Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function
Open accessAbstract
Oxygen is a molecule that is central to cellular respiration and viability, yet there are multiple physiologic and pathological contexts in which cells experience conditions of insufficient oxygen availability, a state known as hypoxia. Given the metabolic challenges of a low oxygen environment, hypoxia elicits a range of adaptive responses at the cellular, tissue, and systemic level to promote continued survival and function. Within this context, T lymphocytes are a highly migratory cell type of the adaptive immune system that frequently encounters a wide range of oxygen tensions in both health and disease. It is now clear that oxygen availability regulates T cell differentiation and function, a response orchestrated in large part by the hypoxia-inducible factor transcription factors. Here, we discuss the physiologic scope of hypoxia and hypoxic signaling, the contribution of these pathways in regulating T cell biology, and current gaps in our understanding. Finally, we discuss how emerging therapies that modulate the hypoxic response may offer new modalities to alter T cell function and the outcome of acute and chronic pathologies.
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TL;DR
This review discusses how oxygen availability and hypoxia-inducible factors, especially Hif-1α, regulate T cell development, differentiation, and function. It emphasizes context-dependent effects, including Hif-1α as both a negative regulator of T cell responses and a promoter of Th17 differentiation, with emerging therapeutic implications.
Key findings
- Cellular hypoxia and hypoxic responses generally occur at a PO2 ≤ ~1 kPa (≤~7–10 mm Hg or ~1% O2). Physiologic hypoxia exists in tissues such as the thymus (mean PO2 1.3 kPa, 10 mm Hg), spleen (0.5–4.5 kPa, 4–34 mm Hg), and lymphatic system (~1.1–4.7 kPa, 8–35 mm Hg).
- Hif-1α is stabilized by hypoxia through inhibition of PHD/VHL-mediated degradation and FIH-1, and in T cells is also induced by TCR stimulation via PI3K/mTOR and by IL-6/STAT3. Hif-1α can act as a negative regulator of T cell responses—Hif-1α-deficient T cells show enhanced IFN-γ and IL-2 production and improved survival in cecal ligation and puncture—while other studies show Hif-1α is required for Th17 differentiation and experimental autoimmune encephalitis and can limit Tregs.
- Culture at physiologic O2 (2–5% O2, ~2–5 kPa, or ~15–38 mm Hg) reduces T cell proliferation and expansion after TCR stimulation, shifts metabolism toward glycolysis, diminishes IL-2 and IFN-γ production, increases VEGF production, enhances CD8 lytic capacity, and can increase IL-17 production and Th17 differentiation.
- HIF activators have shown protection in models of inflammatory bowel disease and LPS-induced shock but are deleterious in polymicrobial sepsis after cecal ligation puncture; HIF inhibitors lack specificity, and early mouse experiments with HIF activators increased regulatory T cells and reduced intestinal inflammation.
Methods
- Narrative review synthesizing published literature on oxygen tensions, HIF biology, T cell development and function, genetic mouse models, in vitro T cell cultures, and disease models.
- No primary experimental data, systematic search strategy, or meta-analysis is described.
- Main analysis is qualitative integration of cited studies, with reference to tables and figures not included in the provided text.
Limitations
- The paper states several gaps: the effect of Hif-1α deficiency alone on thymocyte development is unknown; the precise contribution of Hif-1α in CD4 versus CD8 T cells or naïve versus effector T cells was often not thoroughly investigated; there is a lack of information on Hif-2α, NF-kB, or hypoxic-elicited miRNAs in T cells; the role of Hif-1α in γδ T cells, IELs, and NKT cells remains unknown; and the molecular basis of reduced T cell proliferation under hypoxia is unknown.
- The paper also notes that many in vitro studies use activated peripheral blood T cells, making it difficult to determine hypoxia effects on specific T cell subsets, and that the overall effect of hypoxia on cytokine production and apoptosis depends on culture conditions and cell type.
- Evident from the text: as a narrative review, it does not provide a systematic or quantitative synthesis, and its conclusions depend on the selected cited literature.
Model-written summary. Check it against the paper before relying on it.
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- Premisecitation
At a cellular level, hypoxia and hypoxic responses generally occur at a PO2 ≤ ~1 kPa (≤~7-10 mm Hg or ~1% O2).
“at a cellular level, hypoxia and hypoxic responses generally occur at a PO2 ≤ ~1 kPa (≤~7–10 mm Hg or ~1 % O2) [4].”
- Also stated in: § Physiologic states of hypoxia · plain
“at a cellular level, hypoxia and hypoxic responses generally occur at a PO2 ≤ ~1 kPa (≤~7–10 mm Hg or ~1 % O2) [4].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [4] Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271(4 Pt 1):C1172–80. source
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- Also stated in: § Physiologic states of hypoxia · plain
- Premisereasoning
T cells frequently encounter a wide range of oxygen tensions given their highly mobile nature.
“T cells frequently encounter a wide range of oxygen tensions given their highly mobile nature (Fig. 1; Table 2).”
Quote in the paperSubstantial claim - Premisecitation
Inflammation-associated hypoxia can result from a combination of factors including accumulation of metabolically active leukocytes, interstitial edema, and elevated temperature.
“Inflammation-associated hypoxia (or inflammatory hypoxia) can result from a combination of factors that result in a shift in metabolic supply and demand.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Colgan SP, Taylor CT. Hypoxia: an alarm signal during intestinal inflammation. Nat Rev Gastroenterol Hepatol. 2010;7(5):281–7. source
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- cites [3] Leach RM, Treacher DF. Oxygen transport-2. Tissue hypoxia. BMJ. 1998;317(7169):1370–3. source
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- Premisecitation
Microelectrode measurements of PO2 tensions in the spleen range from 0.5 to 4.5 kPa (4-34 mm Hg), depending on proximity to the splenic artery.
“microelectrode measurements of PO2 tensions in the spleen ranged from 0.5 to 4.5 kPa (4–34 mm Hg), depending on the relative proximity to the splenic artery [8].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9. source
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- Premisecitation
Many tissues experience low PO2 levels even under normal physiologic conditions.
