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CD28 Expression in T Cell Aging and Human Longevity
Abstract
Functional decrements of the immune system have a major contribution to aging and age-related diseases. Here, we further characterize the decline in proportion of CD28-positive T cells previously identified in centenarians. Cohorts of 97 centenarians, 40 subjects aged 70-90 (ELD group), and 40 young adults (under age 40) were phenotyped for T cell surface expression of CD28, CD4, and CD8 antigens. The significant decline in T cells expressing CD28 (p < 10(-4) for comparisons between adults and either ELD or centenarians) affects preferentially the CD8+ subset of T cells. This decline accounts largely for the age-related diminution of T cell responsiveness to mitogenic signals. CD28 expression is modulated in T cell cultures in a growth-related fashion and this modulation is dampened in cultures from centenarians. We propose that the decrease in CD28 expression reflects a compensatory adaptation of the immune system during aging in the face of chronic stimulation.
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“These changes can include an involuted thymus235, fewer naive B and T cells236, diminished T cell receptor diversity237, higher susceptibility to T cell apoptosis238 and reduced expression of crucial receptors such as CD28 on cytotoxic CD8+ T cells239.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [239]
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“While recent investigations have shown an age-associated diminution of CD28+ on peripheral blood CD8+ T cells in healthy elderly human subjects (Fagioni et al., 1996; Boucher et al., 1998; Effros, 1997), little is known about the age-associated differences in the expression of CD28 on antigen-specific CD8+ T cells in…”
ResultTelomere/telomerase dynamics within the human immune system: Effect of chronic infection and stress
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InfluentialPremature Aging of T cells Is Associated With Faster HIV-1 Disease Progression
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“For example, the ability of centenarians’ T cells to respond by medium-term proliferation to alloactivation and mitogen-activation correlates with the percentage of CD28+ cells in their PBMC (Boucher et al., 1998).”
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Replicative senescence of CD8 T cells: Effect on human ageing
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CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells
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BackgroundCHANGES IN IMMUNE FUNCTION WITH AGE
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“1998; Sansoni et al.”
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Self-citationFrom Hayflick to Walford: the role of T cell replicative senescence in human aging
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BackgroundResultT‐Cell Phenotypes Predictive of Frailty and Mortality in Elderly Nursing Home Residents
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“, 2009), and this could be due to the deficient expression of CD28 co-stimulatory molecule on T cells (Boucher et al., 1998) (Weiskopf et al.”
BackgroundSYSTEMIC LUPUS ERYTHEMATOSUS IN THE ELDERLY
Kammer, G. M., & Mishra, N. (2000) · Rheumatic Disease Clinics of North America · doi:10.1016/s0889-857x(05)70152-6 · Cited by 51
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Shimizu, K., Suzuki, N. T., Imai, T., Aizawa, K., Nanba, H., Hanaoka, Y., Kuno, S., Mesaki, N., Kono, I., & Akama, T. (2011) · The Journal of Strength and Conditioning Research · doi:10.1519/jsc.0b013e3181fc5e67 · Cited by 51
“decline is shown predominantly in the CD8 cells (8).”
BackgroundSharma, R., Sharma, A., Kumari, A., Kulurkar, P. M., Raj, R., Gulati, A., & Padwad, Y. S. (2017) · Biogerontology · doi:10.1007/s10522-017-9696-6 · Cited by 51
“The costimulatory molecule CD28 plays a critical role in stimulation of T cells in response to pathogens and shows a characteristic decrease with age (Weng et al. 2009; Boucher et al. 1998).”
BackgroundEffros, R. B. (2004) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-004-0508-x · Cited by 48
“The premature cessation of telomerase induction in the CD8 versus CD4 subset seen under the controlled conditions of cell culture may explain the in vivo preponderance of CD8 T cells versus CD4 T cells with characteristics suggestive of senescence during aging [8] and chronic infection [31].”
BackgroundSelf-citationEffects of Ageing on the Immunoregulation of Parasitic Infection
Humphreys, N. E., & Grencis, R. K. (2002) · Infection and Immunity · doi:10.1128/iai.70.9.5148-5157.2002 · Cited by 48
“Here we investigate whether lymphocytes from our colony of ageing C57BL/Icrfa mice show a similar phenotype to that seen in other ageing mice (9).”
