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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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Bowser, J. L., Phan, L. H., & Eltzschig, H. K. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701414 · Cited by 62
Self-citationMetabolic Regulation of CAR T Cell Function by the Hypoxic Microenvironment in Solid Tumors
Schurich, A., Magalhaes, I., & Mattsson, J. (2019) · Immunotherapy · doi:10.2217/imt-2018-0141 · Cited by 62
Engineering chimeric antigen receptor T cells for solid tumour therapy
Liu, L., Qu, Y., Cheng, L., Yoon, C. W., He, P., Monther, A., Guo, T., Chittle, S. J., & Wang, Y. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.1141 · Cited by 61
Hypoxia signaling during acute lung injury
Vohwinkel, C. U., Hoegl, S., & Eltzschig, H. K. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00226.2015 · Cited by 58
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“Tissue hypoxia within inflammatory lesions dictates an anti-inflammatory program by driving expression of hypoxia-inducible factor (HIF)-1α that acts to increase the frequency and suppressive properties of thymic Treg (60, 61).”
BackgroundSuper-Treg: Toward a New Era of Adoptive Treg Therapy Enabled by Genetic Modifications
Amini, L., Greig, J., Schmueck‐Henneresse, M., Volk, H., Bézie, S., Reinke, P., Guillonneau, C., Wagner, D. L., & Anegón, I. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.611638 · Cited by 58
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“Furthermore, while Treg infiltration in the tumor is associated with poor survival in patients with various cancers (17), hypoxia-activated hypoxia-inducible factor (HIF)-1 has been shown to promote Treg differentiation through upregulation of FoxP3 expression (44).”
BackgroundThe dilemmas and possible solutions for CAR-T cell therapy application in solid tumors
Wang, L., Zhang, L., Dunmall, L. C., Wang, Y. Y., Fan, Z., Cheng, Z., & Wang, Y. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216871 · Cited by 59
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“HIF-1a suppresses iTreg differentiation in favor of Th17 cell differentiation by controlling glycolysis under Th17 differentiation conditions and by inhibiting Foxp3 expression [74, 75, 99].”
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“MODULATION OF FOXP3 EXPRESSION BY ADENOSINE AND HYPOXIA Hypoxia induced factor (HIF) 1α, another downstream target of TORC1, has also been implicated either as a positive (60, 61) or a negative (62, 63) regulator of FOXP3 expression.”
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“Multiple studies show that HIF1a accumulation induces a compensatory immunosuppressive state through recruitment of MDSCs (67), tumor-associated macrophages (68, 69), and Tregs (70).”
BackgroundThe Importance of Metabolism for Immune Homeostasis in Allergic Diseases
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“Nevertheless, this process appears to differ in the gut as HIF-1a expression increased the number of Treg and their inhibitory functions in a colitis mouse model (155).”
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“For example, groups have demonstrated the ability of HIF-1a expression to modulate T cell differentiation into regulatory T cells in the realms of colitis; this requires further evaluation in transplantation (43).”
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“In some other reports, HIF-1a induces Foxp3 and drives the generation and function of Tregs indicating that HIF-1a-deficient Tregs fail to control T-cell-mediated colitis (49, 50).”
BackgroundFOXP3+ regulatory T cells and the immune escape in solid tumours
Qiu, Y., Ke, S., Chen, J., Qin, Z., Zhang, W., Yuan, Y., Meng, D., Zhao, G., Wu, K., Li, B., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.982986 · Cited by 63
Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion
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Metabolic regulation of T cell differentiation and function
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“Besides developmental effects, another study found that HIF-1α may actually contribute to the suppressive capacity of Tregs in vivo as HIF-1α-deficient Tregs were less effective than their WT counterparts at preventing Tcell transfer mediated colitis in mice (Clambey et al., 2012).”
BackgroundThe effect of immunosuppressive molecules on T-cell metabolic reprogramming
Fernández-Ramos, A. A., Poindessous, V., Marchetti, C., Pallet, N., & Loriot, M. (2016) · Biochimie · doi:10.1016/j.biochi.2016.04.016 · Cited by 53
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“Hypoxia leads to induction of Foxp3 in a HIFdependent manner [82] and increased numbers of Tregs in vivo [82] and more potent Tregs in vitro [83].”
HIF-1α-induced xenobiotic transporters promote Th17 responses in Crohn's disease
Xie, A., Robles, R. J., Mukherjee, S., Zhang, H., Feldbrügge, L., Csizmadia, E., Wu, Y., Enjyoji, K., Moss, A. C., Otterbein, L. E., et al. (2018) · Journal of Autoimmunity · doi:10.1016/j.jaut.2018.07.022 · Cited by 53
“Severe hypoxia with tissue ischemia, during inflammatory insults, activates select transcriptional programs resulting in the upregulation of hypoxia-inducible-factor-1-alpha (HIF-1α) [1].”
BackgroundImmunometabolism of pro-repair cells
Singer, B. D., & Chandel, N. S. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124613 · Cited by 53
“In contrast, under hypoxic conditions in mice, HIF-1α can induce Foxp3 expression, forming a negative-feedback loop for proinflammatory T cell populations in hypoxic inflammatory microenvironments (96).”
Background
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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