Abstract
T cell ageing has a pivotal role in rendering older individuals vulnerable to infections and cancer and in impairing the response to vaccination. Easy accessibility to peripheral human T cells as well as an expanding array of tools to examine T cell biology have provided opportunities to examine major ageing pathways and their consequences for T cell function. Here, we review emerging concepts of how the body attempts to maintain a functional T cell compartment with advancing age, focusing on three fundamental domains of the ageing process, namely self-renewal, control of cellular quiescence and cellular senescence. Understanding these critical elements in successful T cell ageing will allow the design of interventions to prevent or reverse ageing-related T cell failure.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nikolich-Zugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19, 10–19 (2018).
Goronzy, J. J. & Weyand, C. M. Successful and maladaptive T cell aging. Immunity 46, 364–378 (2017).
Del Giudice, G. et al. Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging. NPJ Aging Mech. Dis. 4, 1 (2018).
Lal, H. et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N. Engl. J. Med. 372, 2087–2096 (2015).
HIPC-CHI Signatures Project Team & HIPC-I Consortium. Multicohort analysis reveals baseline transcriptional predictors of influenza vaccination responses. Sci. Immunol. 2, eaal4656 (2017).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Palmer, D. B. The effect of age on thymic function. Front. Immunol. 4, 316 (2013).
Yanes, R. E., Gustafson, C. E., Weyand, C. M. & Goronzy, J. J. Lymphocyte generation and population homeostasis throughout life. Semin. Hematol. 54, 33–38 (2017).
Hamilton, S. E. & Jameson, S. C. CD8 T cell quiescence revisited. Trends Immunol. 33, 224–230 (2012).
Newton, R. H. et al. Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat. Immunol. 19, 838–848 (2018).
Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).
Akbar, A. N. & Henson, S. M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).
Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005).
Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).
Ermolaeva, M., Neri, F., Ori, A. & Rudolph, K. L. Cellular and epigenetic drivers of stem cell ageing. Nat. Rev. Mol. Cell Biol. 19, 594–610 (2018).
Dixit, V. D. Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence. Semin. Immunol. 24, 321–330 (2012).
Bains, I., Thiebaut, R., Yates, A. J. & Callard, R. Quantifying thymic export: combining models of naive T cell proliferation and TCR excision circle dynamics gives an explicit measure of thymic output. J. Immunol. 183, 4329–4336 (2009).
Hogan, T., Gossel, G., Yates, A. J. & Seddon, B. Temporal fate mapping reveals age-linked heterogeneity in naive T lymphocytes in mice. Proc. Natl Acad. Sci. USA 112, E6917–E6926 (2015).
Leins, H. et al. Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood 132, 565–576 (2018).
den Braber, I. et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36, 288–297 (2012). This study provides evidence for species-specific differences in T cell replenishment of mice and humans and delineates the implications for T cell homeostasis with age.
Seddon, B. & Yates, A. J. The natural history of naive T cells from birth to maturity. Immunol. Rev. 285, 218–232 (2018).
Naylor, K. et al. The influence of age on T cell generation and TCR diversity. J. Immunol. 174, 7446–7452 (2005).
Westera, L. et al. Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover. Aging Cell 14, 219–227 (2015).
Busque, L., Buscarlet, M., Mollica, L. & Levine, R. L. Concise review: age-related clonal hematopoiesis: stem cells tempting the devil. Stem Cells 36, 1287–1294 (2018).
Czesnikiewicz-Guzik, M. et al. T cell subset-specific susceptibility to aging. Clin. Immunol. 127, 107–118 (2008).
Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143–2155 (2014).
Thome, J. J. et al. Longterm maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, eaah6506 (2016).
Whiting, C. C. et al. Large-scale and comprehensive immune profiling and functional analysis of normal human aging. PLOS ONE 10, e0133627 (2015). Extensive immune profiling in a well-characterized cohort of healthy adults.
Akondy, R. S. et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature 552, 362–367 (2017).
Pulko, V. et al. Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nat. Immunol. 17, 966–975 (2016).
van der Geest, K. S. et al. Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+ T cells in aged humans. Aging Cell 14, 744–753 (2015).
Sprent, J. & Surh, C. D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484 (2011).
Chiu, B. C., Martin, B. E., Stolberg, V. R. & Chensue, S. W. Cutting edge: central memory CD8 T cells in aged mice are virtual memory cells. J. Immunol. 191, 5793–5796 (2013). This study shows that naive CD8 + T cells in mice fail to maintain quiescence and differentiate into virtual memory T cells with age.
Quinn, K. M. et al. Age-related decline in primary CD8+ T cell responses is associated with the development of senescence in virtual memory CD8+ T cells. Cell Rep. 23, 3512–3524 (2018).
