Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?

Akbar, Arne N.; Henson, Sian M.

doi:10.1038/nri2959

Cited by 475T-cell and B-cell ImmunologyTelomeres, Telomerase, and SenescenceCancer Immunotherapy and Biomarkers

Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?

Akbar, Arne N., Henson, Sian M.·2011·Nature Reviews Immunology

DOI 10.1038/nri2959

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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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Senescent T cells have defective killing abilities and develop negative regulatory functions.
“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]
Senescent T cells are phenotypically and functionally distinct from exhausted T cells induced by prolonged antigen stimulation.
“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]
Restriction of proliferation of T cells specific for frequently encountered or persistent antigens may compromise maintenance of specific immunity in older humans.
“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]
Short telomeres are interpreted as DNA damage by cell sensing machinery and initiate a cascade culminating in growth arrest.
“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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Cytomegalovirus infection induces the accumulation of short-lived, multifunctional CD4+ CD45RA+ CD27− T cells: the potential involvement of interleukin-7 in this process: IL-7 induces re-expression of CD45RA in CD4+ T cells
Libri, V., Azevedo, R. I., Jackson, S. E., Di Mitri, D., Lachmann, R., Fuhrmann, S., Vukmanovic-Stejic, M., Yong, K., Battistini, L., Kern, F., et al. (2011) · Immunology · doi:10.1111/j.1365-2567.2010.03386.x · Cited by 111 · see citing works
Self-citation
Telomere Erosion in Memory T Cells Induced by Telomerase Inhibition at the Site of Antigenic Challenge In Vivo
Reed, J. R., Vukmanovic-Stejic, M., Fletcher, J. M., Soares, M. V. D., Cook, J. E., Orteu, C. H., Jackson, S. E., Birch, K. E., Foster, G. R., Salmon, M., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040178 · Cited by 111 · see citing works
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Genetic Manipulation of Telomerase in HIV-Specific CD8+ T Cells: Enhanced Antiviral Functions Accompany the Increased Proliferative Potential and Telomere Length Stabilization
Dagarag, M. D., Evazyan, T., Rao, N. P., & Effros, R. B. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.10.6303 · Cited by 107 · see citing works
Telomerase in T Lymphocytes: Use It and Lose It?
Akbar, A. N., & Vukmanovic-Stejic, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.11.6689 · Cited by 96 · see citing works
Self-citation
Telomerase activity of HIV-1–specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors
Lichterfeld, M. D., Mou, D., Cung, T. D. H., Williams, K. L., Waring, M. T., Huang, J., Pereyra, F., Piechocka‐Trocha, A., Freeman, G. J., Rosenberg, E. S., et al. (2008) · Blood · doi:10.1182/blood-2008-01-135442 · Cited by 82 · see citing works
Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T‐cell aging
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T cell immunosenescence in vitro and in vivo
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The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome
Plunkett, F. J., Franzese, O., Belaramani, L. L., Fletcher, J. M., Gilmour, K. C., Sharifi, R., Khan, N., Hislop, A. D., Cara, A., Salmon, M., et al. (2005) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.03.006 · Cited by 74 · see citing works
Self-citation
Role of Bim in Regulating CD8+T-Cell Responses during Chronic Viral Infection
Grayson, J. M., Weant, A. E., Holbrook, B. C., & Hildeman, D. A. (2006) · Journal of Virology · doi:10.1128/jvi.00855-06 · Cited by 71 · see citing works
Age‐related alterations of gene expression patterns in human CD8+ T cells
Cao, J., Gollapudi, S., Sharman, E. H., Jia, Z., & Gupta, S. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2009.00534.x · Cited by 71 · see citing works
Transcription factor regulation of CD8+ T‐cell memory and exhaustion
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CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection
Hoare, M., Gelson, W. T. H., Das, A., Fletcher, J. M., Davies, S. E., Curran, M. D., Vowler, S. L., Maini, M. K., Akbar, A. N., & Alexander, G. J. M. (2010) · Journal of Hepatology · doi:10.1016/j.jhep.2010.03.005 · Cited by 53 · see citing works
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Differential regulation of CD8+ T cell senescence in mice and men
Akbar, A. N., Soares, M. V. D., Plunkett, F. J., & Salmon, M. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(00)00198-6 · Cited by 46 · see citing works
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Cell death and longevity: implications of Fas‐mediated apoptosis in T‐cell senescence
