The DOI matches its Crossref record; 104 of the 104 references it cites were found in a registry or an index.
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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Cites
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
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“Tregs were first characterized by their expression of the IL-2R -chain (CD25) (16).”
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MethodAn essential role for Scurfin in CD4+CD25+ T regulatory cells
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“CD25CD4 and CD25 CD4 T cells were then purified using a FACSVantage cell sorter as previously described (21).”
MethodCD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells
Liu, W., Putnam, A. L., Xu-yu, Z., Szot, G. L., Lee, M. R., Zhu, S., Gottlieb, P. A., Kapranov, P., Gingeras, T. R., de St. Groth, B. F., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060772 · Cited by 2,606 · cited 2×
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Cited by
Sorted by citations
Inflammation and aging: signaling pathways and intervention therapies
Li, X., Li, C., Zhang, W., Wang, Y., Qian, P., & Huang, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01502-8 · Cited by 1,443
Aging, frailty and age-related diseases
Fülöp, T., Larbi, A., Witkowski, J. M., McElhaney, J. E., Loeb, M. B., Mitnitski, A., & Pawelec, G. (2010) · Biogerontology · doi:10.1007/s10522-010-9287-2 · Cited by 687
“Moreover, Treg may influence the immune response to infections (Lages et al. 2008).”
BackgroundPanduro, M., Benoist, C., & Mathis, D. (2016) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095948 · Cited by 536
“The representation of Foxp3+CD4+ T cells in lymphoid organs increases with age, in both humans and mice (82); however, they are strikingly impoverished in injured skeletal muscle of aged mice (53).”
BackgroundSkin barrier immunity and ageing
Chambers, E. S., & Vukmanovic‐Stejic, M. (2019) · Immunology · doi:10.1111/imm.13152 · Cited by 534
Regulatory T Cells in the Control of Host-Microorganism Interactions
Belkaid, Y., & Tarbell, K. V. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132723 · Cited by 479
“Indeed, in a model of Leishmania infection, Treg cell accumulation at the primary site of infection eventually leads to disease reactivation in elderly mice (243).”
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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