Cutting Edge: Hypoxia-Inducible Factor 1α and Its Activation-Inducible Short Isoform I.1 Negatively Regulate Functions of CD4+ and CD8+ T Lymphocytes
Abstract
To evaluate the role of hypoxia-inducible factor 1α (HIF-1α) and its TCR activation-inducible short isoform I.1 in T cell functions, we genetically engineered unique mice with: 1) knockout of I.1 isoform of HIF-1α; 2) T cell-targeted HIF-1α knockdown; and 3) chimeric mice with HIF-1α gene deletion in T and B lymphocytes. In all three types of mice, the HIF-1α-deficient T lymphocytes, which were TCR-activated in vitro, produced more proinflammatory cytokines compared with HIF-1α-expressing control T cells. Surprisingly, deletion of the I.1 isoform, which represents <30% of total HIF-1α mRNA in activated T cells, was sufficient to markedly enhance TCR-triggered cytokine secretion. These data suggest that HIF-1α not only plays a critical role in oxygen homeostasis but also may serve as a negative regulator of T cells.
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Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy.
“Considerable evidence in mouse models has shown that hypoxia promotes tumor escape from immune surveillance and immunotherapy13–19.”
Hif-1α-deficient T cells have enhanced production of cytokines including IFN-γ and IL-2.
“Hif-1α-deficient T cells had enhanced production of cytokines including IFN-γ and IL-2.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [93]
HIF-1α expression in T cells can be induced by hypoxic and non-hypoxic stimuli, including TCR-triggered and PI3K-mediated pathways, resulting in mRNA up-regulation and protein stabilization.
“HIF-1α expression in T cells can be induced both by hypoxic and non-hypoxic stimuli, including TCR-triggered and PI3K–mediated pathways, that result in mRNA up-regulation and protein stabilization (Lukashev et al., 2006).”
From Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 (2011) · cites this paper as Lukashev et al., 2006
HIF-1α activity in T cells is a general negative regulator of T cell activation.
“Sitkovsky and colleagues have suggested that HIF-1α activity in T cells is a general negative regulator of T cell activation (Lukashev et al., 2006).”
From Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1 (2011) · cites this paper as Lukashev et al., 2006
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Self-citation
- Authors
- Lukashev, D., Klebanov, B., Kojima, H., Grinberg, A., Ohta, A., Berenfeld, L., Wenger, R. H., Ohta, A., & Sitkovsky, M.
- Affiliations
- Northeastern University (US)
- Dokkyo University (JP)
- National Institutes of Health (US)
- University of Zurich (CH)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-10
- Volume
- 177
- Issue
- 8
- Pages
- 4962-4965
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2155662291
- Cited by
- 208
- References
- 31
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 12 · 2023: 10 · 2022: 7 · 2021: 10 · 2020: 13 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 13 · 2015: 11 · 2014: 11 · 2013: 11 · 2012: 21
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- 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 › Signaling Pathways in Disease
- Keywords
- hypoxia-inducible factor-1α, T cell activation, CD4+ T cells, CD8+ T cells, proinflammatory cytokine production, T cell homeostasis, oxygen homeostasis
- MeSH terms
- Animals, Lymphocyte Activation, Receptors, Antigen, T-Cell, RNA, Messenger, CD4-Positive T-Lymphocytes, Cytokines, Mice, Knockout, CD8-Positive T-Lymphocytes, Protein Isoforms, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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