Mountz, J. D., Wu, J., Zhou, T., & Hsu, H. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01024.x · Cited by 39 · see citing works
Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38αMAPK inhibitors in Werner syndrome cells
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Persistence of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Clones in a Subject with Rapid Disease Progression
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Mechanisms That Limit the In Vitro Proliferative Potential of Human CD8+ T Lymphocytes
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Inflammation, antichymotrypsin, and lipid metabolism: autogenic etiology of alzheimer's disease
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Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652 · see citing works
T cell exhaustion
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · see citing works
Cellular senescence in aging and age-related disease: from mechanisms to therapy
Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015) · Nature Medicine · doi:10.1038/nm.4000 · Cited by 2,363 · see citing works
Senescence in Health and Disease
He, S., & Sharpless, N. E. (2017) · Cell · doi:10.1016/j.cell.2017.05.015 · Cited by 1,766 · see citing works
Defining ‘T cell exhaustion’
Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603 · see citing works
Forging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
Gros, A., Robbins, P. F., Yao, X., Li, Y. F., Turcotte, S., Tran, E., Wunderlich, J. R., Mixon, A., Farid, S., Dudley, M. E., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73639 · Cited by 1,113 · see citing works
“Additionally, our present findings showed that the frequency of a specific clonotype in the CD8+ and PD-1+ populations can be used to predict its ability to recognize tumor and isolate tumor-specific TCRs, thus providing means to overcome potential irreversible functional impairments of TILs (52).”
Background
The Principles of Engineering Immune Cells to Treat Cancer
Lim, W. A., & June, C. H. (2017) · Cell · doi:10.1016/j.cell.2017.01.016 · Cited by 1,084 · see citing works
“T cell exhaustion and senescence are often used interchangeably; however, they are now considered as distinct states of differentiation (Akbar and Henson, 2011; Crespo et al., 2013).”
Background
Immunosenescence: molecular mechanisms and diseases
Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y., & Han, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01451-2 · Cited by 1,023 · see citing works
“4).(115,116) For example, cell cycle arrest is a hallmark for identifying all types of senescence, but it is not exclusive to senescent cells.”
Background
Understanding immunosenescence to improve responses to vaccines
Goronzy, J. J., & Weyand, C. M. (2013) · Nature Immunology · doi:10.1038/ni.2588 · Cited by 827 · see citing works
T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma
Brudno, J. N., Marić, I., Hartman, S. D., Rose, J. J., Wang, M., Lam, N., Stetler‐Stevenson, M., Salem, D., Yuan, C. M., Pavletic, S. Z., et al. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2018.77.8084 · Cited by 778 · see citing works
“Senescence is defined as a loss of T-cell proliferative capacity, and T-cell exhaustion refers to a loss of functional capabilities, such as the ability to make cytokines.(37) Both CD4 and CD8 CAR-BCMAT cells had a higher fraction of cells expressing the T-cell senescence marker killer cell lectin-like subfamily recep…”
Background
T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment
Crespo, J., Sun, H., Welling, T. H., Tian, Z., & Zou, W. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.12.003 · Cited by 752 · see citing works
“In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”
Background
Hallmarks of T cell aging
Mittelbrunn, M., & Kroemer, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00927-z · Cited by 702 · see citing works
Mechanisms underlying T cell ageing
Goronzy, J. J., & Weyand, C. M. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0180-1 · Cited by 506 · see citing works
Immunosenescence: a key player in cancer development
Lian, J., Yue, Y., Yu, W., & Zhang, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00986-z · Cited by 510 · see citing works
Senescent cell clearance by the immune system: Emerging therapeutic opportunities
Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2019.04.003 · Cited by 497 · see citing works
The Effect of Age on Thymic Function
Palmer, D. B. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00316 · Cited by 494 · see citing works
“This decline in naïve T cell output is believed to have a major impact on the properties on the peripheral T cell pool such that with increasing age, these cells exhibit alterations in phenotype and function, loss of diversity, and replicative senescence (10, 11).”
