Differential Effects of Physiologically Relevant Hypoxic Conditions on T Lymphocyte Development and Effector Functions
Abstract
Direct measurements revealed low oxygen tensions (0.5–4.5% oxygen) in murine lymphoid organs in vivo. To test whether adaptation to changes in oxygen tension may have an effect on lymphocyte functions, T cell differentiation and functions at varying oxygen tensions were studied. These studies show: 1) differentiated CTL deliver Fas ligand- and perforin-dependent lethal hit equally well at all redox conditions; 2) CTL development is delayed at 2.5% oxygen as compared with 20% oxygen. Remarkably, development of CTL at 2.5% oxygen is more sustained and the CTL much more lytic; and 3) hypoxic exposure and TCR-mediated activation are additive in enhancing levels of hypoxia response element-containing gene products in lymphocyte supernatants. In contrast, hypoxia inhibited the accumulation of nonhypoxia response element-containing gene products (e.g., IL-2 and IFN-γ) in the same cultures. This suggests that T cell activation in hypoxic conditions in vivo may lead to different patterns of lymphokine secretion and accumulation of cytokines (e.g., vascular endothelial growth factor) affecting endothelial cells and vascular permeabilization. Thus, although higher numbers of cells survive and are activated during 20% oxygen incubation in vitro, the CTL which develop at 2.5% oxygen are more lytic with higher levels of activation markers. It is concluded that the ambient 20% oxygen tension (plus 2-ME) is remarkably well suited for immunologic specificity and cytotoxicity studies, but oxygen dependence should be taken into account during the design and interpretation of results of in vitro T cell development assays and gene expression studies in vivo.
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Many tissues experience low PO2 levels even under normal physiologic conditions.
“it is noteworthy that many tissues experience low PO2 levels, even under normal physiologic conditions.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [8]
Microelectrode measurements of PO2 tensions in the spleen range from 0.5 to 4.5 kPa (4-34 mm Hg), depending on proximity to the splenic artery.
“microelectrode measurements of PO2 tensions in the spleen ranged from 0.5 to 4.5 kPa (4–34 mm Hg), depending on the relative proximity to the splenic artery [8].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [8]
TCR activation can induce expression of distinct splice isoforms of Hif-1α mRNA in human and mouse T cells.
“TCR activation can also induce expression of distinct splice isoforms of Hif-1α mRNA in human and mouse T cells, although the unique contribution of these splice isoforms to gene regulation remains unclear [8, 70].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [8]
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- Authors
- Caldwell, C. C., Kojima, H., Lukashev, D., Armstrong, J., Farber, M., Apasov, S. G., & Sitkovsky, M. V.
- Affiliations
- National Institutes of Health (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-12-01
- Volume
- 167
- Issue
- 11
- Pages
- 6140-6149
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2139595663
- Cited by
- 420
- References
- 52
- Citations by year
- 2026: 14 · 2025: 8 · 2024: 20 · 2023: 21 · 2022: 28 · 2021: 20 · 2020: 28 · 2019: 18 · 2018: 18 · 2017: 20 · 2016: 22 · 2015: 20 · 2014: 23 · 2013: 16 · 2012: 24
- FWCI
- 2.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- hypoxia, oxygen partial pressure, T cell development, cytotoxic T lymphocytes, perforin, Fas ligand, T cell activation, hypoxia response element, cytokine production, interleukin-2, interferon-gamma, vascular endothelial growth factor
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Cytotoxicity, Immunologic, DNA-Binding Proteins, Lymphocyte Culture Test, Mixed, Ligands, Lymphoid Tissue, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Inbred DBA, Nuclear Proteins, Oxygen, Receptors, Antigen, T-Cell, T-Lymphocytes, Cytotoxic, Transcription Factors, Cell Hypoxia, Lymphocyte Function-Associated Antigen-1, T-Lymphocyte Subsets, Cytokines, Receptor-CD3 Complex, Antigen, T-Cell, CD8-Positive T-Lymphocytes, Lymphocyte Count, fas Receptor, Response Elements, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Pore Forming Cytotoxic Proteins, Fas Ligand Protein, Perforin
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