“it is noteworthy that many tissues experience low PO2 levels, even under normal physiologic conditions.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Braun RD, Lanzen JL, Snyder SA, Dewhirst MW. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol. 2001;280(6):H2533–44. source
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- cites [8] Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9. source
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- Premisecitation
Hif-1α is hydroxylated on two conserved proline residues by PHD1-3, allowing VHL to bind, ubiquitinate, and target Hif-1α for proteasomal degradation.
“Hif-1α is hydroxylated on two highly conserved proline residues by prolyl hydroxylase enzymes (PHD1-3), which in turn allows the von Hippel–Lindau protein, an E3 ubiquitin ligase, to bind, ubiquitinate, and target Hif-1α for proteasomal degradation [41–43].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [41] Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science. 2001;292(5516):464–8. source
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- cites [42] Yu F, White SB, Zhao Q, Lee FS. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA. 2001;98(17):9630–5. source
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- Premisecitation
T cells are present in a hypoxic environment following sepsis.
“T cells are present in a hypoxic environment following sepsis [10]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P, et al. Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE. 2007;2(9):e853. source
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- Premisecitation
T cells present in inflammatory lesions in inflammatory bowel disease and rheumatoid arthritis express Hif-1α.
“T cells present in inflammatory lesions in inflammatory bowel disease (Crohn’s disease and ulcerative colitis) [34] and rheumatoid arthritis [35] express Hif-1α.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [34] Higashiyama M, Hokari R, Hozumi H, Kurihara C, Ueda T, Watanabe C, et al. HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis. J Leukoc Biol. 2012;91(6):901–9. source
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- Premisecitation
NF-kB is essential for the induction of baseline Hif-1α mRNA.
“NF-kB, which is a master regulator of inflammatory responses, is essential for the induction of baseline Hif-1α mRNA [55]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [55] Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, et al. NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha. Nature. 2008;453(7196):807–11. source
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- Premisecitation
T cells activated at physiologic O2 tension (2-5% O2) have reduced proliferation and expansion following TCR stimulation.
“when T cells are activated in conditions of physiologic oxygen tension (2–5 % O2, ~2–5 kPa, or ~15–38 mm Hg), there are a number of changes in T cell dynamics. First, T cells activated at physiologic O2 tension have reduced proliferation and expansion following TCR stimulation.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [72] Larbi A, Zelba H, Goldeck D, Pawelec G. Induction of HIF-1alpha and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells. J Leukoc Biol. 2010;87(2):265–73. source
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- Premisecitation
Hif-1α and Hif-2α can have redundant, unique, or antagonistic functions in different contexts.
“in different contexts, these transcriptional regulators can have redundant, unique, or antagonistic functions [52].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [52] Keith B, Johnson RS, Simon MC. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 2011;12(1):9–22. source
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- Premisecitation
Elevated levels of succinate or fumarate can inhibit PHD activity.
“elevated levels of succinate or fumarate can inhibit PHD activity [65, 66]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [65] Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8(2):143–53. source
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- Premisecitation
Hypoxic exposure of T cells results in modest Hif-1α stabilization.
“hypoxic exposure of T cells results in modest Hif-1α stabilization [35]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35] Gaber T, Haupl T, Sandig G, Tykwinska K, Fangradt M, Tschirschmann M, et al. Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis. J Rheumatol. 2009;36(12):2655–69. source
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- Premisecitation
Hypoxia activates the NF-kB pathway through p65 and p50 stabilization and nuclear translocation that induces transcription of many genes.
“hypoxia activates the NF-kB pathway through p65 and p50 stabilization and nuclear translocation that induces transcription of many genes [54].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [54] Taylor CT, Cummins EP. The role of NF-kappaB in hypoxia-induced gene expression. Ann N Y Acad Sci. 2009;1177:178–84. source
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- Premisereasoning
Iron chelators including desferrioxamine and bacterial siderophores can induce HIF stabilization.
“HIF stabilization can be induced by iron chelators including desferrioxamine and bacterial siderophores [62, 63].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [62] Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood. 1993;82(12):3610–5. source
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- Premisecitation
Increased Hif-1α protein synthesis following TCR stimulation is mediated by the PI3 kinase/mTOR pathway.
“This increased Hif-1α protein synthesis is mediated by the PI3 kinase/mTOR pathway [69].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [69] Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, et al. TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol. 2005;174(12):7592–9. source
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- Premisecitation
Hif-1α is hydroxylated on a conserved asparagine residue by FIH-1, which blocks recruitment of transcriptional coactivators such as p300/CBP, limiting transcriptional activation under non-hypoxic conditions.
“Hif-1α is also hydroxylated in an oxygen-dependent reaction on a highly conserved asparagine residue by FIH-1 (Factor inhibiting HIF-1), which blocks the ability of Hif-1α to recruit transcriptional coactivators such as p300/CBP, in turn limiting transcriptional activation by Hif-1α under non-hypoxic conditions [45, 46].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [45] Mahon PC, Hirota K, Semenza GL. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 2001;15(20):2675–86. source
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- Premisecitation
Prolyl hydroxylation and PHD activity are regulated by molecular oxygen, such that in limited oxygen availability, PHD function is inhibited.
“prolyl hydroxylation and PHD activity are regulated by molecular oxygen, such that in conditions of limited oxygen availability, PHD function is inhibited, disrupting this proteolytic cascade [44].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30(4):393–402. source
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- Premisecitation
Non-hypoxic stimuli that disrupt the PHD/VHL/HIF proteolytic cascade can induce accumulation of HIF.
“non-hypoxic stimuli that disrupt the PHD/VHL/HIF proteolytic cascade can also induce accumulation of HIF.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [61] Boulahbel H, Duran RV, Gottlieb E. Prolyl hydroxylases as regulators of cell metabolism. Biochem Soc Trans. 2009;37(Pt 1):291–4. source
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- Premisecitation
TCR activation can induce expression of distinct splice isoforms of Hif-1α mRNA in human and mouse T cells.