Background
Skin barrier immunity and ageing
Chambers, E. S., & Vukmanovic‐Stejic, M. (2019) · Immunology · doi:10.1111/imm.13152 · Cited by 505 · see citing works
Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology
Krabbe, G., Halle, A., Matyash, V., Rinnenthal, J. L., Eom, G. D., Bernhardt, U., Miller, K. R., Prokop, S., Kettenmann, H., & Heppner, F. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0060921 · Cited by 478 · see citing works
“In contrast to the microglial phenotype reported here, cellular senescence is irreversible, at least in lymphocytes and at late stages of cellular senescence [40].”
Result
Successful and Maladaptive T Cell Aging
Goronzy, J. J., & Weyand, C. M. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.010 · Cited by 362 · see citing works
“TEMRAs are different from exhausted cells because they have a selective defect in cell cycle progression, including a defect in telomerase expression, but are otherwise functionally competent (Akbar and Henson, 2011).”
Background
p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells
Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75051 · Cited by 389 · see citing works
Self-citation
Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment
Zhao, Y., Shao, Q., & Peng, G. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0344-8 · Cited by 382 · see citing works
From “truly naïve” to “exhausted senescent” T cells: When markers predict functionality
Larbi, A., & Fulop, T. (2014) · Cytometry Part A · doi:10.1002/cyto.a.22351 · Cited by 359 · see citing works
“At present, CD57 and KLRG1 are considered to be inhibitors of proliferation, whereas PD1 is primarily associated with immune exhaustion (46).”
Background
Human T Cell Aging and the Impact of Persistent Viral Infections
Fülöp, T., Larbi, A., & Pawelec, G. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00271 · Cited by 347 · see citing works
“However, since these early observations were made, it has become evident that these differentiated T cells can under some circumstances regain proliferative capacity, such as after manipulation of KLRG1 (26, 27).”
Background
T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses
Saeidi, A., Zandi, K., Cheok, Y. Y., Saeidi, H., Wong, W. F., Lee, C. Y. Q., Cheong, H. C., Yong, Y. K., Larsson, M., & Shankar, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02569 · Cited by 346 · see citing works
Naive T Cell Maintenance and Function in Human Aging
Goronzy, J. J., Fang, F., Cavanagh, M., Qi, Q., & Weyand, C. M. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500046 · Cited by 348 · see citing works
“T cell exhaustion, as found with chronic, actively replicating viral infections, is characterized by the expression of cell surface molecules such as PD1 and TIM3 on memory and effector cell populations and very different from cellular senescence (82).”
Background
T Cell Dysfunction in Cancer Immunity and Immunotherapy
Xia, A., Zhang, Y., Jiang, X., Yin, T., & Lu, X. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01719 · Cited by 338 · see citing works
Sex, the aging immune system, and chronic disease
Bupp, M. G. (2015) · Cellular Immunology · doi:10.1016/j.cellimm.2015.02.002 · Cited by 333 · see citing works
The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells
Lanna, A., Henson, S. M., Escors, D., & Akbar, A. N. (2014) · Nature Immunology · doi:10.1038/ni.2981 · Cited by 328 · see citing works
“One unexpected observation was that key components of the TCR signaling machinery such as LCK, ZAP-70, DLG1, LAT and SLP-76 are naturally lost in senescent CD4+ T cells, which also loose CD27 and CD28 expression (8,35).”
Self-citation
T Cell Replicative Senescence in Human Aging
P. Chou, J., & B. Effros, R. (2013) · Current Pharmaceutical Design · doi:10.2174/138161213805219711 · Cited by 323 · see citing works
Cells exhibiting strong p16 INK4a promoter activation in vivo display features of senescence
Liu, J.-Y., Souroullas, G. P., Diekman, B. O., Krishnamurthy, J., Hall, B. M., Sorrentino, J. A., Parker, J. S., Sessions, G. A., Gudkov, A. V., & Sharpless, N. E. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1818313116 · Cited by 306 · see citing works
“, increased insulin secretion from p16-expressing pancreatic β-cells (47) and increased cell killing in senescent T cells (46, 48)].”
