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Functional Regulatory T Cells Accumulate in Aged Hosts and Promote Chronic Infectious Disease Reactivation
Open accessAbstract
Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (Tregs), a CD4+ T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all Tregs, especially in aged hosts, we characterized Tregs by the expression of FOXP3, a transcription factor crucial for Treg differentiation and function. The proportion of FOXP3+CD4+ Tregs increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3+ Tregs from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral Tregs from elderly humans improves effector T cell responses in most subjects. Importantly, Tregs from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young Tregs. The increased proportion of Tregs in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old Tregs efficiently suppressed the production of IFN-γ by effector T cells. Finally, in vivo depletion of Tregs in old mice attenuated disease severity. Accumulation of functional Tregs in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of Treg numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.
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“Moreover, aged skin exhibits increased numbers of regulatory T cells (Tregs)166 and elevated expression of the immunosuppressive receptor PD-1,165,167 which may contribute to weakened adaptive immunity.”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [166]
Experimental — accuracy not yet measuredIn the citing paper
“Total CD4+ Treg cell numbers in blood are largely stable or increased”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Lages et al., 2008
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“…Fcγ-mediated uptake of antibody coated amastigotes (Kane and Mosser, 2001), or produced by Th2 cells, or CD4+ CD25+ (Belkaid et al., 2001, 2002a; Sacks and Anderson, 2004) or CD4+CD25−FoxP3+ T regulatory cells (Lages et al., 2008) or indeed CD4+CD25−FoxP3− Th1 population (Anderson et al., 2007).”
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“However, the contribution of Tregs to immunosenescence remains unclear as controversial reports are available on the correlation between circulating CD4+ CD25+Treg prevalence and age, as well as the association of aging with loss of Treg suppressive function ([82,83], and reviewed in [84]).”
BackgroundPartial restoration of T‐cell function in aged mice by in vitro blockade of the PD‐1/ PD‐L1 pathway
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“major, suggesting that, if relieved fromTreg suppression, effectorT cells remain functional invivo (15).”
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“), others are due to cell-intrinsic defects (45).”
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“Although CD4CD25 may not define all Tregs, our results are in agreement with others that show aged Foxp3-GFP Tregs maintain suppressive capabilities (47).”
ResultThe Equivocal Role of Th17 Cells and Neutrophils on Immunopathogenesis of Leishmaniasis
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“IL-10 sources have been identified as CD4+/ CD25+ T cells (Th2) (19, 20), CD4+/CD25−/FoxP3+ regulatory T cells (Tregs) (21), and CD4+/CD25−/FoxP3− T cells (Th1) (16), stimulated by the recognition of amastigote antibodies (22).”
BackgroundAging and human CD4+ regulatory T cells
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“However, a mouse study reported an age-associated increase in the frequency of CD4, FOXP3 Treg in the secondary lymphoid tissues including lymph nodes and spleen, which was about 30% of the total CD4 T cells (Lages et al., 2008).”
InfluentialThe characterization of varicella zoster virus-specific T cells in skin and blood during aging
Vukmanovic-Stejic, M., Sandhu, D., Seidel, J. A., Patel, N., Sobande, T. O., Agius, E., Jackson, S. E., Fuentes-Duculan, J., Suárez-Fariñas, M., Mabbott, N. A., et al. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.63 · Cited by 117
“The increase in Tregs during ageing has also been observed in the blood of normal subjects (Gregg et al., 2005; Vukmanovic-Stejic et al., 2006) and has also been reported in the tissues of old mice (Lages et al., 2008; Raynor et al., 2012).”
BackgroundCTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions
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“After these ground-breaking observations, it took 30 years before many studies revealed that there was a significant age-related increase in the number of Tregs in the circulation of both humans [109, 110] and mice [111].”
BackgroundGender specificity of altered human immune cytokine profiles in aging
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“Functional analyses have shown consistently that the suppressive activities of CD4 25 Treg cells are greater for old than young populations of T cells (6, 26).”
BackgroundThe Role of Innate and Adaptive Immune Cells in Skeletal Muscle Regeneration
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“Treg cells increase in lymphoid organs with age; however, they are sparse in aged muscle following injury [183,193].”
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“However, they can also impair effective pathogen clearance [6,7,8], while potentially playing a beneficial role in preventing”
BackgroundImmunosenescence is both functional/adaptive and dysfunctional/maladaptive
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Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases
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“robust Th2 or Th1- responses develop [32,33], accompanied by the recruitment of Foxp3+ Treg cells [34–39].”
