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Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa
Open accessAbstract
Recent studies have demonstrated dramatic shifts in metabolic supply-and-demand ratios during inflammation, a process resulting in localized tissue hypoxia within inflammatory lesions (“inflammatory hypoxia”). As part of the adaptive immune response, T cells are recruited to sites of inflammatory hypoxia. Given the profound effects of hypoxia on gene regulation, we hypothesized that T-cell differentiation is controlled by hypoxia. To pursue this hypothesis, we analyzed the transcriptional consequences of ambient hypoxia (1% oxygen) on a broad panel of T-cell differentiation factors. Surprisingly, these studies revealed selective, robust induction of FoxP3, a key transcriptional regulator for regulatory T cells (Tregs). Studies of promoter binding or loss- and gain-of-function implicated hypoxia-inducible factor (HIF)-1α in inducing FoxP3. Similarly, hypoxia enhanced Treg abundance in vitro and in vivo. Finally, Treg-intrinsic HIF-1α was required for optimal Treg function and Hif1a –deficient Tregs failed to control T-cell–mediated colitis. These studies demonstrate that hypoxia is an intrinsic molecular cue that promotes FoxP3 expression, in turn eliciting potent anti-inflammatory mechanisms to limit tissue damage in conditions of reduced oxygen availability.
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“For instance, tumor hypoxia and/or HIFs can attract myeloid-derived suppressor cells (Corzo et al., 2010), regulatory T-cells (Clambey et al., 2012), and tumor-associated macrophages (Doedens et al., 2010;Imtiyaz et al., 2010) with immunosuppressive functions.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Clambey et al., 2012
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BackgroundInterplay between DNA repair and inflammation, and the link to cancer
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“It has been shown that hypoxia is an intrinsic molecular cue that promotes FoxP3 expression, resulting in immunosuppressive mechanisms to prevent possible tissue damage in conditions of reduced oxygen availability (Clambey et al., 2012).”
BackgroundModulating Treg stability to improve cancer immunotherapy
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BackgroundHIF1A Reduces Acute Lung Injury by Optimizing Carbohydrate Metabolism in the Alveolar Epithelium
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“However, hypoxia can promote FOXP3 expression (and consequently Treg differentiation) and HIF-1α is required for optimal Treg function in models of disease (Clambey and McNamee, 2012).”
BackgroundInfluentialHypoxia-inducible factors as molecular targets for liver diseases
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“In addition, hypoxia was shown to induce T-cell differentiation into Tregs by promoting HIF1adependent induction of FoxP3 (7).”
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“Moreover, recent work suggests that both mTOR and glycolytic metabolism are important mediators of Tfh development (36– 38), and that HIF-1 can either promote (57) or restrain (50, 52) Treg differentiation, in part by effects on glycolysis.”
BackgroundmiR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS
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“Hypoxia induces FOXP3 expression in a HIF1α-dependent manner; HIF1αdeficient Tregs failed to control T cell-mediated colitis (Clambey et al., 2012).”
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“Hypoxia impacts the relative abundance of Treg cells compared with Th17 cells, both in vivo and in vitro (40).”
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HIF-2α is indispensable for regulatory T cell function
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“Hypoxic tumor microenvironment has been shown to promote anti-tumor immunity through increased expression of the master regulator of T regulatory cell differentiation, FoxP3.(73) Increased number of T regulatory cells in the tumor microenvironment suppresses CD8þ T cell-mediated cytotoxic killing of tumor cells.”
BackgroundRadiotherapy induced immunogenic cell death by remodeling tumor immune microenvironment
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“A2AR blockade reduces CD4+ FOXP3+ Tregs infiltration and enhances the anti-tumor response of CD8+ T cells by attenuating hypoxic HIF-1a signaling (30).”
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BackgroundSelf-citation
Metadata
- Authors
- Clambey, E. T., McNamee, E. N., Westrich, J. A., Glover, L. E., Campbell, E. L., Jedlicka, P., de Zoeten, E. F., Cambier, J. C., Stenmark, K. R., Colgan, S. P., & Eltzschig, H. K.
- Affiliations
- Mucosal Inflammation Program,
- Department of Anesthesiology, Departments of bMedicine,
- Pathology, and
- Pediatrics and Genetics (US)
- Integrated Department of Immunology, and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-09-17
- Volume
- 109
- Issue
- 41
- Pages
- E2784-93
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3478644
- OpenAlex
- W1986925527
- Cited by
- 560
- References
- 71
- Citations by year
- 2026: 28 · 2025: 31 · 2024: 35 · 2023: 43 · 2022: 60 · 2021: 49 · 2020: 62 · 2019: 44 · 2018: 39 · 2017: 35 · 2016: 38 · 2015: 35 · 2014: 34 · 2013: 25 · 2012: 2
- FWCI
- 13.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Maynooth University ePrints and eTheses Archive (Maynooth University) (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL60569, R01HL060569, R01HL098294, R01HL092188, R01‑HL0921)
- National Institute of Diabetes and Digestive and Kidney Diseases (R0-1 DK50189, R01DK050189, R37DK050189, R01DK083385, R01DK095491)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia-inducible factor-1α, Foxp3, regulatory T cells, mucosal inflammation, T cell differentiation, transcriptional regulation, T cell-mediated colitis, anti-inflammatory mechanism, oxygen availability
- MeSH terms
- Animals, Hypoxia, Cells, Cultured, Colitis, Female, Flow Cytometry, Gene Expression Regulation, Humans, Inflammation, Interleukin-1, Intestinal Mucosa, Male, Mice, Inbred C57BL, Mice, Transgenic, Cell Hypoxia, Transforming Growth Factor beta, Mice, Knockout, Jurkat Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Forkhead Transcription Factors
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