“TCR activation can also induce expression of distinct splice isoforms of Hif-1α mRNA in human and mouse T cells, although the unique contribution of these splice isoforms to gene regulation remains unclear [8, 70].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [8] Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9. source
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Culture of activated human T cells at physiologic O2 can result in a significantly elevated rate of spontaneous apoptosis in certain T cell subsets.
“culture of activated human T cells at physiologic O2 can result in a significantly elevated rate of spontaneous apoptosis in certain T cell subsets [72].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Larbi A, Zelba H, Goldeck D, Pawelec G. Induction of HIF-1alpha and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells. J Leukoc Biol. 2010;87(2):265–73. source
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- Premisecitation
T cells are able to preserve functionalities including cytokine production even in conditions of severe metabolite restriction including limited oxygen glucose.
“T cells are able to preserve functionalities including cytokine production even in conditions of severe metabolite restriction including limited oxygen glucose [73].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [73] Tripmacher R, Gaber T, Dziurla R, Haupl T, Erekul K, Grutzkau A, et al. Human CD4(+) T cells maintain specific functions even under conditions of extremely restricted ATP production. Eur J Immunol. 2008;38(6):1631–42. source
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- Premisecitation
Tumor hypoxia generates macrophages that can suppress T cell responses, mediated by hypoxic induction of arginase 1 and nitric oxide synthase.
“tumor hypoxia generates macrophages that can suppress T cell responses. This suppressive phenotype is mediated by hypoxic induction of arginase 1 and nitric oxide synthase, both that restrict T cell activation. Strikingly, induction of this hypoxic pathway in macrophages is required for optimal tumor growth [84, 85].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [84] Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 2010;70(19):7465–75. source
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- Premisecitation
HIF activators limit inflammation in models of inflammatory bowel disease and LPS-induced shock.
“and to limit inflammation in models of inflammatory bowel disease and LPS-induced shock [117–120].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [117] Cummins EP, Seeballuck F, Keely SJ, Mangan NE, Callanan JJ, Fallon PG, et al. The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology. 2008;134(1):156–65. source
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Hif-1β is commonly used in both hypoxic signaling and the aryl hydrocarbon receptor pathway.
“the common use of Hif-1β in both hypoxic signaling and the aryl hydrocarbon receptor pathway, which regulates Th17 differentiation and IL-10 production [112, 113]”
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Hif-1α is required for the induction of experimental autoimmune encephalitis, a Th17-driven murine model of autoimmunity.
“both groups showed that Hif-1α was required for the induction of experimental autoimmune encephalitis, a Th17-driven murine model of autoimmunity.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [71] Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–84. source
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c-Myc is uniquely required for the initiation of aerobic glycolysis in activated T cells.
“Hif-1α is not required for the initiation of aerobic glycolysis in activated T cells; instead, c-Myc is uniquely required for this metabolic shift [111].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [111] Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–82. source
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- Premisecitation
Upon T cell activation, T cells shift from a relatively metabolically quiescent state (primarily catabolic) to a highly metabolic phenotype (primarily anabolic and aerobic glycolysis).
“upon T cell activation, T cells shift from a relatively metabolically quiescent state (characterized primarily by catabolic metabolism) to a highly metabolic phenotype (characterized primarily by anabolic metabolism and the induction of aerobic glycolysis) [106].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [106] Pearce EL. Metabolism in T cell activation and differentiation. Curr Opin Immunol. 2010;22(3):314–20. source
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HIF activators potentiate innate antibacterial defense mechanisms in in vivo models.
“HIF activators have been used in a variety of in vivo models, where they have been shown to potentiate innate antibacterial defense mechanisms [116]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [116] Okumura CY, Hollands A, Tran DN, Olson J, Dahesh S, von Kockritz-Blickwede M et al. A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection. J Mol Med (Berl). 2012;90(9):1079–89. source
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- Premisecitation
Hif-1α-deficient T cells have enhanced production of cytokines including IFN-γ and IL-2.
“Hif-1α-deficient T cells had enhanced production of cytokines including IFN-γ and IL-2.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [93] Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L, et al. Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol. 2006;177(8):4962–5. source
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Metabolism is centrally important in regulating T cell function.
“there has been an increasing understanding of the central importance of metabolism in regulating T cell function [5, 106, 107].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Jones RG, Thompson CB. Revving the engine: signal transduction fuels T cell activation. Immunity. 2007;27(2):173–8. source
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- Premisecitation
A major function of Hif-1α in multiple cell types is the induction of metabolic reprogramming to shift metabolism to glycolysis under limited oxygen availability.
“A major function of Hif-1α in multiple cell types is the induction of metabolic reprogramming, to shift metabolism to glycolysis in conditions of limited oxygen availability [110].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [110] Semenza GL. Regulation of Metabolism by Hypoxia-Inducible Factor 1. Cold Spring Harb Symp Quant Biol. 2011;76:347–53. source
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Hif-1α is not required for the initiation of aerobic glycolysis in activated T cells.
“Hif-1α is not required for the initiation of aerobic glycolysis in activated T cells; instead, c-Myc is uniquely required for this metabolic shift [111].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [111] Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–82. source
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Hif-1α can play an important role in promoting optimal metabolism in Th17 differentiation.
“it is clear that Hif-1α can play an important role in promoting optimal metabolism in the case of Th17 differentiation [97].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [97] Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367–76. source
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An increasing list of transcription factors, including IRF4, STAT3, T-bet, GATA3, Bcl-6, and Blimp-1, regulate both effector T cell function and regulatory T cell function.
“an increasing list of transcription factors now shown to regulate both effector T cell function and regulatory T cell function, including IRF4, STAT3, T-bet, GATA3, Bcl-6, and Blimp-1 [98–105].”