BackgroundSelf-citationKidney Transplantation in the Elderly
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Tsukamoto, H., Senju, S., Matsumura, K., Swain, S. L., & Nishimura, Y. (2015) · Nature Communications · doi:10.1038/ncomms7702 · Cited by 104
HSC Aging and Senescent Immune Remodeling
Denkinger, M. D., Leins, H., Schirmbeck, R., Florian, M. C., & Geiger, H. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.10.008 · Cited by 107
“T cells Decrease in naïve T cells narrowing the T cell receptor repertoire TRECs in peripheral blood decline throughout adulthood Imbalance between Th1 and Th2 responses Increased sensitivity to CD95-mediated apoptosis Decreased ratio of CD8 CD28/CD28 T cells, T cell replicative senescence? Increase in Tregs with age…”
Epstein-Barr Virus–Positive Diffuse Large B-Cell Lymphoma of the Elderly: What We Know So Far
Castillo, J. J., Beltrán, B., Miranda, R. N., Paydaş, S., Winer, E. S., & Butera, J. N. (2011) · The Oncologist · doi:10.1634/theoncologist.2010-0213 · Cited by 103
The role of myeloid-derived suppressor cells (MDSC) in the inflammaging process
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.09.001 · Cited by 101
Bueno, V., Sant’Anna, O. A., & Lord, J. M. (2014) · AGE · doi:10.1007/s11357-014-9729-x · Cited by 95
“As stated above, studies of Tregs in healthy older individuals are contradictory with reports of cell frequency showing increases (Lages et al. 2008; Schimtt et al. 2013) or no difference (Hwang et al.”
Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging
Soto‐Heredero, G., Heras, M. M. G. D. L., Escrig-Larena, J. I., & Mittelbrunn, M. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-064501 · Cited by 96
Potentiation of Th17 cytokines in aging process contributes to the development of colitis
Ouyang, X., Yang, Z., Zhang, R., Arnaboldi, P. M., Lu, G., Li, Q., Wang, W., Zhang, B., Cui, M., Zhang, H., et al. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.10.007 · Cited by 97
Self-citationAging, immune senescence, and immunotherapy: a comprehensive review
Elias, R., Hartshorn, K., Rahma, O., Lin, N., & Snyder-Cappione, J. E. (2018) · Seminars in Oncology · doi:10.1053/j.seminoncol.2018.08.006 · Cited by 96
Enumeration of human peripheral blood dendritic cells throughout the life
Orsini, G., Legitimo, A., Failli, A., Massei, F., Biver, P., & Consolini, R. (2012) · International Immunology · doi:10.1093/intimm/dxs006 · Cited by 91
Lefebvre, J. S., Masters, A. R., Hopkins, J. W., & Haynes, L. (2016) · Scientific Reports · doi:10.1038/srep25051 · Cited by 92
T-Cell Biology in Aging, With a Focus on Lung Disease
Lee, N., Shin, M. S., & Kang, I. (2012) · The Journals of Gerontology Series A · doi:10.1093/gerona/glr237 · Cited by 89
Foxp3+ regulatory T cells, immune stimulation and host defence against infection
Rowe, J. H., Ertelt, J. M., & Way, S. S. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03551.x · Cited by 91
Presicce, P., Orsborn, K. I., King, E. C., Pratt, J. M., Fichtenbaum, C. J., & Chougnet, C. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028118 · Cited by 89
“In agreement with our previous data [27], circulating Tregs did not express CD69 (median frequency of CD69 Tregs was 0.”
Self-citationThe Impact of Aging on Regulatory T-Cells
Fessler, J., Ficjan, A., Duftner, C., & Dejaco, C. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00231 · Cited by 88
“These CD25low Tregs occurred predominantly in the spleen (24) but had comparable functional properties to CD25 Tregs.”
BackgroundEpigenetics, aging, and autoimmunity
Yung, R. L., & Grolleau‐Julius, A. (2008) · Autoimmunity · doi:10.1080/08916930802024889 · Cited by 85
Keilich, S. R., Bartley, J. M., & Haynes, L. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2019.103992 · Cited by 92
Coursey, T. G., Bian, F., Zaheer, M., Pflugfelder, S. C., Volpe, E., & de Paiva, C. S. (2016) · Mucosal Immunology · doi:10.1038/mi.2016.83 · Cited by 82
“(64) (65) (66) There are reports that increased infiltration of Foxp3+ cells is positively correlated with increased lymphocyte infiltration and increase disease severity in the lacrimal and salivary gland of SS patients.”
