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Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections.
Open accessAbstract
A diverse and well-balanced repertoire of T cells is thought to be crucial for the efficacious defence against infection with new or re-emerging pathogens throughout life. In the last third of the mammalian lifespan, the maintenance of a balanced T-cell repertoire becomes highly challenging because of the changes in T-cell production and consumption. In this Review, I question whether latent persistent pathogens might be key factors that drive this imbalance and whether they determine the extent of age-associated immune deficiency.
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“The impact of HIV disease on this process is not known, but emerging data suggest that these co-infections interact in a potential negative manner (41–44).”
From HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group (2012) · cites this paper as [41]
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Karigane, D., Takaya, S., Seki, Y., Mastumoto, Y., Onose, A., Kosakai, A., Sugaya, N., & Mori, T. (2014) · Journal of Infection and Chemotherapy · doi:10.1016/j.jiac.2013.12.004 · Cited by 44
“Evidence has accumulated to show an association between aging and impaired immune reactions [36,37].”
BackgroundTranslational research in immune senescence: Assessing the relevance of current models
High, K. P., Akbar, A. N., & Nikolich‐Žugich, J. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.007 · Cited by 42
Functional CD8 T Cell Memory Responding to Persistent Latent Infection Is Maintained for Life
Lang, A. M., & Nikolich‐Žugich, J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100666 · Cited by 44
“The decreased capacity to mount a primary response is a result of cellintrinsic defects and changes at the organ and cell population level, including thymic involution (9) and the related decrease in the number and clonotypic diversity of naive T cells (1, 10).”
BackgroundTuft cells and fibroblasts promote thymus regeneration through ILC2-mediated type 2 immune response
Nevo, S., Frenkel, N., Kadouri, N., Gome, T., Rosenthal, N., Givony, T., Avin, A., Cruz, C. P., Kedmi, M., Lindzen, M., et al. (2024) · Science Immunology · doi:10.1126/sciimmunol.abq6930 · Cited by 42
“In contrast to age-related involution, ATI is completely reversible, although this regenerative capacity also declines with age ( 11 , 12 ).”
BackgroundChen, I.-H., Lai, Y., Wu, C., Chang, Y., Chu, C., Tsai, I., Sun, F., & Lu, Y. (2009) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-009-0753-0 · Cited by 42
“Increasing evidence indicates that repeated stimulation by viruses could force memory T cell accumulation, which is known as memory inXation [ 21 ].”
BackgroundSchwanninger, A., Weinberger, B., Weiskopf, D., Herndler‐Brandstetter, D., Reitinger, S., Gassner, C., Schennach, H., Parson, W., Würzner, R., & Grubeck‐Loebenstein, B. (2008) · Immunity & Ageing · doi:10.1186/1742-4933-5-14 · Cited by 42
“The link between CMV-infection, immunosenescence and longevity has recently been a subject of great interest [ 6 ,7].”
BackgroundCytomegalovirus Exposure in the Elderly Does Not Reduce CD8 T Cell Repertoire Diversity
Lindau, P., Mukherjee, R., Gutschow, M. V., Vignali, M., Warren, E. H., Riddell, S. R., Makar, K. W., Turtle, C. J., & Robins, H. S. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800217 · Cited by 42
Childhood environments and cytomegalovirus serostatus and reactivation in adults
Janicki‐Deverts, D., Cohen, S., Doyle, W. J., Marsland, A. L., & Bosch, J. A. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.03.010 · Cited by 38
Üner, A., Akyürek, N., Sağlam, A., Abdullazade, S., Üzüm, N., Onder, S. C., Barışta, İ., & Beneklı, M. (2011) · Apmis · doi:10.1111/j.1600-0463.2011.02736.x · Cited by 38
Speranza, E. E., Ruibal, P., Port, J. R., Feng, F., Burkhardt, L., Grundhoff, A. T., Günther, S., Oestereich, L., Hiscox, J. A., Connor, J. H., et al. (2018) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiy352 · Cited by 39
Self-recognition drives the preferential accumulation of promiscuous CD4(+) T-cells in aged mice
Deshpande, N. R., Parrish, H. L., & Kuhns, M. S. (2015) · eLife · doi:10.7554/elife.05949 · Cited by 35
“Finally, time—with its age-associated changes in thymic expression of tissue-restricted antigens (TRAs), thymic architecture, antigen experience, and homeostasis—imposes an overarching pressure that limits the binding capacity of a repertoire for self- and foreign-pMHC to each constituent’s prior history of TCR–pMHC i…”
BackgroundKao, C., Charmsaz, S., Tsai, H., Aziz, K., Shu, D. H., Munjal, K., Griffin, E., Leatherman, J. M., Lipson, E. J., Ged, Y. M. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58512-z · Cited by 37
Stervbo, U., Bozzetti, C., Baron, U., Jürchott, K., Meier, S., Mälzer, J. N., Nienen, M., Olek, S., Rachwalik, D., Schulz, A. R., et al. (2015) · AGE · doi:10.1007/s11357-015-9829-2 · Cited by 37
Shifrut, E., Baruch, K., Gal, H., Ndifon, W. O., Deczkowska, A., Schwartz, M., & Friedman, N. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00379 · Cited by 37
“In addition, susceptibility to infectious diseases inclines with age (32) due to a combination of several factors such as immune senescence (33), transcriptional changes (34), and loss of de novo production of naïve T cells (35).”
