Cited by 121Sirtuins and Resveratrol in MedicineT-cell and B-cell ImmunologyFOXO transcription factor regulation

Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1

Open access
Jeng, Mark Y., Hull, Philip A., Fei, Mingjian, Kwon, Hye-Sook, Tsou, Chia-Lin, Kasler, Herb, Ng, Che-Ping, Gordon, David E. +4 more·2018·Journal of Experimental Medicine

Abstract

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 CD8+CD28− T cell population is characterized by decreased SIRT1 and FOXO1 levels, resulting in enhanced glycolytic capacity and granzyme B production.

    “This cell population is characterized by decreased SIRT1 and FOXO1 levels, resulting in an enhanced glycolytic capacity and granzyme B production116.”

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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
Venue
Journal of Experimental Medicine
Published
2017-11-30
Volume
215
Issue
1
Pages
51-62
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
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
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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