending on the antigenic load generated by the infectious agent the impaired memory formation can result in T cells becoming either senescent or exhausted (9).”
BackgroundSelf-citationAge-Related Expansion of Tim-3 Expressing T Cells in Vertically HIV-1 Infected Children
Tandon, R., Giret, M. T. M., SenGupta, D., York, V. A., WIZNIA, A. A., Rosenberg, M. G., Kallas, E. G., Ndhlovu, L. C., & Nixon, D. F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045733 · Cited by 21
“Detailed assessment of the signaling pathways that regulate T cell senescence and exhaustion suggest that they appear to be distinct processes [35].”
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“The decline of CD8+ T cell- mediated immune responses with age is in part associated with changes in CD8+ T- cell phenotype and defects in proliferation, often referred to as T- cell exhaustion and/or senescence (reviewed in (Akbar & Henson, 2011; Akbar et al., 2016)).”
BackgroundKim, K. H., Pyo, H., Lee, H., Oh, D., Noh, J. M., Ahn, Y. C., Yoon, H. I., Moon, H., Lee, J., Park, S., et al. (2022) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2022.02.003 · Cited by 21
Increased frequency of late‐senescent T cells lacking CD 127 in chronic hepatitis C disease
Barathan, M., Mohamed, R. B., Saeidi, A., Vadivelu, J., Chang, L. Y., Gopal, K., Ram, M. R., Ansari, A. W., Kamarulzaman, A., Velu, V., et al. (2015) · European Journal of Clinical Investigation · doi:10.1111/eci.12429 · Cited by 21
Meta-epigenetic shifts in T cell aging and aging-related dysfunction
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“T cell senescence resembles to features of exhausted T cells observed in chronic infections and tumors, including reduced proliferative capacity, mitochondrial damage and impaired effector function [21].”
Aubert, G., Strauss, K. A., Lansdorp, P. M., & Rider, N. L. (2017) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2016.11.051 · Cited by 20
“CD57(1) T and NK lymphocytes have been shown to increase in frequency with aging,(22) and the characteristics of senescent T cells include high CD57 expression, low proliferative capacity, and low telomerase expression after activation.(31) Taken together, these data support that telomere shortening is part of the cel…”
BackgroundLalani, A. A., Bossé, D., McGregor, B. A., & Choueiri, T. K. (2017) · European Urology Focus · doi:10.1016/j.euf.2017.11.008 · Cited by 20
Finding Balance: T cell Regulatory Receptor Expression during Aging.
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“However, factors that induce prolonged cell senescence, such as UV radiation, cause inflammation as a tissue response to the injury, which further induces fibroblasts to enter senescence [197–201].”
Badell, I. R., Kitchens, W. H., Wagener, M. E., Lukacher, A. E., Larsen, C. P., & Ford, M. L. (2015) · American Journal of Transplantation · doi:10.1111/ajt.13399 · Cited by 19
“PD-1 and KLRG1 expression levels generally parallel each other and are proportionally related to the degree of T cell differentiation (55), but the temporal relationship between these markers of exhaustion and senescence and how they relate to susceptibility to immunosuppression following transplantation are unknown.”
BackgroundThe Immune System and Cellular Senescence: A Complex Interplay in Aging and Disease
Ayoub, M., Jaoude, C. A., Ayoub, M., Hamadé, A., & Rima, M. (2025) · Immunology · doi:10.1111/imm.70036 · Cited by 25
“Their accumulation is linked to systemic inflammation, weakened adaptive immunity, and poor clinical outcomes, particularly in the elderly and immunocompromised individuals [53].”
van den Brom, R. R. H., van Es, S. C., Leliveld, A. M., Gietema, J. A., Hospers, G. A. P., de Jong, I. J., de Vries, E. G. E., & Oosting, S. F. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.04.002 · Cited by 18
“Exhaustion is characterized by loss of essential functional activity necessary for immune protection and senescence is a loss of replicative capacity of antigen-specific T cell populations [24].”
BackgroundAging-associated immune system changes in multiple myeloma: The dark side of the moon.
Visram, A., & Kourelis, T. (2021) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2021.100494 · Cited by 20
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“Both types of cells arise from a continuous stimulation of the TCR [7,22].”