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- cites [101] Chung Y, Tanaka S, Chu F, Nurieva RI, Martinez GJ, Rawal S, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med. 2011;17(8):983–8. source
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- cites [102] Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med. 2011;17(8):975–82. source
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- cites [103] Cretney E, Xin A, Shi W, Minnich M, Masson F, Miasari M, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol. 2011;12(4):304–11. source
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- cites [104] Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity. 2011;35(3):337–48. source
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- cites [105] Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, et al. GATA3 controls Foxp3 regulatory T cell fate during inflammation in mice. J Clin Invest. 2011;121(11):4503–15. source
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- Premisecitation
T cell-specific Hif-1α KO mice have increased inflammatory cell infiltration and vascular remodeling in a vascular injury model.
“T cell-specific Hif-1α KO mice also had increased inflammatory cell infiltration and vascular remodeling in a vascular injury model [94].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [94] Kurobe H, Urata M, Ueno M, Ueki M, Ono S, Izawa-Ishizawa Y, et al. Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling. Arterioscler Thromb Vasc Biol. 2010;30(2):210–7. source
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- Premisecitation
Different subsets of T cells and different stages following T cell activation are characterized by the use of different metabolic pathways.
“Different subsets of T cells, as well as different stages following T cell activation, are characterized by the use of different metabolic pathways [97, 108, 109].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [97] Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367–76. source
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- cites [108] Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186(6):3299–303. source
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- cites [109] van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012;36(1):68–78. source
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- Premisecitation
Constitutive activation of Hif-1α in Vhl-deficient thymocytes results in a reduced calcium response following TCR cross-linking due to increased removal of calcium from the cytoplasm via Hif-1α-induced increases in SERCA2 calcium pumps.
“Constitutive activation of Hif-1α in Vhl-deficient thymocytes also resulted in a reduced calcium response following TCR cross-linking that resulted from increased removal of calcium from the cytoplasm via Hif-1α-induced increases in SERCA2 calcium pumps [92].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [92] Neumann AK, Yang J, Biju MP, Joseph SK, Johnson RS, Haase VH, et al. Hypoxia inducible factor 1 alpha regulates T cell receptor signal transduction. Proc Natl Acad Sci USA. 2005;102(47):17071–6. source
Not checked in the free run.
- Premisecitation
Researchers have identified compounds that activate HIF and hypoxic signaling by disrupting the HIF proteolytic pathway.
“By disrupting the HIF proteolytic pathway, researchers have identified compounds that activate HIF and hypoxic signaling [115].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [115] Fraisl P, Aragones J, Carmeliet P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat Rev Drug Discov. 2009;8(2):139–52. source
Not checked in the free run.
- Interpretationnone given
From development to maturity, T cells traffic through tissues in which oxygen tensions are low enough to induce hypoxic signaling and Hif-1α expression.
“Notably, from development to maturity, T cells traffic through tissues in which oxygen tensions are low enough to induce hypoxic signaling and Hif-1α expression.”
Quote in the paperNot a substantial claim- Rests on an assumption: The migratory pattern of naïve and effector T cells exposes T cells to a variety of oxygen tensions.
- Premiseown data
Hif-1α is activated under certain cytokine-driven differentiation pathways (e.g., Th17 differentiation).
“data demonstrating that Hif-1α is activated following T cell receptor stimulation and under certain cytokine-driven differentiation pathways (e.g., Th17 differentiation) suggest that Hif-1α might have an important role in T cell activation and differentiation programs beyond its role in coordinating responses to hypoxia.”
Quote in the paperSubstantial claim - Premisecitation
Systemic treatment with HIF activators is potentially useful in boosting EPO levels in patients with end-stage renal disease.
“recent phase I studies have shown that systemic treatment with HIF activators is safe and potentially useful in boosting EPO levels in patients with end-stage renal disease [121].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [121] Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Gunzler V, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010;21(12):2151–6. source
Not checked in the free run.
- Premisecitation
In mice, HIF activators can locally increase the abundance of regulatory T cells in the context of inflammatory bowel disease.
“early experiments in mice using two distinct HIF activators have demonstrated that these compounds can locally increase the abundance of regulatory T cells and reduce inflammation in the context of inflammatory bowel disease [128].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [128] Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, et al. Hif-1 alpha dependent induction of FoxP3 drives regulatory T cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA. In press.
Not checked in the free run.
- Interpretationreasoning
Hif-1α might have an important role in T cell activation and differentiation programs beyond its role in coordinating responses to hypoxia.
“data demonstrating that Hif-1α is activated following T cell receptor stimulation and under certain cytokine-driven differentiation pathways (e.g., Th17 differentiation) suggest that Hif-1α might have an important role in T cell activation and differentiation programs beyond its role in coordinating responses to hypoxia.”
Quote in the paperSubstantial claim - Premisecitation
Systemic treatment with HIF activators is safe in phase I studies.
“recent phase I studies have shown that systemic treatment with HIF activators is safe and potentially useful in boosting EPO levels in patients with end-stage renal disease [121].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [121] Bernhardt WM, Wiesener MS, Scigalla P, Chou J, Schmieder RE, Gunzler V, et al. Inhibition of prolyl hydroxylases increases erythropoietin production in ESRD. J Am Soc Nephrol. 2010;21(12):2151–6. source
Not checked in the free run.
- Premisecitation
In mice, HIF activators can reduce inflammation in the context of inflammatory bowel disease.
“early experiments in mice using two distinct HIF activators have demonstrated that these compounds can locally increase the abundance of regulatory T cells and reduce inflammation in the context of inflammatory bowel disease [128].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [128] Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, et al. Hif-1 alpha dependent induction of FoxP3 drives regulatory T cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA. In press.
Not checked in the free run.
- Premisecitation
HIF activators protect epithelial cells from apoptosis.
“HIF activators appear capable of triggering multiple tissue protective pathways that protect epithelial cells from apoptosis, elicit an M2-like macrophage phenotype, and induce IL-10 production in B cells [119, 120].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [119] Hindryckx P, De Vos M, Jacques P, Ferdinande L, Peeters H, Olievier K, et al. Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD. J Immunol. 2010;185(10):6306–16. source
Not checked in the free run.
- cites [120] Hams E, Saunders SP, Cummins EP, O’Connor A, Tambuwala MT, Gallagher WM, et al. The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells. Shock. 2011;36(3):295–302. source
Not checked in the free run.