Jacomet, F. et al. Evidence for eomesodermin-expressing innate-like CD8+ KIR/NKG2A+ T cells in human adults and cord blood samples. Eur. J. Immunol. 45, 1926–1933 (2015).
Link, A. et al. Fibroblastic reticular cells in lymph nodes regulate the homeostasis of naive T cells. Nat. Immunol. 8, 1255–1265 (2007).
Surh, C. D. & Sprent, J. Homeostasis of naive and memory T cells. Immunity 29, 848–862 (2008).
Becklund, B. R. et al. The aged lymphoid tissue environment fails to support naive T cell homeostasis. Sci. Rep. 6, 30842 (2016).
Thompson, H. L. et al. Lymph nodes as barriers to T cell rejuvenation in aging mice and nonhuman primates. Aging Cell 18, e12865 (2018). This study shows that ageing of the lymph node niche impairs T cell homeostasis.
Zeng, M. et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J. Clin. Invest. 121, 998–1008 (2011).
Kityo, C. et al. Lymphoid tissue fibrosis is associated with impaired vaccine responses. J. Clin. Invest. 128, 2763–2773 (2018). This paper provides evidence in humans that inflammation impairs the T cell niche in lymph nodes, with negative implications for T cell homeostasis and T cell responses.
Ucar, D. et al. The chromatin accessibility signature of human immune aging stems from CD8+ T cells. J. Exp. Med. 214, 3123–3144 (2017). This study shows that age-associated epigenetic changes affect CD8 + T cells more than CD4 + T cells.
Gustafson, C. E., Cavanagh, M. M., Jin, J., Weyand, C. M. & Goronzy, J. J. Functional pathways regulated by microRNA networks in CD8 T cell aging. Aging Cell 18, e12879 (2018).
Johnson, P. L., Yates, A. J., Goronzy, J. J. & Antia, R. Peripheral selection rather than thymic involution explains sudden contraction in naive CD4 T cell diversity with age. Proc. Natl Acad. Sci. USA 109, 21432–21437 (2012).
Lythe, G., Callard, R. E., Hoare, R. L. & Molina-Paris, C. How many TCR clonotypes does a body maintain? J. Theor. Biol. 389, 214–224 (2016).
Schonland, S. O. et al. Homeostatic control of T cell generation in neonates. Blood 102, 1428–1434 (2003).
Goronzy, J. J., Qi, Q., Olshen, R. A. & Weyand, C. M. High-throughput sequencing insights into T cell receptor repertoire diversity in aging. Genome Med. 7, 117 (2015).
Britanova, O. V. et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192, 2689–2698 (2014).
Warren, R. L. et al. Exhaustive T cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes. Genome Res. 21, 790–797 (2011).
Laydon, D. J., Bangham, C. R. & Asquith, B. Estimating T cell repertoire diversity: limitations of classical estimators and a new approach. Phil. Trans. R. Soc. B 370, 20140291 (2015).
Qi, Q. et al. Diversity and clonal selection in the human T cell repertoire. Proc. Natl Acad. Sci. USA 111, 13139–13144 (2014). This study provides quantitative estimates of the decrease in T cell receptor richness and increase in clonality in human adults with age.
Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).
Tomasetti, C., Li, L. & Vogelstein, B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017).
Savola, P. et al. Somatic mutations in clonally expanded cytotoxic T lymphocytes in patients with newly diagnosed rheumatoid arthritis. Nat. Commun. 8, 15869 (2017).
Klenerman, P. The (gradual) rise of memory inflation. Immunol. Rev. 283, 99–112 (2018).
Pangrazzi, L. et al. Increased IL-15 production and accumulation of highly differentiated CD8+ effector/memory T cells in the bone marrow of persons with cytomegalovirus. Front. Immunol. 8, 715 (2017).
Miron, M. et al. Human lymph nodes maintain TCF-1hi memory T cells with high functional potential and clonal diversity throughout life. J. Immunol. 201, 2132–2140 (2018).
Crotty, S. & Ahmed, R. Immunological memory in humans. Semin. Immunol. 16, 197–203 (2004).
Hammarlund, E. et al. Duration of antiviral immunity after smallpox vaccination. Nat. Med. 9, 1131–1137 (2003).
Borghans, J. A. M., Tesselaar, K. & de Boer, R. J. Current best estimates for the average lifespans of mouse and human leukocytes: reviewing two decades of deuterium-labeling experiments. Immunol. Rev. 285, 233–248 (2018).
Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).