BackgroundCunha, C. F., Ferraz‐Nogueira, R., Costa, V. F. A., Pimentel, M. I. F., Chometon, T. Q., Lyra, M. R., Schubach, A. D. O., Da‐Cruz, A. M., & Bertho, Á. L. (2020) · PLoS ONE · doi:10.1371/journal.pone.0229400 · Cited by 18
HIV infection and immunosenescence: challenges and intervention strategies
Jin, J., Xu, Q., Zhang, X., Zhu, A., Xia, W., Moog, C., Chan, A. S. W., Zhang, T., & Su, B. (2025) · BMC Medicine · doi:10.1186/s12916-025-04545-6 · Cited by 20
“HIV infection drives T cells to exhibit an ageing phenotype through persistent antigenic stimulation, characterized by the upregulation of markers such as PD-1 and CX3CR1, along with chronic activation and systemic inflammation [115, 116].”
A Key Role of CD8+ T Cells in Controlling of Tuberculosis Infection
Kudryavtsev, I. V., Zinchenko, Y. S., Серебрякова, М. К., Akisheva, T., Rubinstein, A., Савченко, А. А., Борисов, А. Г., Belenjuk, V. D., Malkova, A. M., Yаblonskiy, P. K., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13182961 · Cited by 17
“Furthermore, exhausted CD57+ CD8+ T cells had a low proliferative capacity [40].”
BackgroundXu, Y., Wang, Z., Li, S., Su, J., Gao, L., Ou, J., Lin, Z., Luo, O. J., Xiao, C., & Chen, G. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2695-x · Cited by 20
“Moreover, the proliferative capacity of senescent T cells is significantly reduced, with diminished responsiveness to antigens and decreased cytotoxicity (Akbar and Henson, 2011).”
Fungi, immunosenescence and cancer
Xu, B., Luo, Z., Niu, X., Li, Z., Lu, Y., & Li, J. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.01.002 · Cited by 17
Elevated HbA1c levels and the accumulation of differentiated T cells in CMV+ individuals
Rector, J. L., Thomas, G. N., Burns, V. E., Dowd, J. B., Herr, R. M., Moss, P. A. H., Jarczok, M. N., Hoffman, K., Fischer, J. E., & Bosch, J. A. (2015) · Diabetologia · doi:10.1007/s00125-015-3731-4 · Cited by 17
“For example, these T cells show a high production of proinflammatory cytokines, have short telomeres and have an aberrant proliferative capacity [13, 14].”
BackgroundATM activity in T cells is critical for immune surveillance of lymphoma in vivo
Riabinska, A., Lehrmann, D., Jachimowicz, R. D., Knittel, G., Fritz, C., Schmitt, A., Geyer, A., Heneweer, C., Wittersheim, M., Frenzel, L. P., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0618-2 · Cited by 17
“To further investigate the functional state of Atm T cells, we selected transcripts associated with T cell exhaustion, senescence and anergy [36, 38, 39].”
Backgroundde Mare-Bredemeijer, E., Shi, X., Mancham, S., van Gent, R., van der Heide‐Mulder, M., de Boer, R., Heemskerk, M. H. M., de Jonge, J., van der Laan, L. J. W., Metselaar, H. J., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500440 · Cited by 18
“senescence has been related to impaired proliferative capacity (45).”
BackgroundBeneficial and Detrimental Effects of Antiretroviral Therapy on HIV-Associated Immunosenescence
Franzese, O., Barbaccia, M. L., Bonmassar, E., & Graziani, G. (2018) · Chemotherapy · doi:10.1159/000487534 · Cited by 17
Kudryavtsev, I. V., Борисов, А. Г., Vasilyeva, E., Ивановна, К. И., Савченко, А. А., Серебрякова, М. К., & Тотолян, А. А. (2018) · Medical Immunology (Russia) · doi:10.15789/1563-0625-2018-2-227-240 · Cited by 17
Biomodulina T partially restores immunosenescent CD4 and CD8 T cell compartments in the elderly
Saavedra, D., Marraco, S. A. F., Suárez, G. M., González, A., Lorenzo-Luaces, P., Verdecia, B. G., García, E. A., Mazorra, Z., Crombet, T., Speiser, D. E., et al. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110633 · Cited by 17
Soares, L. S., Espíndola, M. S., Zambuzi, F. A., Galvão-Lima, L. J., Cacemiro, M. D. C., Soares, M. R., Santana, B. A., Calado, R. T., Bóllela, V. R., & Frantz, F. G. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106568 · Cited by 15
Neoadjuvant chemotherapy modulates exhaustion of T cells in breast cancer patients
Rodríguez, I. J., Bernal-Estévez, D. A., Llano-León, M., Bonilla, C., & Parra-López, C. (2023) · PLoS ONE · doi:10.1371/journal.pone.0280851 · Cited by 16
“Senescent T cells are terminally differentiated cells with decreased CD28 expression and increased CD57 and KLRG1 expression that can produce large amounts of proinflammatory cytokines, similar to the senescence-associated secretory phenotype [14, 16].”
