Cited by 561T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCancer, Hypoxia, and Metabolism

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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

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Clambey, Eric T., McNamee, Eóin N., Westrich, Joseph A., Glover, Louise E., Campbell, Eric L., Jedlicka, Paul, de Zoeten, Edwin F., Cambier, John C., Stenmark, Kurt R., Colgan, Sean P., Eltzschig, Holger K.·2012·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1202366109PMC PMC3478644

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Abstract

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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Result
Rhein enhances the cytotoxicity of effector lymphocytes in colon cancer under hypoxic conditions
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“…immunosuppressive cells, which include tumor-associated macrophages, myeloid-derived suppressor cells and regulatory T-cells, are components of the immunosuppressive tumor microenvironment and the immunosuppressive function of these cells is dependent on immunosuppressive molecules and HIF (23-25).”
Intrabody against prolyl hydroxylase 2 ameliorates acetaminophen-induced acute liver injury in mice via concomitant promotion of angiogenesis and redox homeostasis
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Metabolic orchestration of T lineage differentiation and function
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Hypoxia and activation of hypoxia inducible factor alpha as influencers of inflammatory helper T cells in autoimmune disease – a link between cancer and autoimmunity
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Cannabis and Cannabinoids in Multiple Sclerosis: From Experimental Models to Clinical Practice—A Review
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Abnormal energy metabolism in the pathogenesis of systemic lupus erythematosus
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Morphological Characteristics of the Thymus and Spleen and the Subpopulation Composition of Lymphocytes in Peripheral Blood during Systemic Inflammatory Response in Male Rats with Different Resistance to Hypoxia
Dzhalilova, D. S., Kosyreva, A. M., Diatroptov, M. E., Zolotova, N. A., Цветков, И. С., Аршакович, М. В., Makarova, O. V., & Khochanskiy, D. N. (2019) · International Journal of Inflammation · doi:10.1155/2019/7584685 · Cited by 15
“Oxygen deficiency causes activation of cells of both innate and adaptive immunity, inhibits neutrophil apoptosis [14], increases migration of neutrophils and macrophages [15, 16], and stimulates differentiation of T-helper cells [17] and T-regulatory cells [18].”
In Mixed Lymphocyte Reaction, the Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat Suppresses Cellular and Humoral Alloimmunity
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HIF1A(rs11549465) andAKNA(rs10817595) Gene Polymorphisms Are Associated with Primary Sjögren’s Syndrome
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Induced Pluripotent Stem Cell-Derived T Cells for Cancer Immunotherapy
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“The Tregs without HIF-1α could not control T cellmediated colitis (Clambey et al., 2012).”
Background
Treatment with a Rho Kinase Inhibitor Improves Survival from Graft-Versus-Host Disease in Mice after MHC-Haploidentical Hematopoietic Cell Transplantation
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Background
PTPROt maintains T cell immunity in the microenvironment of hepatocellular carcinoma
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Background
Metabolic Optimisation of Regulatory T Cells in Transplantation
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“When murine tTreg cells (CD4FOXP3) were cultured for 5 days under acute hypoxia (1% O2) with antiCD3/28-based activation and IL-2, there was no change in their FOXP3 expression (76).”
BackgroundMethodResultInfluential
Inversed Ratio of CD39/CD73 Expression on γδ T Cells in HIV Versus Healthy Controls Correlates With Immune Activation and Disease Progression
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Antigen receptor‐engineered Tregs inhibit CNS autoimmunity in cell therapy using nonredundant immune mechanisms in mice
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“7 HIF-1 also binds FoxP3 to promote regulatory T cell formation, 8 9 and therefore, suppression of effector T cell responses.”
BRD4 Inhibition Enhances the Antitumor Effects of Radiation Therapy in a Murine Breast Cancer Model
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Sustained and intermittent hypoxia differentially modulate primary monocyte immunothrombotic responses to IL-1β stimulation
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Sugars and fat – A healthy way to generate functional regulatory T cells
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Upregulation of FOXP3 is associated with severity of hypoxia and poor outcomes in COVID-19 patients
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“This effect depends mainly on hypoxia-inducible factor-1α (HIF-1 α), which drives the abundance and the function of Treg during inflammation (Ben-Shoshan et al., 2008; Clambey et al., 2012; Wu et al., 2014).”
Antiangiogenic therapy using endostatin increases the number of ALDH+ lung cancer stem cells by generating intratumor hypoxia
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BackgroundInfluential
Nanomaterials-involved strategies for reversing the immunosuppressive factors and improving antitumor immunotherapy
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High glucose/ChREBP-induced Hif-1α transcriptional activation in CD4+ T cells reduces the risk of diabetic kidney disease by inhibiting the Th1 response
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“…notion that HIF-1α can constrain T cell responses, studies demonstrate that hypoxia and HIF-1α enhance the abundance of Tregs through direct transcriptional induction of forkhead box protein P3 (FoxP3) and HIF-1α plays a Treg-intrinsic role in promoting Treg function, to restrict inflammation [34].”
Regulation of immune metabolism in Th17 and Treg cells
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“Others have shown that HIF-1 induces FoxP3, the key transcription factor influencing the development of regulatory T cells (Treg) and that HIF-1-deficent Tregs fail to control T cell-mediated colitis (10).”
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Intranuclear Delivery of HIF-1α-TMD Alleviates EAE via Functional Conversion of TH17 Cells
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PHD2 Constrains Antitumor CD8+ T-cell Activity
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Age-Specific Features of Hypoxia Tolerance and Intensity of Lipopolysaccharide-Induced Systemic Inflammatory Response in Wistar Rats
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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: Clambey, Eric T.
McNamee, Eóin N.
Westrich, Joseph A.
Glover, Louise E.
Campbell, Eric L.
Jedlicka, Paul
de Zoeten, Edwin F.
Cambier, John C.
Stenmark, Kurt R.
Colgan, Sean P.
Eltzschig, Holger K.
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
DOI: 10.1073/pnas.1202366109
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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Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa

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