BackgroundNandakumar, S., Kannanganat, S., Posey, J. E., Amara, R. R., & Sable, S. B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113951 · Cited by 37
Uhrlaub, J. L., Brien, J. D., Widman, D. G., Mason, P. W., & Nikolich‐Žugich, J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002799 · Cited by 37
“The vulnerability of older adults to infection is believed to be caused by a decline of the immune defense due to the aging of the immune system, also called immunosenescence (13, 14).”
BackgroundComorbidity of mental and physical disorders
(2014) · Key Issues in Mental Health · doi:10.1159/isbn.978-3-318-02604-7 · Cited by 37
Friend or foe: the dichotomous impact of T cells on neuro-de/re-generation during aging
Coder, B., Wang, W., Wang, L., Wu, Z., Zhuge, Q., & Su, D. (2016) · Oncotarget · doi:10.18632/oncotarget.12572 · Cited by 36
Implications of inflammatory states on dysfunctional immune responses in aging and obesity
Thomas, A. L., Alarcon, P. C., Divanovic, S., Chougnet, C. A., Hildeman, D. A., & Moreno-Fernandez, M. E. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.732414 · Cited by 35
Long-term caloric restriction ameliorates T cell immunosenescence in mice
Asami, T., Endo, K., Matsui, R., Sawa, T., Tanaka, Y., Saiki, T., Tanba, N., Haga, H., & Tanaka, S. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111710 · Cited by 37
Iglesias-Escudero, M., Moro‐García, M. A., Marcos-Fernández, R., García‐Torre, A., Álvarez-Argüelles, M. E., Suárez-Fernández, M. L., Martínez‐Camblor, P., Rodríguez, M., & Alonso‐Arias, R. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194789 · Cited by 35
Despeghel, M., Reichel, T., Zander, J., Krüger, K., & Weyh, C. (2021) · Cells · doi:10.3390/cells10040843 · Cited by 36
Metelo, A. M., Jóźwik, A., Luong, L. A., Dominey-Foy, D., Graham, C., Attwood, C., Inam, S., Dunlop, A. S., Sanchez, K., Cuthill, K., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0157 · Cited by 35
“T-cell memory is also directly affected by age and MM treatment (36, 40) and high levels of naïve and stem cell memory T cells in the leukapheresis product have been associated with higher expansion of anti-BCMA CAR T cells in vivo and better clinical responses (24, 26).”
BackgroundInfluence of age, sex and HCMV-serostatus on blood lymphocyte subpopulations in healthy adults
Apoil, P. A., Puissant‐Lubrano, B., Congy‐Jolivet, N., Pérès, M., Tkaczuk, J., Roubinet, F., & Blancher, A. (2017) · Cellular Immunology · doi:10.1016/j.cellimm.2017.02.001 · Cited by 34
Orlando, V., Manna, M. P. L., Goletti, D., Palmieri, F., Presti, E. L., Joosten, S. A., Mendola, C. L., Buccheri, S., Ottenhoff, T. H. M., Dieli, F., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01119 · Cited by 34
“Our results reported here are in agreement with data on CD8+ T cells reported by Nikolich-Zugich and coworkers (23) showing that West Nile virus infection resulted in the expansion of CD8+ T cells producing IFN-γ while expressing a naive phenotype, which were termed TMNP cells.”