BackgroundInfluentialKennedy, R. B., Ovsyannikova, I. G., Haralambieva, I. H., Oberg, A. L., Zimmermann, M. T., Grill, D. E., & Poland, G. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00450 · Cited by 45
“It has been proposed that CD28 downregulation occurs in response to chronic immune stimulation in older individuals (72).”
BackgroundLong-term immunological memory against viruses
Effros, R. B. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(00)00207-4 · Cited by 45
Self-citationBen‐Smith, A., Gorak‐Stolinska, P., Floyd, S., Weir, R. E., Lalor, M. K., Mvula, H., Crampin, A. C., Wallace, D. L., Beverley, P. C. L., Fine, P., et al. (2008) · BMC Infectious Diseases · doi:10.1186/1471-2334-8-139 · Cited by 43
“This is the first study to show such a difference in proportions of naïve T cells in age-matched adolescents from two countries although this has been described for elderly (>60 year olds) compared to younger individuals [24,29].”
ResultTraitanon, O., Gorbachev, A. V., Bechtel, J., Keslar, K. S., Baldwin, W. M., Poggio, E. D., & Fairchild, R. L. (2014) · American Journal of Transplantation · doi:10.1111/ajt.12719 · Cited by 41
“Accumulation of CD28 memory CD8þ T cells is a prominent feature of age-associated changes in T cell function (12,13).”
BackgroundHuman CD4+ CD25+ CD127hi cells and the Th1/Th2 phenotype
Narsale, A. A., Moya, R., & Davies, J. D. (2018) · Clinical Immunology · doi:10.1016/j.clim.2018.01.003 · Cited by 41
“CD25+CD127hi cells are a mix of central memory and effector memory cells CD25+CD127hi cells makeup around 20% of total CD4+ memory T cells and are evident both within the CM (CD197+ CD28+) and EM (CD197−) compartments of the CD45RO+ memory cell compartment.”
BackgroundInfluentialGardner, J. K., Mamotte, C. D. S., Jackaman, C., & Nelson, D. J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.07.002 · Cited by 40
“In contrast, CD28 expression on human CD8+ and CD4+ T cells declines during aging (Boucher et al., 1998; Effros et al., 1994; Fagnoni et al., 1996; Leng et al., 2002; Vallejo et al., 1998; Warrington et al., 2003; Weng et al., 2009; Weyand et al., 1998), and this is paralleled by increased CTLA-4 expression on elderly…”
Gamberg, J., Pardoe, I. U., Bowmer, M. I., Howley, C., & Grant, M. D. (2004) · Immunology and Cell Biology · doi:10.1111/j.1440-1711.2004.01204.x · Cited by 38
Bonanno, M., Papa, D., Cerasa, A., Maggio, M. G., & Calabrò, R. S. (2024) · Medicina · doi:10.3390/medicina60020285 · Cited by 40
“While healthy individuals may exhibit flexibility in responding to stress, aging and diseases compromise this adaptability, potentially leading to stress-related immune dysregulation with clinical implications [48,49].”
BackgroundMulti-color flow cytometry for evaluating age-related changes in memory lymphocyte subsets in dogs
Withers, S. S., Moore, P. F., Chang, H., Choi, J. W., McSorley, S. J., Kent, M. S., Monjazeb, A. M., Canter, R. J., Murphy, W. J., Sparger, E. E., et al. (2018) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2018.05.022 · Cited by 43
“Interestingly, the association of aging with an increase in circulating CD28- T cells, particularly from the CD8+ lineage, is well documented in both primates and humans (Boucher et al., 1998; Dennett et al., 2002; Weng et al., 2009).”
Dolcetti, R., & Rossi, A. D. (2010) · Medicinal Research Reviews · doi:10.1002/med.20211 · Cited by 34
“Moreover, crosssectional analysis of T cells from different age groups clearly showed that the number of CD28 T cells progressively increased with age.(54) Consistently, ex vivo analyses demonstrated that telomeres of CD28 T cells were shorter than those of other T lymphocytes from the same individuals, suggesting a m…”
BackgroundAging, imbalanced inflammation and viral infection
Goldstein, D. R. (2010) · Virulence · doi:10.4161/viru.1.4.12009 · Cited by 35
Immunophenotyping and T-cell proliferative capacity in a healthy aged population
Peres, A., Bauer, M. E., da Cruz, I. B. M., Nardi, N. B., & Chies, J. A. B. (2003) · Biogerontology · doi:10.1023/a:1026282917406 · Cited by 35
“has been shown to be reduced in aged subjects (Effros 1997; Boucher et al. 1998; Pawelec et al. 1999).”