- Premiseown data
Hif-1α is activated following T cell receptor stimulation.
“data demonstrating that Hif-1α is activated following T cell receptor stimulation and under certain cytokine-driven differentiation pathways (e.g., Th17 differentiation) suggest that Hif-1α might have an important role in T cell activation and differentiation programs beyond its role in coordinating responses to hypoxia.”
Quote in the paperSubstantial claim - Premisecitation
Therapies designed to interfere with HIF signaling in tumors are already in clinical trials in humans to assess antitumor efficacy.
“Despite these caveats, therapies designed to interfere with HIF signaling in tumors are already in clinical trials in humans to assess antitumor efficacy [127].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [127] Wilczynski J, Duechler M, Czyz M. Targeting NF-kappaB and HIF-1 pathways for the treatment of cancer: part II. Arch Immunol Ther Exp (Warsz). 2011;59(4):301–7. source
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- Premisecitation
PHDs are capable of modulating the activity of multiple pathways including NF-kB.
“Since PHDs are capable of modulating the activity of multiple pathways including NF-kB [122]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Cummins EP, Berra E, Comerford KM, Ginouves A, Fitzgerald KT, Seeballuck F, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci USA. 2006;103(48):18154–9. source
Not checked in the free run.
- Premisecitation
A number of molecules that impair HIF at various transcriptional and translational stages have been identified.
“The search for possible HIF inhibitors has led to the identification of a number of molecules that impair HIF at various transcriptional and translational stages (ranging from protein stabilization to dimerization to DNA binding) [123].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [123] Semenza GL. HIF-1 inhibitors for cancer therapy: from gene expression to drug discovery. Curr Pharm Des. 2009;15(33):3839–43. source
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- Premisecitation
HIF activators elicit an M2-like macrophage phenotype.
“HIF activators appear capable of triggering multiple tissue protective pathways that protect epithelial cells from apoptosis, elicit an M2-like macrophage phenotype, and induce IL-10 production in B cells [119, 120].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [119] Hindryckx P, De Vos M, Jacques P, Ferdinande L, Peeters H, Olievier K, et al. Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD. J Immunol. 2010;185(10):6306–16. source
Not checked in the free run.
- cites [120] Hams E, Saunders SP, Cummins EP, O’Connor A, Tambuwala MT, Gallagher WM, et al. The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells. Shock. 2011;36(3):295–302. source
Not checked in the free run.
- Premisecitation
HIF activators induce IL-10 production in B cells.
“HIF activators appear capable of triggering multiple tissue protective pathways that protect epithelial cells from apoptosis, elicit an M2-like macrophage phenotype, and induce IL-10 production in B cells [119, 120].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [119] Hindryckx P, De Vos M, Jacques P, Ferdinande L, Peeters H, Olievier K, et al. Hydroxylase inhibition abrogates TNF-alpha-induced intestinal epithelial damage by hypoxia-inducible factor-1-dependent repression of FADD. J Immunol. 2010;185(10):6306–16. source
Not checked in the free run.
- cites [120] Hams E, Saunders SP, Cummins EP, O’Connor A, Tambuwala MT, Gallagher WM, et al. The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells. Shock. 2011;36(3):295–302. source
Not checked in the free run.
- Premisecitation
HIF inhibitors identified to date lack specificity for specific blockade of HIF.
“One significant hurdle for the use of these compounds, however, is the lack of specificity of these compounds for specific blockade of HIF (such as digoxin, acriflavine, and 17-AAG) identified to date [124–126].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [124] Stravopodis DJ, Margaritis LH, Voutsinas GE. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr Med Chem. 2007;14(29):3122–38. source
Not checked in the free run.
- cites [125] Zhang H, Qian DZ, Tan YS, Lee K, Gao P, Ren YR, et al. Digoxin and other cardiac glycosides inhibit HIF-1alpha synthesis and block tumor growth. Proc Natl Acad Sci USA. 2008;105(50):19579–86. source
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- cites [126] Lee K, Zhang H, Qian DZ, Rey S, Liu JO, Semenza GL. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization. Proc Natl Acad Sci USA. 2009;106(42):17910–5. source
Not checked in the free run.
- Premisecitation
HIF activation protects against LPS-induced shock.
“while HIF activation protects against LPS-induced shock, it is deleterious in mice subjected to polymicrobial sepsis following cecal ligation puncture [120].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [120] Hams E, Saunders SP, Cummins EP, O’Connor A, Tambuwala MT, Gallagher WM, et al. The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells. Shock. 2011;36(3):295–302. source
Not checked in the free run.
- Premisecitation
HIF activation is deleterious in mice subjected to polymicrobial sepsis following cecal ligation puncture.
“while HIF activation protects against LPS-induced shock, it is deleterious in mice subjected to polymicrobial sepsis following cecal ligation puncture [120].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [120] Hams E, Saunders SP, Cummins EP, O’Connor A, Tambuwala MT, Gallagher WM, et al. The hydroxylase inhibitor dimethyloxallyl glycine attenuates endotoxic shock via alternative activation of macrophages and IL-10 production by B1 cells. Shock. 2011;36(3):295–302. source
Not checked in the free run.
- May combine two claims. 29
- Classified as probably not a substantial claim. 5
May combine two claims.
PremisecitationHypoxia is an important cofactor in solid tumors, ischemic injury, and obesity.
“Prominent examples of diseases in which hypoxia is thought to have significant impact include: (i) solid tumors, with an insufficient or irregular vascular bed supply [19, 20], (ii) ischemic injury, including liver or kidney ischemic injury, myocardial infarction, and transplants [21], and (iii) obesity, in which adipose tissue hypoxia contributes to metabolic and inflammatory changes [22].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [19] Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer. 2008;8(12):967–75. source
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- cites [20] Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27. source
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- cites [21] Eltzschig HK, Eckle T. Ischemia and reperfusion—from mechanism to translation. Nat Med. 2011;17(11):1391–401. source
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- cites [22] Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes (Lond). 2009;33(1):54–66. source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe bone marrow contains hypoxic niches that are home to hematopoietic stem cells.