BackgroundT-lymphocyte populations following a period of high volume training in female soccer players
Brown, F. F., Bigley, A. B., Ross, J. C., LaVoy, E. C. P., Simpson, R. J., & Galloway, S. D. R. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.09.027 · Cited by 16
“CD57 CD28 CD45RA CCR7) and have been referred to by some as ‘senescent’ or ‘exhausted’ cells [1].”
Prato, S., Zhan, Y., Mintern, J. D., & Villadangos, J. A. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300803 · Cited by 16
Zhu, X., & Niedermann, G. (2015) · Oncoscience · doi:10.18632/oncoscience.164 · Cited by 15
“, processes that are induced by repetitive chronic TCRmediated stimulation [7-9].”
Backgroundvan den Brom, R. R. H., van der Geest, K. S. M., Brouwer, E., Hospers, G. A. P., & Boots, A. M. H. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2148-6 · Cited by 15
“PD-1 is an inhibitory receptor expressed by memory T cells and an early marker of exhausted T cells [24].”
BackgroundVillarroya‐Beltri, C., Osório, A., Torres-Ruiz, R., Gómez-Sánchez, D., Trakala, M., Sánchez-Belmonte, A., Mercadillo, F., Hurtado, B., Pitarch, B., Hernández‐Núñez, A., et al. (2022) · Science Advances · doi:10.1126/sciadv.abq5914 · Cited by 15
Perlstein, D., Shlagman, O., Kogan, Y., Halevi-Tobias, K., Yakobson, A., Lazarev, I., & Agur, Z. (2019) · PLoS ONE · doi:10.1371/journal.pone.0226869 · Cited by 17
“We also include in the model the effects of senescence on the cellular immune arm [46], e.”
T-cell exhaustion in multiple myeloma
Żyłka, K., Kubicki, T., Gil, L., & Dytfeld, D. (2024) · Expert Review of Hematology · doi:10.1080/17474086.2024.2370552 · Cited by 15
“Another important dysfunctional T-cell state associated with cellular aging is senescence, characterized by regulatory receptor expression, inability to reproduce, lack of CD28 expression, cell cycle arrest, and increased secretion of inflammatory cytokines [50,51].”
BackgroundThe role of T cells in vascular aging, hypertension, and atherosclerosis
DeConne, T. M., Buckley, D. J., Trott, D. W., & Martens, C. R. (2024) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00570.2024 · Cited by 15
Tanimine, N., Markmann, J. F., Wood, M. A., Demetris, A. J., Mason, K. L., Silva, J. A. F., Levitsky, J., Feng, S., Humar, A., Emond, J. C., et al. (2024) · American Journal of Transplantation · doi:10.1016/j.ajt.2024.10.022 · Cited by 15
Lambracht‐Washington, D., & Rosenberg, R. N. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.12.011 · Cited by 14
“Immunosenescence leads also to a higher propensity to develop autoimmune responses (Akbar and Henson, 2011; Chen et al., 2009; Gruver et al., 2007; Sakata-Kaneko et al., 2000; Solana et al., 2012; Uciechowski et al., 2008; Vasudev et al., 2014; Vukmanovic-Stejic et al., 2011; Weksler, 2000).”