Ahmed, R. et al. Human stem cell-like memory T cells are maintained in a state of dynamic flux. Cell Rep. 17, 2811–2818 (2016).
Di Benedetto, S. et al. Impact of age, sex and CMV-infection on peripheral T cell phenotypes: results from the Berlin BASE-II Study. Biogerontology 16, 631–643 (2015).
Costa Del Amo, P. et al. Human TSCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness. PLOS Biol. 16, e2005523 (2018).
Schluns, K. S. & Lefrancois, L. Cytokine control of memory T cell development and survival. Nat. Rev. Immunol. 3, 269–279 (2003).
Lees, J. R. & Farber, D. L. Generation, persistence and plasticity of CD4 T cell memories. Immunology 130, 463–470 (2010).
Kedzierska, K., Valkenburg, S. A., Doherty, P. C., Davenport, M. P. & Venturi, V. Use it or lose it: establishment and persistence of T cell memory. Front. Immunol. 3, 357 (2012).
Wallace, D. L. et al. Direct measurement of T cell subset kinetics in vivo in elderly men and women. J. Immunol. 173, 1787–1794 (2004).
Westera, L. et al. Closing the gap between T cell life span estimates from stable isotope-labeling studies in mice and humans. Blood 122, 2205–2212 (2013).
Gossel, G., Hogan, T., Cownden, D., Seddon, B. & Yates, A. J. Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels. eLife 6, e23013 (2017).
Asanuma, H., Sharp, M., Maecker, H. T., Maino, V. C. & Arvin, A. M. Frequencies of memory T cells specific for varicella-zoster virus, herpes simplex virus, and cytomegalovirus by intracellular detection of cytokine expression. J. Infect. Dis. 181, 859–866 (2000).
Levin, M. J. et al. Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-dose VZV vaccine. J. Infect. Dis. 188, 1336–1344 (2003).
Klenerman, P. & Oxenius, A. T cell responses to cytomegalovirus. Nat. Rev. Immunol. 16, 367–377 (2016).
Yao, X. et al. Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. Vaccine 29, 5015–5021 (2011).
Moehling, K. K. et al. The effect of frailty on HAI response to influenza vaccine among community-dwelling adults ≥50 years of age. Hum. Vaccin. Immunother. 14, 361–367 (2018).
Van Epps, P. et al. Preexisting immunity, not frailty phenotype, predicts influenza postvaccination titers among older veterans. Clin. Vaccine Immunol. 24, e00498–16 (2017).
Thomasini, R. L. et al. Aged-associated cytomegalovirus and Epstein-Barr virus reactivation and cytomegalovirus relationship with the frailty syndrome in older women. PLOS ONE 12, e0180841 (2017).
Polymenis, M. & Kennedy, B. K. in Cell Division Machinery and Disease (eds Gotta, M. & Meraldi, P.) 189–208 (Springer, 2017).
Wang, J. et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell 148, 1001–1014 (2012).
Chakkalakal, J. V., Jones, K. M., Basson, M. A. & Brack, A. S. The aged niche disrupts muscle stem cell quiescence. Nature 490, 355–360 (2012).
Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A. & Weissman, I. L. The aging of hematopoietic stem cells. Nat. Med. 2, 1011–1016 (1996).
Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).
Haluszczak, C. et al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J. Exp. Med. 206, 435–448 (2009).
White, J. T. et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7, 11291 (2016).
Lee, J. Y., Hamilton, S. E., Akue, A. D., Hogquist, K. A. & Jameson, S. C. Virtual memory CD8 T cells display unique functional properties. Proc. Natl Acad. Sci. USA 110, 13498–13503 (2013).
Goronzy, J. J., Hu, B., Kim, C., Jadhav, R. R. & Weyand, C. M. Epigenetics of T cell aging. J. Leukoc. Biol. 104, 691–699 (2018).
Keenan, C. R. & Allan, R. S. Epigenomic drivers of immune dysfunction in aging. Aging Cell 18, e12878 (2018).
Cheung, P. et al. Single-cell chromatin modification profiling reveals increased epigenetic variations with aging. Cell 173, 1385–1397 (2018).
van den Broek, T., Borghans, J. A. M. & van Wijk, F. The full spectrum of human naive T cells. Nat. Rev. Immunol. 18, 363–373 (2018).
Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017). This study shows similarities in the epigenetic changes that occur with differentiation and ageing of human CD8 + T cells.
Martinez-Jimenez, C. P. et al. Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355, 1433–1436 (2017). This study shows that response patterns of mouse CD4 + T cells to stimulation exhibit increasing heterogeneity with age.
Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat. Med. 18, 1518–1524 (2012).