Background
IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma
Yang, Z., Grote, D. M., Ziesmer, S. C., Niki, T., Hirashima, M., Novak, A. J., Witzig, T. E., & Ansell, S. M. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59806 · Cited by 309 · see citing works
CD57 in human natural killer cells and T-lymphocytes
Kared, H., Martelli, S., Ng, T. P., Pender, S. L. F., & Larbi, A. (2016) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-016-1803-z · Cited by 309 · see citing works
A pilot study of yogic meditation for family dementia caregivers with depressive symptoms: effects on mental health, cognition, and telomerase activity
Lavretsky, H., Epel, E. S., Siddarth, P., Nazarian, N., Cyr, N. S., Khalsa, D. S., Lin, J., Blackburn, E., & Irwin, M. R. (2013) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.3790 · Cited by 298 · see citing works
Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
Akbar, A. N., Henson, S. M., & Lanna, A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.09.002 · Cited by 285 · see citing works
“progressively driven towards senescence [1, 9, 10] and this is highlighted further by the”
BackgroundSelf-citation
A sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging
Lanna, A., Gomes, D. C. O., Muller-Durovic, B., McDonnell, T., Escors, D., Gilroy, D. W., Lee, J. H., Karin, M., & Akbar, A. N. (2017) · Nature Immunology · doi:10.1038/ni.3665 · Cited by 284 · see citing works
Self-citation
Reduced Expression of MYC Increases Longevity and Enhances Healthspan
Hofmann, J. W., Zhao, X., De Cecco, M., Peterson, A. L., Pagliaroli, L., Manivannan, J., Hubbard, G. B., Ikeno, Y., Zhang, Y., Feng, B., et al. (2015) · Cell · doi:10.1016/j.cell.2014.12.016 · Cited by 293 · see citing works
“Immunosenescence results in part from thymic involution as well as replicative senescence of some T cell populations (Akbar and Henson, 2011).”
Progressive Loss of Memory T Cell Potential and Commitment to Exhaustion during Chronic Viral Infection
Angelosanto, J., Blackburn, S. D., Crawford, A., & Wherry, E. J. (2012) · Journal of Virology · doi:10.1128/jvi.00889-12 · Cited by 285 · see citing works
“Both senescent and exhausted CD8 T cells have poor proliferative potential, but it has been unclear whether senescence and exhaustion represented distinct or overlapping biological processes (3).”
Background
Inclusion body myositis: clinical features and pathogenesis
Greenberg, S. A. (2019) · Nature Reviews Rheumatology · doi:10.1038/s41584-019-0186-x · Cited by 273 · see citing works
Human CD 8 + EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK
Callender, L. A., Carroll, E. C., Beal, R. W. J., Chambers, E. S., Nourshargh, S., Akbar, A. N., & Henson, S. M. (2017) · Aging Cell · doi:10.1111/acel.12675 · Cited by 265 · see citing works
“…cell cycle arrest; however, it has now been shown to be more than a process of reduced proliferative capacity but rather an active process regulating cellular homoeostasis in response to numerous stresses, such as DNA damage or a reduction in growth factors (Campisi, 2005; Akbar & Henson, 2011).”
BackgroundSelf-citation
The role of T cells in age-related diseases
Carrasco, E., Heras, M. M. G. D. L., Gabandé‐Rodríguez, E., Desdín-Micó, G., Aranda, J. F., & Mittelbrunn, M. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00557-4 · Cited by 244 · see citing works
Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells
Di Mitri, D., Azevedo, R. I., Henson, S. M., Libri, V., Riddell, N. E., Macaulay, R., Kipling, D., Soares, M. V. D., Battistini, L., & Akbar, A. N. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100978 · Cited by 231 · see citing works
“entiate both functionally and phenotypically (1, 2).”
Self-citation
Influence of Inflammation in the Process of T Lymphocyte Differentiation: Proliferative, Metabolic, and Oxidative Changes
Moro‐García, M. A., Mayo, J. C., Sainz, R. M., & Alonso‐Arias, R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00339 · Cited by 232 · see citing works
“Initially, exhausted T lymphocytes have a defect in proliferative progression and a defect in the expression of telomerase, but the rest of their functions are completely conserved (115).”
