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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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Schumacher, T. M., Gottloeber, E. M., Koziel, E., Saçma, M., Eichhorn, K., Raiber, L., Gout, J., Lindenmayer, J., Roger, É., Melzer, M. K., et al. (2026) · Scientific Reports · doi:10.1038/s41598-026-46045-4
Immunological impact of age and comorbidities: findings from the REALISM and SENIOR-HLA-DR cohorts
Vieilledent, L., Gaujard, S., Gossez, M., Broyer, A., Bodinier, M., Goff, S. L., Di-Valentin, K., Renaud, E., Dumay, C., Foray, A., et al. (2026) · Aging Clinical and Experimental Research · doi:10.1007/s40520-026-03389-1
“Additionally, suppressor cell lineages, including regulatory T cells [10] and myeloid-derived suppressor cells [11], tend to increase with age, likely as a compensatory response to the aforementioned chronic inflammation.”
Immunotherapy for senescent cell clearance: Hallmarks, strategies and translational challenges
Zhang, W., Chen, S., & Zhuang, X. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103174
Anti-Aging the Immune System: Hype or Hope? A Mechanistic Review
Ilyas, A. (2026) · Premier Journal of Immunology · doi:10.70389/pji.100011
Lymphocyte subsets in untreated thalassemia patients: differences by genotype and age
Zhao, R., Yao, X., Feng, S., Hu, P., Zou, Y., Yang, Z., Zhang, J., Guan, X., Zhang, C., Wang, Z., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1832294
“Dysfunction of Tregs can impair anti-infection and anti-tumor capabilities, exerting negative effects on immune function (18, 19).”
Arnold, C. R., Mangesius, J., Weinberger, B., Portnaia, I., Santacroce, A., Ganswindt, U., & Muacevic, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1888282
“Tregs also accumulate in several aged-host settings, although age-associated changes in their phenotype and suppressive function are tissue-and context-dependent (30, 31).”
Aniagyei, W., Womelsdorf, S. L., Bittner, S., Mohayideen, S., Sarfo‐Kantanka, O., Adankwah, E., Owusu, D., Nafu, H. Y. B., Vivekanandan, M. M., Yeboah, A., et al. (2026) · Journal of Translational Autoimmunity · doi:10.1016/j.jtauto.2026.100400
Immune system ontogeny—a subtle evolution to perfection
Munteanu, A. N., Surcel, M., Dobre, E. G., Constantin, C., & Neagu, M. (2026) · Frontiers in Aging · doi:10.3389/fragi.2026.1872955
“However, most studies show that the percentage of Tregs may increase or remain stable with age, although their function is altered (Lages et al., 2008; Palatella et al., 2022; Rosenkranz et al., 2007).”
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“…with characteristic changes in cutaneous T-cell populations, including an increase in CD8 ⁺ T cells [43], higher numbers of regulatory T cells [44], and elevated expression of inhibitory receptors such as programmed cell death protein 1 [45], contributing to a low-grade in fl amma-tory but…”
Synergistic effects of physical and psychological distress on immunesenescence
Duggal, N. A. (2014) · University of Birmingham Institutional Research Archive (University of Birmingham)
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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