T CELLS ARE POTENT EARLY MEDIATORS OF THE HOST RESPONSE TO SEPSIS
Kasten, K. R., Tschöp, J., Adediran, S., Hildeman, D. A., & Caldwell, C. C. (2010) · Shock · doi:10.1097/shk.0b013e3181e14c2e · Cited by 82
“In aged mice and humans, Treg cell proportions can increase to 30% of the CD4 T-cell pool and are thought to contribute to age-related immunosuppression (21).”
BackgroundSelf-citation(2017) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2016-egsguideline.001 · Cited by 83
The ocular surface immune system through the eyes of aging
Galletti, J. G., & de Paiva, C. S. (2021) · The Ocular Surface · doi:10.1016/j.jtos.2021.02.007 · Cited by 78
Impact of aging on viral infections
Leng, J., & Goldstein, D. R. (2010) · Microbes and Infection · doi:10.1016/j.micinf.2010.08.009 · Cited by 81
“Studies in mice have demonstrated increased number of regulatory T cells with aging [19].”
BackgroundBhadricha, H., Patel, V. V., Singh, A. K., Savardekar, L., Patil, A. D., Surve, S. V., & Desai, M. P. (2021) · Scientific Reports · doi:10.1038/s41598-021-95640-0 · Cited by 77
An Association between Immunosenescence and CD4+CD25+ Regulatory T cells: A Systematic Review
Wang, L., Xie, Y., Zhu, L., CHANG, T.-T., Yan-Q ing, M. A. O., & Li, J. (2010) · Biomedical and Environmental Sciences · doi:10.1016/s0895-3988(10)60072-4 · Cited by 75
“Evidences from animals also indicated the increased percentage of Treg cells in peripheral lymphoid organs in aged SJL/J mice, which was in consistent with the findings reported in aged BALB/c mice [18-19] and C57BL/6 mice [12,17] suggesting that an age-related increase of Treg cells was a common phenomenon among diff…”
BackgroundResultInfluentialMechanisms underpinning poor antibody responses to vaccines in ageing
Lee, J. L., & Linterman, M. A. (2021) · Immunology Letters · doi:10.1016/j.imlet.2021.11.001 · Cited by 73
Cakala, M., Kołodziej, P., & Puzianowska‐Kuźnicka, M. (2021) · Cells · doi:10.3390/cells10113148 · Cited by 81
“Their increased number and, thus, suppressor activity in the follicles of old animals may likely reflect their increased circulating numbers [147].”
BackgroundT cells in idiopathic pulmonary fibrosis: crucial but controversial
Deng, L., Huang, T., & Zhang, L. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01344-x · Cited by 78
“Additionally, regulatory T cells are increased in older humans [44], but the mechanism of this change remains unclear, particularly the association with the decreased number of regulatory CD4 T cells [43].”
BackgroundGrebenciucova, E., & Berger, J. R. (2017) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-017-0771-9 · Cited by 75
Age-Related Changes in Thymic Central Tolerance
Srinivasan, J., Lancaster, J. N., Singarapu, N., Hale, L. P., Ehrlich, L. I. R., & Richie, E. R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.676236 · Cited by 67
Decman, V., Laidlaw, B. J., DiMenna, L. J., Abdulla, S., Mozdzanowska, K., Erikson, J., Ertl, H. C. J., & Wherry, E. J. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902063 · Cited by 71
“Finally, other cell-intrinsic or external factors such as inherent T cell senescence (51–53) or Tregs (23, 24) could influence the initial development of T cell memory in aged mice.”
BackgroundImmunosenescence, Inflammaging, and Lung Senescence in Asthma in the Elderly
Soma, T., & Nagata, M. (2022) · Biomolecules · doi:10.3390/biom12101456 · Cited by 77
Bogdan, C. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-200596 · Cited by 71
IL-15 Fosters Age-Driven Regulatory T Cell Accrual in the Face of Declining IL-2 Levels
Raynor, J. L., Sholl, A., Plas, D. R., Bouillet, P., Chougnet, C. A., & Hildeman, D. A. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00161 · Cited by 73
“…is multi-factorial, encompassing cell-intrinsic defects within T and B cells, as well as population based defects such as a loss of naïve T cells and increased levels of regulatory T cells (Valmori et al., 2005; Nishioka et al., 2006; Sharma et al., 2006; Lages et al., 2008; Agius et al., 2009).”
