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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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“Hypoxia/HIF-1a pathway is shown to upregulate the forkhead box P3 (FOXP3), a transcription factor and specific marker for Tregs, indicating that hypoxia enhances the formation of Tregs from CD4+ T cells.(91) Hypoxia also promotes the recruitment of Tregs by inducing the chemoattractant CCL28.”
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Sánz-Rubio, D., Sanz, A., Varona, L., Bolea, R., Forner, M., Gil, A. V., Cubero, P., Marín‐Oto, M., Martín‐Burriel, I., & Marín, J. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21062233 · Cited by 9
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“[126] Thus, removing Treg cells from the tumor microenvironment or inhibiting their activity is a strategic approach to cancer treatment.”
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“In other human studies and model systems, HBOT has been demonstrated to inhibit neutrophil adhesion and pro-inflammatory cytokines (interleukin-1, interleukin-6, and TNF-α) pro-duction, improve hypoxia tolerance through upregulation of response pathways (hypoxia inducible factor-1α and heme oxygenase-1), and enhance w…”
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“Additionally, even though systemic hypoxia is known to enhance the pro-inflammatory response, exercise mediates the upregulation of various myokines, such as IL-6, which re-establishes the anti-inflammatory balance through HIF1-α activity (Clambey et al. 2012; Benavente et al. 2021).”
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“Opposite roles for HIF-1α in Treg and Th17 cell differentiation have been reported, with some studies demonstrating that HIF-1α inhibited Tregs and promoted Th17 cell differentiation and others showing, conversely, that HIF-1α promoted FoxP3 expression and Treg differentiation [ 42, 43].”
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“For instance, on the one hand, HIF-Foxp3 interaction can trigger Foxp3 degradation via the proteasome pathway, inhibiting Treg differentiation; on the other hand, HIF can also bind to the HRE within Foxp3 promoter, inducing Foxp3 transcription and inhibiting Th17 differentiation [60,69].”
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“CD39 and CD73 as well as adenosine receptors could be induced by hypoxia (HIF) and chronic inflammation (transforming growth factor-beta [TGF]- b ) and other stressors or stimuli (Allard et al, 2020; Clambey et al, 2012).”
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“Some hypoxia outcomes through HIF pathways included in our model are up-regulating the VEGF, IL-6, and IL-10 production [94], promoting the maturation of the dendritic cells [68, 40], increasing the regulatory T-cells differentiation [19, 26] and increasing the T-cells cytotoxicity [37, 45].”
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Improved human hematopoietic reconstitution in HepaRG co-transplanted humanized NSG mice
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“The genes involve in Rap1 signaling pathway (KEGG hsa04015) (17), HIF-1 signaling pathway (hsa 04066) (18), endocytosis (hsa04144), Lysosome (hsa04142), antigen processing and presentation (hsa04612), and IL-17 signaling pathway (hsa04657) (19), which regulate lymphocytic differentiation and function.”
BackgroundThe hypoxia-associated genes in immune infiltration and treatment options of lung adenocarcinoma
Liu, L., Han, L., Dong, L., He, Z., Gao, K., Chen, X., Guo, J., & Zhao, Y. C. (2023) · PeerJ · doi:10.7717/peerj.15621 · Cited by 4
The Role of Regulatory T Cells and Indoleamine-2,3-dioxygenase in Brain Tumor Immunosuppression
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Ubiquitous points of control over regulatory T cells
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“Interestingly, others have reported that HIF-1 has a positive effect on the transcription of the Foxp3 gene [49].”
Wagage, S., & Hunter, C. A. (2014) · Current Immunology Reviews · doi:10.2174/1573395510666141105234917 · Cited by 4
“Regardless of the varying effects of different AHR ligands, both the AHR and HIF1α can increase FoxP3 expression, the induction of Tregs, and their suppressive function [108, 114, 115].”
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“…interventions are presented as potentially useful but mechanistically nuanced, with reports of divergent effects across cytotoxic T lymphocytes and Tregs via FoxP3-associated regulation and mitochondrial metabolic shifts (Clambey et al., 2012; Gropper et al., 2017; Palazon et al., 2017).”
The Role of Intra-Tumor Hypoxia in Cancer Cells Immune Escape Mechanism
Farhangnia, P., Delbandi, A., Aghamohamadi, N., Safdarian, A. R., & Akbarpour, M. (2022) · Springer eBooks · doi:10.1007/978-3-030-80962-1_61-1 · Cited by 3
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“Specifically, it has been demonstrated that the Tregs lacking the ability to express HIF-1α (hypoxia-inducible factor-1 α), a key transcriptional regulator of glycolysis, exhibit low suppressor activity in the model of experimental ulcerative colitis [81].”
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“There have also been studies showing that hypoxia enhances the number of Treg cells in inflamed tissue.(36) Hypoxia is also known to affect monocytes/macrophages(15,16) and neutrophils(17).”
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Li, C., Qin, C., Li, X., Wang, J., Li, Y., & Sun, Q. (2026) · International Journal of Oncology · doi:10.3892/ijo.2026.5845 · Cited by 3
“Despite some controversy (59), with reports suggesting that hypoxia promotes the expression of Foxp3 (60,61), a more detailed examination indicates that hypoxia inhibits the differentiation of Tregs, while HIF‑1 α deletion rescues the differentiation of Tregs under hypoxic conditions, providing increasing evidence of…”
InfluentialBiological clock-inspired polymeric micelles for enhanced photoimmunotherapy of hypoxic tumors
Dai, Y., Tang, Y., Jiang, W., Chen, Q., Xue, X., Huang, J., & Qian, C. (2025) · Nano Research · doi:10.26599/nr.2025.94907675 · Cited by 2
The implied dysregulated RKIP-hypoxia axis in cancer and immune evasion: Clinical implications
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Regulatory T cells in hypoxic environments
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Metabolic reprogramming drives homeostasis and specialization of regulatory T cells in cancer
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“Additionally, Hif1a has been reported to enhance Foxp3 expression in hypoxic environments, thereby supporting Treg function and promoting anti-inflammatory responses to mitigate tissue damage under low oxygen conditions [29,30].”
Regulatory T-Cells and Th17 Cells in Tumor Microenvironment
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Natural Products as Immunomodulatory and Chemosensitizing Agents in Colon Cancer Treatment
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Hypoxia in the Pathophysiology of Inflammatory Bowel Disease
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Stage-Specific Effects of Hypoxia on Interstitial Lung Disease
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“Uncontrolled inflammation is one of the major players in ALI and suppression of inflammation is beneficial for injury resolution [58, 59].”
BackgroundHIF-1α and VEGF polymorphisms and systemic lupus erythematosus susceptibility
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Hypoxia and the Hypoxia-Inducible Factors in Lymphocyte Differentiation and Function
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miR147 promotes mucosal integrity and healing in intestinal inflammation
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“FOXP3, a key transcription factor in Tregs, is upregulated in response to hypoxia, thereby improving their immune regulatory function and promoting mucosal healing (46).”
Self-citationThe Role of Intra-tumor Hypoxia in Cancer Cells Immune Escape Mechanism
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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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