“the bone marrow contains hypoxic niches that are home to hematopoietic stem cells [11]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA. 2007;104(13):5431–6. source
Not checked in the free run.
May combine two claims.
PremisecitationHif-1α is a basic helix-loop-helix, PAS domain containing transcription factor that is profoundly induced by hypoxia.
“Hif-1α is a basic helix-loop-helix, PAS domain containing transcription factor that is profoundly induced by hypoxia.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [38] Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117(23):e207–17. source
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- cites [39] Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE. 2005;2005(306):re12. source
Not checked in the free run.
May combine two claims.
PremisecitationHypoxic microenvironments have been observed in a range of tissues, including the retina, the medulla of the kidney, the epidermis of the skin, the thymus, hypoxic niches within the bone marrow, regions within the spleen, and the epithelium lining of the GI tract.
“the presence of hypoxic microenvironments has been observed in a range of tissues, including the retina, the medulla of the kidney, the epidermis of the skin [13], the thymus [7, 11], hypoxic niches within the bone marrow [11, 14], and even regions within the spleen [8].”
- Also stated in: § Physiologic states of hypoxia · boosted
“the epithelium lining of the GI tract also demonstrates steady state hypoxia [6].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [13] Boutin AT, Weidemann A, Fu Z, Mesropian L, Gradin K, Jamora C, et al. Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell. 2008;133(2):223–34. source
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- cites [7] Braun RD, Lanzen JL, Snyder SA, Dewhirst MW. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol. 2001;280(6):H2533–44. source
Not checked in the free run.
- cites [11] Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA. 2007;104(13):5431–6. source
Not checked in the free run.
- cites [14] Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402. source
Not checked in the free run.
- Also stated in: § Physiologic states of hypoxia · boosted
May combine two claims.
PremisecitationIn hypoxia, Hif-1α heterodimerizes with Hif-1β and translocates to the nucleus, where it binds to hypoxia response elements (HREs) in promoters of genes.
“In hypoxia, Hif-1α heterodimerizes with the constitutively expressed Hif-1β (also known as Arnt, the aryl hydrocarbon receptor nuclear transporter) and translocates to the nucleus, where it binds to hypoxia response elements (HREs) in the promoters of a variety of genes [38, 39].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [38] Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011;117(23):e207–17. source
Not checked in the free run.
- cites [39] Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE. 2005;2005(306):re12. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIntestinal inflammation is characterized by inflammation-associated hypoxia.
“intestinal inflammation is characterized by inflammation-associated hypoxia [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Karhausen J, Furuta GT, Tomaszewski JE, Johnson RS, Colgan SP, Haase VH. Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis. J Clin Invest. 2004;114(8):1098–106. source
Not checked in the free run.
May combine two claims.
PremisecitationThe mean PO2 in the thymus is 1.3 kPa (10 mm Hg), with the majority of readings between 0 and 2.3 kPa (0-17 mm Hg).
“the mean PO2 in the thymus was 1.3 kPa (10 mm Hg), with the majority of readings between 0 and 2.3 kPa (0–17 mm Hg) [7].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Braun RD, Lanzen JL, Snyder SA, Dewhirst MW. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents. Am J Physiol Heart Circ Physiol. 2001;280(6):H2533–44. source
Not checked in the free run.
May combine two claims.
PremisecitationCobalt chloride is an effective stabilizer of Hif-1α and can induce hypoxic responses in vivo.
“cobalt chloride is an effective stabilizer of Hif-1α and can induce hypoxic responses in vivo [64].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [64] Maxwell PH, Pugh CW, Ratcliffe PJ. Inducible operation of the erythropoietin 3′ enhancer in multiple cell lines: evidence for a widespread oxygen-sensing mechanism. Proc Natl Acad Sci USA. 1993;90(6):2423–7. source
Not checked in the free run.
May combine two claims.
PremisecitationHuman T cells activated in hypoxia are protected from activation-induced cell death, potentially through hypoxic transcriptional induction of adrenomedulin.
“human T cells activated in hypoxia are protected from activation-induced cell death, potentially through hypoxic transcriptional induction of adrenomedulin [79].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [79] Makino Y, Nakamura H, Ikeda E, Ohnuma K, Yamauchi K, Yabe Y, et al. Hypoxia-inducible factor regulates survival of antigen receptor-driven T cells. J Immunol. 2003;171(12):6534–40. source
Not checked in the free run.
May combine two claims.
PremisecitationCulture at physiologic O2 levels increases IL-17 production and Th17 differentiation.
“culture at physiologic O2 levels increases IL-17 production and Th17 differentiation [81]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [81] Ikejiri A, Nagai S, Goda N, Kurebayashi Y, Osada-Oka M, Takubo K, et al. Dynamic regulation of Th17 differentiation by oxygen concentrations. Int Immunol. 2012;24(3):137–46. source
Not checked in the free run.
May combine two claims.
PremisecitationCulture with IL-6 activates STAT3 and induces Hif-1α in T cells.
“A second mechanism of Hif-1α induction in T cells is mediated by culture with the pro-inflammatory cytokine IL-6, which activates the STAT3 transcription factor [71].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [71] Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–84. source
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May combine two claims.
PremisecitationTCR stimulation results in robust Hif-1α protein stabilization that can be further enhanced by combining TCR stimulation with hypoxia.
“T cell receptor (TCR) stimulation results in robust Hif-1α protein stabilization that can be further enhanced by combining TCR stimulation with hypoxia [35, 69].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] Gaber T, Haupl T, Sandig G, Tykwinska K, Fangradt M, Tschirschmann M, et al. Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis. J Rheumatol. 2009;36(12):2655–69. source
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- cites [69] Nakamura H, Makino Y, Okamoto K, Poellinger L, Ohnuma K, Morimoto C, et al. TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol. 2005;174(12):7592–9. source
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May combine two claims.
PremisecitationT cells activated at physiologic O2 shift their metabolism to glycolysis and have an altered redox state more closely aligned with that observed in vivo.