BackgroundDémolis, L. L., Henriquez, S., Lambotte, O., Santo, J. P. D., Grand, R. L., Pflumio, F., Arcangeli, M.-L., Legrand, N., & Bourgeois, C. (2019) · Journal of Leukocyte Biology · doi:10.1002/jlb.5hi1018-410rr · Cited by 15
CD8+ T Cells in Immunotherapy, Radiotherapy, and Chemotherapy
Wang, W., Green, M. D., Liu, J. R., Lawrence, T. S., & Zou, W. (2017) · Springer eBooks · doi:10.1007/978-3-319-62431-0_3 · Cited by 14
Immune senescence: A key player in cancer biology
Yang, Y., Fan, L., Li, M., & Wang, Z. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.12.001 · Cited by 15
Kulikowska de Nałęcz, A., Ciszak, L., Usnarska-Zubkiewicz, L., Pawlak, E., Frydecka, I., Szmyrka, M., & Kosmaczewska, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24065730 · Cited by 13
Mitochondrial Dysfunction in CD4+ T Effector Memory RA+ Cells
Strickland, M., Lee, S., Neo, S., Balachander, A., Low, I., Mustafah, S., Goh, W. I., Wright, G. D., Larbi, A., & Pender, S. L. F. (2023) · Biology · doi:10.3390/biology12040597 · Cited by 14
“TEMRA cells have previously been shown to represent a senescent population of cells that accumulate with age and as a result of specific infections such as cytomegalovirus [6,9].”
BackgroundT-cell lymphocytes’ aging clock: telomeres, telomerase and aging
Chebly, A., Khalil, C., Kuzyk, A. C., Beylot-Barry, M., & Chevret, E. (2023) · Biogerontology · doi:10.1007/s10522-023-10075-6 · Cited by 13
“These memory T-cells in older people exhibit extremely differentiated phenotypes along with several molecular changes including TCR diversity decline and altered signaling pathways; thus becoming senescent or exhausted (Akbar and Henson 2011; Elyahu et al. 2019).”
Shi, H., Xiao, M., Li, Y., Liu, X., Na, J., Liang, C., Hua, J., Meng, Q., Wei, M., Wang, W., et al. (2025) · Theranostics · doi:10.7150/thno.112633 · Cited by 12
“Fourth, senescent T cells display a highly differentiated phenotype marked by the loss of CD27 and CD28 [4], whereas exhausted T cells can be categorized into several subsets based on their differentiation [192].”
Terpstra, M. L., Remmerswaal, E. B. M., van Aalderen, M. C., Wever, J. J., Sinnige, M. J., van der Bom‐Baylon, N. D., Bemelman, F. J., & Geerlings, S. E. (2020) · Immunity Inflammation and Disease · doi:10.1002/iid3.287 · Cited by 11
EBV-specific CD8 T lymphocytes and B cells during glatiramer acetate therapy in patients with MS
Guerrera, G., Ruggieri, S., Picozza, M., Piras, E., Gargano, F., Placido, R., Gasperini, C., Salvetti, M., Buscarinu, M. C., Battistini, L., et al. (2020) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000876 · Cited by 12
“Lymphocytes’ senescence involves the reduced ability to respond to new antigens and in general to support an effective immune response.(20,21) Immunosenescence is due to the general aging of the organism, to the overall history of antigenic exposure, to the infectious load, and above all to chronic or latent infection…”
BackgroundHao, Y., Miraghazadeh, B., Chand, R., Davies, A. R., Cardinez, C., Kwong, K., Downes, M. B., Sweet, R. A., Cañete, P. F., D'Orsogna, L. J. A., et al. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01027-8 · Cited by 12
“T-cell outcomes in response to chronic or recurrent infection include the adoption of dysfunctional phenotypes of senescence, exhaustion and cytotoxicity, which have all been reported to be marked by CD57 expression and/or CD45RA reversion of effector memory cells (TEMRA), but the ontogeny, function and significance o…”
BackgroundChronic inflammation degrades CD4 T cell immunity to prior vaccines in treated HIV infection
Kießling, M., Cole, J. J., Kübel, S., Klein, P., Korn, K., Henry, A. R., Laboune, F., Fourati, S., Harrer, E. G., Harrer, T., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-54605-3 · Cited by 18
Specific types of male infertility are correlated with T cell exhaustion or senescence signatures
Amodio, G., Giacomini, G., Boeri, L., Raffo, M., Cilio, S., Pozzi, E., Belladelli, F., Negri, F., Ferrara, A. M., d’Arma, A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56193-2 · Cited by 16
“During chronic in fl ammation, the persistent stimulation of T cells reprograms their phenotype and functions, thus leading them to exhaustion or senescence 20 .”
