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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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ResultVukmanovic‐Stejic, M., Zhang, Y., Cook, J. E., Fletcher, J. M., McQuaid, A. J., Masters, J. E., Rustin, M. H. A., Taams, L. S., Beverley, P. C. L., Macallan, D. C., et al. (2006) · Journal of Clinical Investigation · doi:10.1172/jci28941 · Cited by 484
Zou, L., Barnett, B. G., Safah, H. F., LaRussa, V. F., Evdemon-Hogan, M., Mottram, P. J., Wei, S., David, O., Curiel, T. J., & Zou, W. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1987 · Cited by 466 · cited 1×
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BackgroundInfluentialThe number of human peripheral blood CD4+ CD25high regulatory T cells increases with age
Gregg, R., Smith, C. M., Clark, F. J., Dunnion, D., Khan, N., Chakraverty, R. K., Nayak, L., & Moss, P. A. H. (2005) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2005.02798.x · Cited by 383
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MethodCoexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia
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Transient regulatory T-cells: A state attained by all activated human T-cells
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BackgroundA peripheral circulating compartment of natural naive CD4 Tregs
Valmori, D., Merlo, A., Souleimanian, N. E., Hesdorffer, C. S., & Ayyoub, M. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23963 · Cited by 319 · cited 2×
“The proportion of naive Tregs was lower in young individuals than the proportion of naive Teffs, as previously reported (53).”
ResultThe aging innate immune system
Gómez, C. R., Boehmer, E. D., & Kovacs, E. J. (2005) · Current Opinion in Immunology · doi:10.1016/j.coi.2005.07.013 · Cited by 315
Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens
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Peripheral blood dendritic cells and monocytes are differently regulated in the elderly
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“Interestingly, DC subsets and maturation levels are changed during aging (94, 95), and this could play a role in Treg accumulation in elderly individuals.”
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“For intracellular staining, the eBioscience protocol for FOXP3 staining and the following Abs were used: anti-FOXP3-FITC (clone PCH101) and anti-CTLA-4-PE (clone 14D3) from eBioscience; anti-programmed death-1 (PD-1; clone MIH4) and antigranzyme A-PE (clone CB9) from BD; anti-granzyme B-allophycocyanin (clone GB12) fr…”
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High Accumulation of T Regulatory Cells Prevents the Activation of Immune Responses in Aged Animals
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“Our data in an infectious model are thus in agreement with the recent study showing that Treg accumulation in aged mice plays a crucial role in inhibiting the activation of anti-tumor responses (34).”
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“In support of that argument, in vivo expanded Tregs become CD25 low while maintaining similar levels of other Treg-associated molecules (96).”
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Self-citationCD4+CD25+Foxp3+ T Cells and CD4+CD25−Foxp3+ T Cells in Aged Mice
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A Kinetic and Dynamic Analysis of Foxp3 Induced in T Cells by TGF-β
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Tsaknaridis, L., Spencer, L., Culbertson, N. E., Hicks, K., LaTocha, D. H., Chou, Y. K., Whitham, R. H., Bakke, A. C., Jones, R. E., Offner, H., et al. (2003) · Journal of Neuroscience Research · doi:10.1002/jnr.10766 · Cited by 197 · cited 1×
“Indeed, some studies show maintenance of the suppressive activity of Tregs in aged mice (34, 36) and elderly people (37, 39), whereas other studies report decreased Treg-mediated suppression in aged mice (35) and humans (42).”
BackgroundCirculating, Interferon‐Producing Plasmacytoid Dendritic Cells Decline During Human Ageing
Shodell, M., & Siegal, F. P. (2002) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.2002.01148.x · Cited by 189 · cited 1×
“Interestingly, DC subsets and maturation levels are changed during aging (94, 95), and this could play a role in Treg accumulation in elderly individuals.”
BackgroundKwon, B., Yu, K.-Y., Ni, J., Yu, G.-L., Jang, I. K., Kim, Y., Xing, L., Liu, D., Wang, S.-X., & Kwon, B. S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6056 · Cited by 181 · cited 1×
“FOXP3, CD25, GITR, and CTLA-4 are not only markers for Tregs but are also transiently up-regulated on human non-Tregs upon activation (22, 63, 64).”
BackgroundHoming of naive and memory T lymphocyte subsets to Peyer’s patches, lymph nodes, and spleen
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Age-related changes in Type 1 and Type 2 cytokine production in humans
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“These dysfunctions arise from alterations in every component of the immune system (7–10), but the most consistent and significant alterations are seen in the T lymphocyte compartment (11, 12), particularly within CD4 T cells (8, 13–15).”
BackgroundTolerogenic dendritic cells and regulatory T cells: A two-way relationship
Mahnke, K., Johnson, T., Ring, S., & Enk, A. (2007) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2007.03.002 · Cited by 159 · cited 2×
“They have been shown to decrease the levels of activation, proliferation, and cytokine production of effector T cells (Teffs) in mice and humans (21–24), as well as control the immune function of dendritic cells (DCs) (25, 26).”
BackgroundChanges of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice
Zhao, L., Sun, L., Wang, H., Ma, H., Liu, G., & Zhao, Y. X. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0506364 · Cited by 154 · cited 6×
“Tregs in aged hosts are mostly memory cells with a highly differentiated phenotype as shown in this study and by others (35, 41, 79, 84, 85).”
BackgroundInfluentialRole of T lymphocyte replicative senescence in vaccine efficacy
Effros, R. B. (2007) · Vaccine · doi:10.1016/j.vaccine.2006.08.032 · Cited by 152
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“Indeed, some studies show maintenance of the suppressive activity of Tregs in aged mice (34, 36) and elderly people (37, 39), whereas other studies report decreased Treg-mediated suppression in aged mice (35) and humans (42).”
BackgroundCD4 CD25high regulatory T cells are not impaired in patients with primary Sjögren's syndrome
Gottenberg, J., Lavie, F., Abbed, K., Gasnault, J., Nevot, E. L., Delfraissy, J., Taoufik, Y., & Xavier Mariette, A. (2005) · Journal of Autoimmunity · doi:10.1016/j.jaut.2005.01.015 · Cited by 147
The roles for cytokines in the generation and maintenance of regulatory T cells
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Inflammation and aging: signaling pathways and intervention therapies
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“Moreover, Treg may influence the immune response to infections (Lages et al. 2008).”
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BackgroundSelf-citation
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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