BackgroundHabitual exercise did not affect the balance of type 1 and type 2 cytokines in elderly people
Ogawa, K., Oka, J., Yamakawa, J., & Higuchi, M. (2003) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(03)00167-2 · Cited by 34
Psychoneuroimmunology examined: The role of subjective stress.
Thornton, L. M., & Andersen, B. L. (2006) · PubMed · Cited by 34
Witkowski, J. M., & Bryl, E. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2003.10.028 · Cited by 34
Frailty impacts immune responses to Moderna COVID-19 mRNA vaccine in older adults
Semelka, C., DeWitt, M., Blevins, M. W., Holbrook, B. C., Sanders, J. W., & Alexander‐Miller, M. A. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00327-x · Cited by 35
“age and impaired vaccine responses from the established immune aging literature [43, 45, 46, 80].”
BackgroundMethodEffros, R. B. (2000) · Microbes and Infection · doi:10.1016/s1286-4579(00)00283-5 · Cited by 32
Self-citationLiu, W., Zhu, P., Li, M., Li, Z., Yu, Y., Liu, G., Du, J., Wang, X., Yang, J., Tian, R., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022112740 · Cited by 29
Revisiting T-cell adhesion molecules as potential targets for cancer immunotherapy: CD226 and CD2
Jo, Y., Sim, H.-I., Yun, B., Park, Y., & Jin, H. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01317-9 · Cited by 31
Martínez-Taboada, V. M., Bartolomé, M. J., Amado, J., Blanco, R., García‐Unzueta, M. T., Rodrı́guez-Valverde, V., & López‐Hoyos, M. (2002) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(02)00116-1 · Cited by 29
Problems and solutions to the development of vaccines in the elderly
Effros, R. B. (2003) · Immunology and Allergy Clinics of North America · doi:10.1016/s0889-8561(02)00055-3 · Cited by 27
“The CD28 molecule is expressed on more than 99% of human T cells at birth, but the proportion of T cells that are CD28 progressively increases with age, particularly within the CD8 T-cell subset [58], which is the major immune mediator of viral clearance.”
BackgroundSelf-citationLeng, J., Stout-Delgado, H. W., Kavita, U., Jacobs, A., Tang, J. T., Du, W., Tussey, L., & Goldstein, D. R. (2011) · Vaccine · doi:10.1016/j.vaccine.2011.08.027 · Cited by 26
“Aging also impairs T-cell CD28 surface upregulation [10] and immune synapse formation [11].”
BackgroundKatz, P. S., Siggins, R. W., Porretta, C., Armstrong, M. L., Zea, A. H., Mercante, D. E., Parsons, C. H., Veazey, R. S., Bagby, G. J., Nelson, S., et al. (2015) · Alcohol · doi:10.1016/j.alcohol.2015.09.003 · Cited by 25
“Human CD28 expression is ubiquitous at birth, and declines with age (Boucher et al., 1998; Effros, 2000).”
Background
Metadata
- Authors
- Boucher, N., Dufeu-Duchesne, T., Vicaut, E., Farge, D., Effros, R. B., & Schächter, F.
- Affiliations
- Fondation Jean Dausset-CEPH (FR)
- Hôpital Saint-Louis (FR)
- University of California, Los Angeles (US)
- Corresponding author
- Schächter, François
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 1998-05
- Volume
- 33
- Issue
- 3
- Pages
- 267-282
- ISSN
- 0531-5565 (ISSN-L)
- OpenAlex
- W1973076242
- Semantic Scholar
- 56c903c155c96dbf324ec10a879404754b4df8af
- Cited by
- 194
- References
- 65
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 6 · 2022: 2 · 2021: 7 · 2020: 2 · 2019: 9 · 2018: 11 · 2017: 8 · 2016: 5 · 2015: 5 · 2014: 6 · 2013: 3 · 2012: 5
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- CD28, T cell senescence, centenarians, human longevity, CD8+ T cells, immunosenescence, T cell responsiveness, mitogen stimulation, chronic immune stimulation, CD4+ T cells
- MeSH terms
- Adult, Aged, Aged, 80 and over, Blood Cells, Cell Division, Cells, Cultured, Humans, Longevity, T-Lymphocytes, Cellular Senescence, CD28 Antigens
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