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Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1
Open accessAbstract
The expansion of CD8+CD28– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28– T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.
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“This cell population is characterized by decreased SIRT1 and FOXO1 levels, resulting in an enhanced glycolytic capacity and granzyme B production116.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [116]
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Metadata
- Authors
- Jeng, M. Y., Hull, P. A., Fei, M., Kwon, H.-S., Tsou, C.-L., Kasler, H., Ng, C.-P., Gordon, D. E., Johnson, J., Krogan, N., Verdin, E., & Ott, M.
- Affiliations
- Gladstone Institutes (US)
- Gladstone Institutes, San Francisco, CA 1
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2017-11-30
- Volume
- 215
- Issue
- 1
- Pages
- 51-62
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5748845
- OpenAlex
- W2771883021
- Cited by
- 121
- References
- 78
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 3 · 2023: 15 · 2022: 17 · 2021: 20 · 2020: 17 · 2019: 16 · 2018: 6 · 2017: 1
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (P30 AI027763, 1DP1DA038043)
- James B. Pendleton Charitable Trust (NIH S10 RR028962)
- Gladstone Institutes
- National Science Foundation (1144247)
- Evangelische Studienwerk Villigst
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- CD8+CD28- T cells, SIRT1, FOXO1, metabolic reprogramming, glycolysis, memory T cells, aging, proteasomal degradation, granzyme B, cytotoxic T lymphocytes, NAD+-dependent deacetylase, transcriptional reprogramming
- MeSH terms
- Forkhead Box Protein O1, Cytotoxicity, Immunologic, Energy Metabolism, Gene Expression Regulation, Humans, Immunologic Memory, Biomarkers, T-Lymphocyte Subsets, CD28 Antigens, CD8-Positive T-Lymphocytes, Sirtuin 1
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