Ye, Z. et al. Regulation of miR-181a expression in T cell aging. Nat. Commun. 9, 3060 (2018).
Kim, C. et al. Activation of miR-21-regulated pathways in immune aging selects against signatures characteristic of memory T cells. Cell Rep. 25, 2148–2162 (2018).
Fang, F. et al. Expression of CD39 on activated T cells impairs their survival in older individuals. Cell Rep. 14, 1218–1231 (2016).
Gupta, P. K. et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLOS Pathog. 11, e1005177 (2015).
Lu, Y. et al. Systematic analysis of cell-to-cell expression variation of T lymphocytes in a human cohort identifies aging and genetic associations. Immunity 45, 1162–1175 (2016).
Hu, B. et al. Transcription factor networks in aged CD4 naïve T cells bias lineage differentiation. Aging Cell (in the press).
von Kobbe, C. Cellular senescence: a view throughout organismal life. Cell. Mol. Life Sci. 75, 3553–3567 (2018).
Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).
Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012).
Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).
Chou, J. P. & Effros, R. B. T cell replicative senescence in human aging. Curr. Pharm. Des. 19, 1680–1698 (2013).
Rufer, N. et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J. Exp. Med. 190, 157–167 (1999).
Weng, N. P., Levine, B. L., June, C. H. & Hodes, R. J. Human naive and memory T lymphocytes differ in telomeric length and replicative potential. Proc. Natl Acad. Sci. USA 92, 11091–11094 (1995).
McNally, J. P. et al. Manipulating DNA damage-response signaling for the treatment of immune-mediated diseases. Proc. Natl Acad. Sci. USA 114, E4782–E4791 (2017).
Shao, L. et al. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J. Exp. Med. 206, 1435–1449 (2009).
Qi, Q. et al. Defective T memory cell differentiation after varicella zoster vaccination in older individuals. PLOS Pathog. 12, e1005892 (2016).
Liu, Y. et al. Expression of p16 INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell 8, 439–448 (2009).
Chandra, T. et al. Independence of repressive histone marks and chromatin compaction during senescent heterochromatic layer formation. Mol. Cell 47, 203–214 (2012).
Zhang, R. & Adams, P. D. Heterochromatin and its relationship to cell senescence and cancer therapy. Cell Cycle 6, 784–789 (2007).
Adams, P. D. Remodeling chromatin for senescence. Aging Cell 6, 425–427 (2007).
Schonland, S. O. et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc. Natl Acad. Sci. USA 100, 13471–13476 (2003).
Li, Y. et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 45, 903–916 (2016).
Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl Med. 8, 331ra38 (2016).
Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLOS Biol. 6, 2853–2868 (2008).
Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).
Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).
Kuilman, T. & Peeper, D. S. Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer 9, 81–94 (2009).
Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).
Akbar, A. N., Henson, S. M. & Lanna, A. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).
Martens, P. B., Goronzy, J. J., Schaid, D. & Weyand, C. M. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum. 40, 1106–1114 (1997).
Liuzzo, G. et al. Monoclonal T cell proliferation and plaque instability in acute coronary syndromes. Circulation 101, 2883–2888 (2000).
Goronzy, J. J. et al. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J. Virol. 75, 12182–12187 (2001).
Pawelec, G. Age and immunity: what is “immunosenescence”? Exp. Gerontol. 105, 4–9 (2018).
Di Mitri, D. et al. Reversible senescence in human CD4+CD45RA+CD27- memory T cells. J. Immunol. 187, 2093–2100 (2011).
Weng, N. P., Akbar, A. N. & Goronzy, J. CD28- T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).
Pereira, B. I. & Akbar, A. N. Convergence of innate and adaptive immunity during human aging. Front. Immunol. 7, 445 (2016).
Gustafson, C. E. et al. Immune checkpoint function of CD85j in CD8 T cell differentiation and aging. Front. Immunol. 8, 692 (2017).
Jeng, M. Y. et al. Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1. J. Exp. Med. 215, 51–62 (2018).
Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).
Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004–4016 (2014).
Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017). This study describes signalling pathways in terminally differentiated T cells that account for their senescence features but are different from classical senescent cells.
Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015).
Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017).
Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).
Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). This study shows the benefits of depleting senescent cells in model systems.
Weinberg, A. & Levin, M. J. VZV T cell-mediated immunity. Curr. Top. Microbiol. Immunol. 342, 341–357 (2010).
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013).
Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).
Winthrop, K. L. et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 66, 2675–2684 (2014).
Winthrop, K. L. et al. Herpes zoster and tofacitinib: clinical outcomes and the risk of concomitant therapy. Arthritis Rheumatol. 69, 1960–1968 (2017).
