The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index.
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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Ischemia and reperfusion—from mechanism to translation
Eltzschig, H. K., & Eckle, T. D. L. G. (2011) · Nature Medicine · doi:10.1038/nm.2507 · Cited by 3,468
Self-citationDeaglio, S., Dwyer, K. M., Gao, W., Friedman, D. J., Usheva, A., Erat, A., Chen, J., Enjyoji, K., Linden, J. M., Oukka, M., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062512 · Cited by 2,613
Eltzschig, H. K., & Carmeliet, P. (2011) · New England Journal of Medicine · doi:10.1056/nejmra0910283 · Cited by 2,061
Self-citationTGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function
Zhou, L., Lopes, J. E., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., Shen, Y., Du, J., Rubtsov, Y. P., Rudensky, A. Y., et al. (2008) · Nature · doi:10.1038/nature06878 · Cited by 1,928
Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803
Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1
Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., et al. (2011) · Cell · doi:10.1016/j.cell.2011.07.033 · Cited by 1,595
Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces
Rubtsov, Y. P., Rasmussen, J. P., Chi, E. Y., Fontenot, J., Castelli, L., Ye, X., Treuting, P., Siewe, L., Roers, A., Henderson, W. R., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.02.017 · Cited by 1,586
Foxp3+ follicular regulatory T cells control the germinal center response
Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F., Srivastava, M., Divekar, D. P., Beaton, L., Hogan, J. J., et al. (2011) · Nature Medicine · doi:10.1038/nm.2425 · Cited by 1,292
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Research works printed but not linked: 3
- 10.1056/NEJMra0910283 · DOI · Paper page
- 10.1084/jem.20110278 · DOI · Paper page
- 10.1016/j.cell.2011.07.033 · DOI · Paper page
Cited by
Sorted by citations
Noman, M. Z., Desantis, G., Janji, B., Hasmim, M., Karray, S., Dessen, P., Bronte, V., & Chouaib, S. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20131916 · Cited by 2,166
“Hypoxic zones in tumors attract immunosuppressive cells such as myeloidderived suppressor cells (MDSCs; Corzo et al., 2010), tumor-associated macrophages (TAMs; Doedens et al., 2010; Imtiyaz et al., 2010), and regulatory T cells (T reg cells; Clambey et al., 2012).”
BackgroundFueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363
“Asmentioned, HIF-1a has been implicated in the differentiation of both proinflammatory TH17 cells (35, 36) and CD4FoxP3 Treg cells (76).”
BackgroundHIF transcription factors, inflammation, and immunity
Palazon, A., Goldrath, A. W., Nizet, V., & Johnson, R. S. (2014) · Immunity · doi:10.1016/j.immuni.2014.09.008 · Cited by 1,195
“Consistent with HIF-1a promoting Th17 cell formation, these groups also observed enhanced Treg cell differentiation with deletion of HIF-1a in conditions favoring Th17 cells (Clambey et al., 2012; Dang et al., 2011; Shi et al., 2011); inhibition of glycolysis had the same effect (Shi et al., 2011).”
BackgroundTargeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy
Bader, J. E., Voss, K., & Rathmell, J. C. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.05.034 · Cited by 1,055
“Treg are also sensitive to hypoxia and may be enhanced under low oxygen condition, as HIF-1α can bind to the promoter region of the Treg transcription factor, FOXP3, in CD4+ T cells to increase transcription and was required for Treg suppression in vivo (Clambey et al., 2012).”
BackgroundThe hypoxic tumour microenvironment
Petrova, V., Annicchiarico‐Petruzzelli, M., Melino, G., & Amelio, I. (2018) · Oncogenesis · doi:10.1038/s41389-017-0011-9 · Cited by 1,077
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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