“Moreover, T cells shift their metabolism to glycolysis and have an altered redox state that is more closely aligned with that observed in vivo [72–75].”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [72] Larbi A, Zelba H, Goldeck D, Pawelec G. Induction of HIF-1alpha and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells. J Leukoc Biol. 2010;87(2):265–73. source
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- cites [73] Tripmacher R, Gaber T, Dziurla R, Haupl T, Erekul K, Grutzkau A, et al. Human CD4(+) T cells maintain specific functions even under conditions of extremely restricted ATP production. Eur J Immunol. 2008;38(6):1631–42. source
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- cites [74] Atkuri KR, Herzenberg LA, Herzenberg LA. Culturing at atmospheric oxygen levels impacts lymphocyte function. Proc Natl Acad Sci USA. 2005;102(10):3756–9. source
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- cites [75] Atkuri KR, Herzenberg LA, Niemi AK, Cowan T, Herzenberg LA. Importance of culturing primary lymphocytes at physiological oxygen levels. Proc Natl Acad Sci USA. 2007;104(11):4547–52. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenIn T cells, stimuli that activate NF-kB such as antigen or cytokine stimulation also induce Hif-1α protein.
“in T cells, stimuli that activate NF-kB such as antigen or cytokine stimulation also induce Hif-1α protein (see below for more details).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationTumor-associated hypoxia induces expression of chemokine CCL28, which selectively induces recruitment of regulatory T cells (Tregs) leading to induction of tumor tolerance and neoangiogenesis.
“tumor-associated hypoxia induces the expression of chemokine CCL28, which selectively induces the recruitment of regulatory T cells (Tregs) leading to induction of tumor tolerance and neoangiogenesis [83].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [83] Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475(7355):226–30. source
Not checked in the free run.
May combine two claims.
PremisecitationCulture in physiologic O2 levels alters acquisition of CTL functions, resulting in diminished cytokine production (IL-2, IFN-γ), yet increased VEGF production, and enhanced lytic capacity in CD8 T cells.
“Culture in physiologic O2 levels also alters the acquisition of CTL functions, resulting in diminished cytokine production (IL-2, IFN-γ), yet increased VEGF production, and enhanced lytic capacity in CD8 T cells [8].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, et al. Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol. 2001;167(11):6140–9. source
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May combine two claims.
PremisecitationHif-2α is an important transcriptional regulator of hypoxic responses, controlling processes including hypoxic regulation of EPO synthesis and macrophage function.
“Hif-2α is an important transcriptional regulator of hypoxic responses, controlling a variety of processes including hypoxic regulation of EPO synthesis [48, 49] and macrophage function [50, 51].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [48] Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, et al. Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Invest. 2007;117(4):1068–77. source
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- cites [49] Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci USA. 2007;104(7):2301–6. source
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- cites [50] Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, et al. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24(5):491–501. source
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- cites [51] Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, et al. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010;120(8):2699–714. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningIn normoxia, Hif-1α is rapidly degraded and has limited transcriptional activation capacity; in limiting oxygen conditions, Hif-1α stability and activity are substantially increased.
“Based on these mechanisms, in normoxia, Hif-1α is rapidly degraded and has limited transcriptional activation capacity. In contrast, in limiting oxygen conditions, Hif-1α stability and activity are substantially increased, allowing a transcriptional response that is tightly induced in hypoxic conditions.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationHypoxic tumor cells have increased resistance to CTL-mediated lysis, correlated with hypoxic induction of tumor cell autophagy.
“the increased resistance of hypoxic tumor cells to CTL-mediated lysis. This increased resistance to CD8 T cell-mediated killing is correlated with the hypoxic induction of tumor cell autophagy [86, 87].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [86] Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N, et al. The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. J Immunol. 2009;182(6):3510–21. source
Not checked in the free run.
- cites [87] Noman MZ, Janji B, Kaminska B, Van Moer K, Pierson S, Przanowski P, et al. Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression. Cancer Res. 2011;71(18):5976–86. source
Not checked in the free run.
May combine two claims.
PremisecitationHif-1α promotes production of pro-inflammatory Th17 cells while simultaneously limiting generation of Tregs.
“two recent reports identified an alternative role for Hif-1α in T cell differentiation in promoting the production of pro-inflammatory Th17 cells while simultaneously limiting the generation of Tregs [71, 97].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [71] Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–84. source
Not checked in the free run.
- cites [97] Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367–76. source
Not checked in the free run.
May combine two claims.
InterpretationcitationThe phenotype of Vhl-deficient thymocytes is partially reversed following deletion of Hif-1α, indicating that constitutive Hif-1α expression in the absence of Vhl is deleterious to normal thymocyte development and differentiation.
“This phenotype is partially reversed following the deletion of Hif-1α on the Vhl-deficient background, indicating that constitutive Hif-1α expression in the absence of Vhl is deleterious to normal thymocyte development and differentiation, potentially by enhancing a caspase 8-dependent apoptotic pathway [91].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [91] Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA, Haase VH. Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol. 2004;24(20):9038–47. source
Not checked in the free run.
May combine two claims.
PremisecitationHif-1α-deficient T cells have enhanced production of IFN-γ and IL-2 following in vitro activation, and Hif-1α KO T cells produce less IL-17.
“Hif-1α-deficient T cells had enhanced production of IFN-γ and IL-2 following in vitro activation; interestingly, it was also observed that Hif-1α KO T cells produced less IL-17 (see below).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [94] Kurobe H, Urata M, Ueno M, Ueki M, Ono S, Izawa-Ishizawa Y, et al. Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling. Arterioscler Thromb Vasc Biol. 2010;30(2):210–7. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningHif-1α can be induced by at least 3 distinct mechanisms in T cells, with each condition inducing Hif-1α with a different magnitude and duration.
“Hif-1α can be induced by at least 3 distinct mechanisms in T cells (discussed above), with each condition inducing Hif-1α with a different magnitude and duration.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningHypoxic signaling likely regulates the function of γδ T cells, IELs, and NKT cells.