ResultAge and CMV-Infection Jointly Affect the EBV-Specific CD8+ T-Cell Repertoire
Lanfermeijer, J., de Greef, P. C., Hendriks, M., Vos, M. W., van Beek, J., Borghans, J. A. M., & van Baarle, D. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.665637 · Cited by 34
“…leads to changes in the CD8+ T-cell pool similar to those observed with aging, including the presence of large fractions of terminally differentiated cells (Almanzar et al., 2005; Chidrawar et al., 2009) and a more skewed and less diverse TCR repertoire (Khan et al., 2002; Nikolich-Zugich, 2008).”
BackgroundCentral tolerance is impaired in the middle‐aged thymic environment
Lancaster, J. N., Keatinge-Clay, D. L., Srinivasan, J., Li, Y., Selden, H. J., Nam, S., Richie, E. R., & Ehrlich, L. I. R. (2022) · Aging Cell · doi:10.1111/acel.13624 · Cited by 33
“As the thymus involutes and fewer recent thymic emigrants are exported, the peripheral T compartment is progressively comprised of cells with a memory phenotype (Nikolich-Žugich 2008; Srinivasan et al. 2021; Goronzy & Weyand 2019).”
BackgroundChami, K., Gavazzi, G., Bar‐Hen, A., Carrat, F., de Wazières, B., Lejeune, B., Armand, N., Rainfray, M., Hajjar, J., Piette, F., et al. (2012) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2012.04.008 · Cited by 34
B7-Mediated Costimulation of CD4 T Cells Constrains Cytomegalovirus Persistence
Arens, R., Loewendorf, A. I., Her, M. J., Schneider, K., SHELLAM, G. R., Janssen, E. M., Ware, C. F., Schoenberger, S. P., & Benedict, C. A. (2010) · Journal of Virology · doi:10.1128/jvi.01839-10 · Cited by 34
Ortega, M. R., Spisak, N., Mora, T., & Walczak, A. M. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010652 · Cited by 34
Johnson, P. L. F., Goronzy, J. J., & Antia, R. (2014) · Immunology · doi:10.1111/imm.12244 · Cited by 34
Exhaustion and Inflation at Antipodes of T Cell Responses to Chronic Virus Infection
Čičin‐Šain, L., & Arens, R. (2017) · Trends in Microbiology · doi:10.1016/j.tim.2017.11.012 · Cited by 32
Müller, N., & Bechter, K. (2013) · Neurology Psychiatry and Brain Research · doi:10.1016/j.npbr.2013.04.004 · Cited by 37
Metadata
- Authors
- Nikolich-Žugich, J.
- Venue
- Nature reviews. Immunology
- Published
- 2008-07
- Volume
- 8
- Issue
- 7
- Pages
- 512-522
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- PMC
- PMC5573867
- OpenAlex
- W1926141441
- Cited by
- 463
- References
- 128
- Citations by year
- 2026: 23 · 2025: 28 · 2024: 18 · 2023: 26 · 2022: 28 · 2021: 30 · 2020: 24 · 2019: 17 · 2018: 28 · 2017: 20 · 2016: 21 · 2015: 24 · 2014: 35 · 2013: 35 · 2012: 23
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (n01ai50027-8-0-1)
- U.S. Public Health Service (N01 50027)
- National Institute on Aging (AG 20719, AG23664, P01AG023664, AG 21384, R01AG020719, U01AG021384, R37AG020719)
- National Institute of Allergy and Infectious Diseases (N01 AI050027)
- National Center for Research Resources (RR-0163, P51RR000163, K01RR000163)
- 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
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Keywords
- immunosenescence, T cell homeostasis, T cell subsets, persistent viruses, T cell receptor repertoire, aging
- MeSH terms
- Aging, Animals, Cell Differentiation, Herpes Simplex, Homeostasis, Humans, Infections, Receptors, Antigen, T-Cell, Thymus Gland, T-Lymphocyte Subsets, Cellular Senescence
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