Fleischmann, R. et al. Safety and efficacy of baricitinib in elderly patients with rheumatoid arthritis. RMD Open 3, e000546 (2017).
Walters, H. E., Deneka-Hannemann, S. & Cox, L. S. Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging 8, 231–244 (2016).
Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl Med. 10, eaaq1564 (2018).
Araki, K., Youngblood, B. & Ahmed, R. The role of mTOR in memory CD8 T cell differentiation. Immunol. Rev. 235, 234–243 (2010).
Henson, S. M., Macaulay, R., Riddell, N. E., Nunn, C. J. & Akbar, A. N. Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8+ T cell proliferation by distinct pathways. Eur. J. Immunol. 45, 1441–1451 (2015).
Acknowledgements
This work was supported by the US National Institutes of Health (R01 AR042527, R01 HL117913, R01 AI108906, R01 HL142068, and P01 HL129941 to C.M.W. and R01 AI108891, R01 AG045779, U19 AI057266, R01 AI129191, and I01 BX001669 to J.J.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Reviewer information
Nature Reviews Immunology thanks J. Lord, B. Seddon and N.-P. Weng for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Quiescence
-
A phase in the cell cycle in which the cell is not dividing or preparing to divide but still has the ability to do so in the presence of an appropriate signal. Quiescent cells have low metabolic activity and reduced protein synthesis.
- Senescence
-
A cellular state in which an irreversible growth arrest programme has been initiated that limits the lifespan of the cell and prevents unlimited cell proliferation. It can be caused by replication-induced telomere shortening or DNA damage. In contrast to quiescent cells, senescent cells have a secretory phenotype and upregulated protein synthesis.
- Exhaustion
-
Refers to an impaired ability of effector T cells to carry out their functions, such as cytotoxicity and cytokine secretion, owing to chronic stimulation by antigen.
- Homeostatic proliferation
-
A process of activation and proliferation of lymphocytes in the lymphopenic environment. T cell homeostatic proliferation is driven by T cell receptor interactions with self-peptide–MHC and T cell responses to cytokines such as IL-7, IL-15 and possibly IL-21.
- Virtual memory T cells
-
Antigen-inexperienced memory-phenotype T cells, which may be induced by T cell receptor cross reactivity, low-affinity peptide and/or MHC ligands and certain cytokines.
- Fibroblastic reticular cells
-
(FRCs). Specialized reticular fibroblasts located in the T cell areas of lymph nodes and other secondary lymphoid organs. They provide IL-7 for T cell survival and produce collagen-rich reticular fibres and form stromal networks and conduits that are important for the trafficking of immune cells.
- TCR excision circles
-
Small, stable circles of DNA excised during T cell receptor gene rearrangement in the thymus.
- T effector memory CD45RA cells
-
(TEMRA cells). Terminally differentiated antigen-specific memory T cells that re-express CD45RA. These cells have been identified in both CD4+ and CD8+ T cell compartments, have short telomeres, exhibit cell cycle arrest, express DNA damage foci and have a secretome reminiscent of senescent cells.
- Memory inflation
-
The gradual accumulation of peptide-specific CD8+ T cells with an effector memory phenotype that occurs after the resolution of certain acute viral infections during viral latency (for example, cytomegalovirus infection). Induction in the setting of chronic antigen persistence suggests the clonal expansion is antigen driven and not mutation driven.
- Stem cell-like memory T cells
-
A subset of memory T cells that has naive-like features and phenotypes including enhanced self-renewal and multifunctional capacity.
- DNA damage responses
-
A cell response triggered by DNA damage such as single or double strand breaks. The DNA damage response stops cell cycle progression to enable repair before the damage is transmitted to progeny cells. Checkpoints in the mammalian DNA damage response are controlled by the phosphoinositide 3-kinase-related kinases ATM and ATR.
- Senolytics
-
Pharmacological compounds that preferentially deplete senescent cells.
Rights and permissions
About this article
Cite this article
Goronzy, J.J., Weyand, C.M. Mechanisms underlying T cell ageing. Nat Rev Immunol 19, 573–583 (2019). https://doi.org/10.1038/s41577-019-0180-1
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41577-019-0180-1
This article is cited by
-
Causal relationship between immune cells and telomere length: mendelian randomization analysis
BMC Immunology (2024)
-
Immunological factors linked to geographical variation in vaccine responses
Nature Reviews Immunology (2024)
-
T-cell lymphocytes’ aging clock: telomeres, telomerase and aging
Biogerontology (2024)
-
Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice
Nature Communications (2024)
-
The inter-link of ageing, cancer and immunity: findings from real-world retrospective study
Immunity & Ageing (2023)