Induction of HIF-1α and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells
Abstract
T cell differentiation and functions are altered at low oxygen, possibly via HIF-1α and glycolysis up-regulation. The majority of in vitro studies involving lymphocytes is performed in AtmO2, and the PhysO2 that T cells encounter are variable but commonly much lower. Previous studies showed changed kinetics and delayed proliferation of human T cells at PhysO2. Here, we show that CD3/CD28-dependent T cell activation induces faster cell cycling at AtmO2 than at PhysO2 (here taken to be 2%). Concomitantly with HIF-1α expression, we observed a switch in the T cell respiratory pathway toward glycolysis at PhysO2. Thus, modulating available glucose levels showed that at PhysO2, T cells rely more on glycolysis, associated with a higher phosphorylation of Aktser473. Although no difference in spontaneous apoptosis of resting cells was detected, it was increased significantly at PhysO2 after T cell activation and was different within the different T cell subsets. This may explain at least partly the differently altered proliferation and subset distribution observed in CD4+ and CD8+ T cells as a result of differences in naïve and memory subset distribution. Together, these findings suggest that T cell activation thresholds, subsequent proliferative capacity, and susceptibility to apoptosis, hitherto studied in air and thought to be crucial for monitoring immune responsiveness, may require re-assessment.
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T cells activated at physiologic O2 tension (2-5% O2) have reduced proliferation and expansion following TCR stimulation.
“when T cells are activated in conditions of physiologic oxygen tension (2–5 % O2, ~2–5 kPa, or ~15–38 mm Hg), there are a number of changes in T cell dynamics. First, T cells activated at physiologic O2 tension have reduced proliferation and expansion following TCR stimulation.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [72]
Culture of activated human T cells at physiologic O2 can result in a significantly elevated rate of spontaneous apoptosis in certain T cell subsets.
“culture of activated human T cells at physiologic O2 can result in a significantly elevated rate of spontaneous apoptosis in certain T cell subsets [72].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [72]
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- Authors
- Larbi, A., Zelba, H., Goldeck, D., & Pawelec, G.
- Affiliations
- University of Tübingen (DE)
- Corresponding author
- Larbi, Anis
- Venue
- Journal of Leukocyte Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-11-05
- Volume
- 87
- Issue
- 2
- Pages
- 265-273
- ISSN
- 0741-5400 (ISSN-L)
- 1938-3673
- OpenAlex
- W2146094257
- Cited by
- 58
- References
- 41
- Citations by year
- 2026: 3 · 2025: 4 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 7 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 4 · 2012: 5
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Leukocyte Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (DFG PA 361/11-1, SFB 685-B4)
- Fortüne Program
- European Commission (EU-LSHG-CT-2007-036894)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- HIF-1α, hypoxia, T cell activation, glycolysis, aerobic glycolysis, T cell proliferation, apoptosis, Akt phosphorylation, glucose metabolism, CD4+ T cells, CD8+ T cells, T cell differentiation, oxygen partial pressure
- MeSH terms
- Cell Differentiation, Glycolysis, Humans, Lymphocyte Activation, Oxygen, Oxygen Consumption, CD4-Positive T-Lymphocytes, Apoptosis, CD8-Positive T-Lymphocytes, Cell Proliferation, Proto-Oncogene Proteins c-akt, Hypoxia-Inducible Factor 1, alpha Subunit
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