Background
Targeting lysosomes in human disease: from basic research to clinical applications
Cao, M., Luo, X., Wu, K., & He, X. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00778-y · Cited by 225 · see citing works
Age‐related thymic involution: Mechanisms and functional impact
Liang, Z., Dong, X., Zhang, Z., Zhang, Q., & Zhao, Y. X. (2022) · Aging Cell · doi:10.1111/acel.13671 · Cited by 229 · see citing works
“Naïve T cells from aged mice express elevated levels of senescence markers and display reduced proliferation ability upon antigen stimulation (Akbar & Henson, 2011; Chaudhry et al., 2016).”
Background
The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology
Huff, W. X., Kwon, J. H., Henriquez, M., Fetcko, K., & Dey, M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112810 · Cited by 217 · see citing works
“There is theoretical concern that reversing the growth arrest by selective blockage of senescent T cells carries a risk of malignancy, which is less of a concern for targeting functionally exhausted T cells [185].”
Background
Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy
Knaus, H. A., Berglund, S., Hackl, H., Blackford, A. L., Zeidner, J. F., Montiel-Esparza, R., Mukhopadhyay, R., Vanura, K., Blazar, B. R., Karp, J. E., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.120974 · Cited by 216 · see citing works
T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy
Chung, D. J., Pronschinske, K. B., Shyer, J. A., Sharma, S., Leung, S., Curran, S. A., Lesokhin, A. M., Devlin, S. M., Giralt, S., & Young, J. W. (2015) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-15-0055 · Cited by 210 · see citing works
“Although investigators have not fully distinguished the molecular characteristics of exhaustion and senescence (41), cell surface markers can be used to segregate these T-cell states phenotypically.”
BackgroundInfluential
The Third Signal Cytokine IL-12 Rescues the Anti-Viral Function of Exhausted HBV-Specific CD8 T Cells
Schurich, A., Pallett, L. J., Lubowiecki, M., Singh, H. D., Gill, U. S., Kennedy, P. T. F., Nastouli, E., Tanwar, S., Rosenberg, W. M., & Maini, M. K. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003208 · Cited by 186 · see citing works
“This suggests there are different requirements in the activation of exhausted versus senescent T cells, respectively, strengthening the notion that these two processes are independently regulated [22].”
BackgroundResult
Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma
Drent, E., Groen, R. W. J., Noort, W. A., Themeli, M., van Bueren, J. J. L., Parren, P. W. H. I., Kuball, J. H. E., Sebestyén, Z., Yuan, H., de Bruijn, J. D., et al. (2016) · Haematologica · doi:10.3324/haematol.2015.137620 · Cited by 186 · see citing works
Properties of end-stage human T cells defined by CD45RA re-expression
Henson, S. M., Riddell, N. E., & Akbar, A. N. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.04.001 · Cited by 180 · see citing works
“Therefore CD45RA re-expressing T cells have multiple signatures of senescence and end-stage differentiation however these characteristics are not totally dependent on telomere erosion [21].”
BackgroundInfluentialSelf-citation
Thymus: the next (re)generation
Chaudhry, M. S., Velardi, E., Dudakov, J. A., & van den Brink, M. R. M. (2016) · Immunological Reviews · doi:10.1111/imr.12418 · Cited by 182 · see citing works
“However, even those naive T cells that are produced in the aged thymus are functionally impaired; expressing higher levels of senescence markers such as CD57 and exhibiting limited proliferation in response to antigen stimulation (88).”
Background
The function and dysfunction of memory CD 8+ T cells in tumor immunity
Reading, J. L., Gálvez‐Cancino, F., Swanton, C., Lladser, Á., Peggs, K. S., & Quezada, S. A. (2018) · Immunological Reviews · doi:10.1111/imr.12657 · Cited by 182 · see citing works
Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly
Pereira, B. I., Xu, X., & Akbar, A. N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.583019 · Cited by 182 · see citing works
Self-citation
Aerobic fitness is associated with lower proportions of senescent blood T-cells in man
Spielmann, G., McFarlin, B. K., O’Connor, D. P., Smith, P. J. W., Pircher, H., & Simpson, R. J. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.07.226 · Cited by 180 · see citing works
Functional T cells are capable of supernumerary cell division and longevity
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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
Publisher: Springer Science and Business Media LLC
Published: 2011-03-25
Volume: 11
Issue: 4
Pages: 289-295
ISSN: 1474-1733 (ISSN-L)
1474-1741
DOI: 10.1038/nri2959
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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
Health Sciences › Medicine › Physiology › 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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Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?

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