Constitutively CD40-activated B cells regulate CD8 T cell inflammatory response by IL-10 induction
Koni, P., Bolduc, A., Takezaki, M., Ametani, Y., Huang, L., Lee, J. R., Nutt, S., Kamanaka, M., Flavell, R., Mellor, A., et al. (2013) · Journal of Immunology · doi:10.4049/jimmunol.1203364 · Cited by 13
“IL-2 production (48) as well as by causing exhaustion in fully differentiated effector CD8 T cells to block cytotoxicity in association with upregulation of various negative regulators (49, 50).”
BackgroundBurke, C. G., Myers, J. R., Post, C. M., Boulé, L. A., & Lawrence, B. P. (2021) · Environmental Health Perspectives · doi:10.1289/ehp7699 · Cited by 12
“Thus, observing enhancement of markers related to these processes in nonaged animals and in the absence of chronic immune challenge is indicative of dysfunctional T-cell responses (Akbar and Henson 2011; Kasakovski et al. 2018).”
BackgroundDJ‐1 depletion prevents immunoaging in T‐cell compartments
Zeng, N., Capelle, C., Baron, A., Kobayashi, T., Cire, S., Tslaf, V., Leonard, C., Coowar, D., Koseki, H., Westendorf, A. M., et al. (2022) · EMBO Reports · doi:10.15252/embr.202153302 · Cited by 13
Restoring resident tissue macrophages to combat aging and cancer
Park, M. D., Yatim, N., Zhang, J., Cho, B. A., Yoo, S., Schaefer, M. M., Chowell, D., Puleston, D. J., & Mérad, M. (2025) · Nature Aging · doi:10.1038/s43587-025-00898-y · Cited by 14
“Studies since then have yielded insights into thymic involution 15,16 , T cell exhaustion 17 and an aging-related bias of hematopoietic differentiation toward the myeloid lineage 18 .”
Pieren, D. K. J., Smits, N. A. M., Imholz, S., Nagarajah, B., van Oostrom, C. T., Brandt, R. M. C., Vermeij, W. P., Dollé, M. E. T., & Guichelaar, T. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.667193 · Cited by 12
“The decline in T-cell function with age can in part be explained by changes to their phenotype and proliferative capacity, often referred to as T-cell exhaustion and/or T-cell senescence (Akbar and Henson, 2011).”
BackgroundSystems level immune response analysis and personalized medicine
Brodin, P., Valentini, D., Uhlin, M., Mattsson, J., Zumla, A. I., & Maeurer, M. J. (2013) · Expert Review of Clinical Immunology · doi:10.1586/eci.13.9 · Cited by 11
Defining and targeting patterns of T cell dysfunction in inborn errors of immunity
Campos, J. S., & Henrickson, S. E. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.932715 · Cited by 12
Immunosenescence in Neurological Diseases—Is There Enough Evidence?
Rommer, P. S., Bsteh, G., Zrzavy, T., Höftberger, R., & Berger, T. (2022) · Biomedicines · doi:10.3390/biomedicines10112864 · Cited by 13
“aging is thought to be accelerated by chronic infections such as cytomegalovirus (CMV) or autoimmune diseases [9,15,16].”
BackgroundHigh-Dimensional Analysis of Human CD8+ T Cell Phenotype, Function, and Antigen Specificity
Newell, E. W., & Lin, W. (2013) · Current topics in microbiology and immunology · doi:10.1007/82_2013_354 · Cited by 11
Wu, J., Zhang, L., Zhao, Z., Liu, Y., Li, Z., Feng, X., Zhang, L., Yao, X., Du, J., Chen, L., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102783 · Cited by 10
Piątosa, B., Wolska‐Kuśnierz, B., Tkaczyk, K., Heropolitańska–Pliszka, E., Grycuk, U., Wakulińska, A., & Gregorek, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01319 · Cited by 9
“PD1 as a marker of exhaustion was detected on a significantly higher proportion of both CD4+ and CD8+ lymphocytes in NBS patients than in healthy controls, with median CD4+PD1+ lymphocytes composing 10.7 vs. 2.6% (p 0.01) and CD8+PD1+ composing 7.3 vs. 3.3% (p 0.01).”
BackgroundResultInfluentialSenescence and Senescence-Related Disorders
Wang, Z. P., & Inuzuka, H. (2013) · InTech eBooks · doi:10.5772/56158 · Cited by 12
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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