BackgroundMethodInfluentialSelf-citationBaptist, A. P., & Nyenhuis, S. M. (2016) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2015.12.010 · Cited by 69
“Finally, with aging, an increase in FOXP3(1)CD4(1) regulatory T cells exerting suppressive effects on T-cell function along with a shift in cytokine pattern from T-helper type 1 to T-helper type 2 cells also have been described.(26,27) These changes in cytokine patterns may explain late onset rhinitis and the decrease…”
IL-6 and ICOS Antagonize Bim and Promote Regulatory T Cell Accrual with Age
Raynor, J. L., Karns, R. A., Almanan, M., Li, K., Divanovic, S., Chougnet, C. A., & Hildeman, D. A. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500443 · Cited by 67
Self-citationAging of the CD4 T Cell Compartment
Lefebvre, J. S. (2012) · Open Longevity Science · doi:10.2174/1876326x01206010083 · Cited by 65
“In both cases, the elimination of the regulatory T cells using an αCD25 antibody improved the immune function of the aged animals that were then able to reject the tumor cells [27], or had reduced disease severity following Leishmania major infection [29].”
BackgroundResultInfluentialNovel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis
Fessler, J., Raicht, A., Husic, R., Ficjan, A., Schwarz, C., Duftner, C., Schwinger, W., Graninger, W. B., Stradner, M. H., & Dejaco, C. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00300 · Cited by 65
“These CD25low Tregs occurred predominantly in the spleen (48) but had comparable functional properties to CD25+ Tregs.”
BackgroundClinical perspectives on the age-related increase of immunosuppressive activity
Salminen, A. (2022) · Journal of Molecular Medicine · doi:10.1007/s00109-022-02193-4 · Cited by 57
“Accordingly, the number of Tregs was augmented with aging in human blood [78, 99].”
BackgroundConsiderations for successful cancer immunotherapy in aged hosts
Hurez, V, Padrón, Á. S., Svatek, R. S., & Curiel, T. J. (2016) · Clinical and Experimental Immunology · doi:10.1111/cei.12875 · Cited by 65
Zöphel, D., Angenendt, A., Kaschek, L., Ravichandran, K., Hof, C., Janku, S., Hoth, M., & Lis, A. (2022) · Aging Cell · doi:10.1111/acel.13668 · Cited by 64
“The current data have revealed a variety of intrinsic and extrinsic factors that could influence the function of CD8+ T cells (Decman et al., 2010; Jergovic et al., 2019; Jiang et al., 2013; Lages et al., 2008).”
Background
Metadata
- Authors
- Lages, C. S., Suffia, I., Velilla, P. A., Huang, B., Warshaw, G., Hildeman, D. A., Belkaid, Y., & Chougnet, C.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- National Institutes of Health (US)
- Division of Molecular Immunology
- University of Cincinnati (US)
- Mucosal Immunology Unit, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892
- Corresponding author
- Chougnet, Claire
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-08-01
- Volume
- 181
- Issue
- 3
- Pages
- 1835-1848
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2587319
- OpenAlex
- W1510545292
- Cited by
- 399
- References
- 104
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 21 · 2023: 15 · 2022: 22 · 2021: 36 · 2020: 17 · 2019: 21 · 2018: 14 · 2017: 34 · 2016: 16 · 2015: 24 · 2014: 24 · 2013: 27 · 2012: 18
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R21AG025149, AG025149)
- National Institute of Allergy and Infectious Diseases (R01AI057753)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- regulatory T cells, immunosenescence, aging, Foxp3, Leishmania major, CTLA-4, GITR, Treg depletion, effector T cells, CD4+ T cells
- MeSH terms
- Adult, Aged, Aging, Animals, Antibodies, Cell Movement, Chronic Disease, Health, Humans, Mice, Inbred C57BL, Phenotype, Biomarkers, Cytokines, Leishmaniasis, Cutaneous, CD3 Complex, Leishmania major, Cell Proliferation, T-Lymphocytes, Regulatory, Mice
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