“Given the presence of these cell types at sites of physiologic hypoxia (e.g., γδ T cells residing in the skin and IELs lining the anaerobic environment of the gut lumen), it is extremely likely that hypoxic signaling will also regulate their function”
Quote in the paperNot a substantial claim- Rests on an assumption: γδ T cells reside in the skin and IELs line the anaerobic environment of the gut lumen.
May combine two claims.
PremisecitationT cells lacking Hif-1α have impaired Th17 differentiation and increased production of Tregs.
“T cells lacking Hif-1α had impaired Th17 differentiation and increased production of Tregs.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [71] Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772–84. source
Not checked in the free run.
- cites [97] Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367–76. source
Not checked in the free run.
May combine two claims.
PremisecitationIn vitro activation of CD4 T cells from Hif-1α heterozygous mice demonstrates increased IFN-γ production and decreased eosinophilia in a model of antigen-elicited airway eosinophilia.
“in vitro activation of CD4 T cells from Hif-1α heterozygous mice demonstrated increased IFN-γ production and decreased eosinophilia in a model of antigen-elicited airway eosinophilia [80].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [80] Guo J, Lu W, Shimoda LA, Semenza GL, Georas SN. Enhanced interferon-gamma gene expression in T Cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient mice. Int Arch Allergy Immunol. 2009;149(2):98–102. source
Not checked in the free run.
May combine two claims.
PremisecitationThymocyte deletion of Vhl results in a pronounced deficit in thymocyte development, with increased apoptosis of CD4+CD8+ double-positive thymocytes.
“Thymocyte deletion of Vhl results in a pronounced deficit in thymocyte development, with increased apoptosis of CD4+CD8+ double-positive thymocytes [91].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [91] Biju MP, Neumann AK, Bensinger SJ, Johnson RS, Turka LA, Haase VH. Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes. Mol Cell Biol. 2004;24(20):9038–47. source
Not checked in the free run.
May combine two claims.
PremisecitationHif-1α has an important role in negatively regulating T cell function in vivo; T cell Hif-1α-deficient mice had improved survival and decreased bacterial loads associated with enhanced cytokine production, increased proliferation, and enhanced NF-kB activity in T cells.
“Hif-1α had an important role in negatively regulating T cell function in vivo [10]. Whereas wild-type mice had a high rate of mortality following cecal ligation, T cell Hif-1α-deficient mice had improved survival and decreased bacterial loads associated with enhanced cytokine production (including IL-2 and IFN-γ), increased proliferation, and enhanced NF-kB activity (both p50 and p65) in T cells [”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P, et al. Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE. 2007;2(9):e853. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHif-1α is essential for embryonic development and has widespread, cell type-specific roles in vivo.
“Hif-1α is essential for embryonic development and has widespread, cell type-specific roles in vivo [90].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [90] Doedens A, Johnson RS. Transgenic models to understand hypoxia-inducible factor function. Meth Enzymol. 2007;435:87–105. source
Not checked in the free run.
May combine two claims.
Premiseown dataHypoxia enhances abundance of Tregs through direct transcriptional induction of FoxP3, and Hif-1α plays a Treg-intrinsic role in promoting Treg function to restrict intestinal inflammation.
“our recent data demonstrate that hypoxia enhances the abundance of Tregs through direct transcriptional induction of FoxP3 and that Hif-1α plays a Treg-intrinsic role in promoting Treg function, to restrict intestinal inflammation [128].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [128] Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, et al. Hif-1 alpha dependent induction of FoxP3 drives regulatory T cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA. In press.
Not checked in the free run.
May combine two claims.
PremisecitationThe aryl hydrocarbon receptor pathway regulates Th17 differentiation and IL-10 production.
“the common use of Hif-1β in both hypoxic signaling and the aryl hydrocarbon receptor pathway, which regulates Th17 differentiation and IL-10 production [112, 113]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [112] Esser C, Rannug A, Stockinger B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 2009;30(9):447–54. source
Not checked in the free run.
- cites [113] Pot C, Apetoh L, Kuchroo VK. Type 1 regulatory T cells (Tr1) in autoimmunity. Semin Immunol. 2011;23(3):202–8. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningCurrent HIF activators, many of which are PHD inhibitors, likely have pleiotropic effects beyond activation of HIF, which can lead to potentially unpredictable side effects.
“these compounds likely have pleiotropic effects beyond activation of HIF, which can lead to potentially unpredictable side effects.”
Quote in the paperSubstantial claim- Rests on an assumption: Many current HIF activators are prolyl hydroxylase (PHD) inhibitors.
The paper relies on this without support.
The role of Hif-1α in the regulation of γδ T cells, IELs, and NKT cells remains unknown.
“To date, the role of Hif-1α in the regulation of other T cell subsets including γδ T cells, IELs, and NKT cells remains unknown.”
The paper relies on this without support.
γδ T cells reside in the skin and IELs line the anaerobic environment of the gut lumen.
“γδ T cells residing in the skin and IELs lining the anaerobic environment of the gut lumen”
The paper relies on this without support.
There is a complete lack of information on hypoxic regulation in T cells mediated by Hif-2α, NF-kB, or hypoxic-elicited miRNAs.
“there is a complete lack of information on hypoxic regulation in T cells mediated by Hif-2α, NF-kB, or hypoxic-elicited miRNAs.”
The paper relies on this without support.
Many current HIF activators are prolyl hydroxylase (PHD) inhibitors.
“many are prolyl hydroxylase (PHD) inhibitors.”
The paper relies on this without support.
The migratory pattern of naïve and effector T cells exposes T cells to a variety of oxygen tensions.
“The migratory pattern of naïve and effector T cells exposes T cells to a variety of oxygen tensions.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Some tissue sites, such as the thymus, bone marrow, and the gastrointestinal epithelium, are naturally hypoxic, whereas inflammation can promote local hypoxic regions in tissues.
“Some tissue sites, such as the thymus, bone marrow, and the gastrointestinal epithelium, are naturally hypoxic, whereas inflammation can promote local hypoxic regions in tissues (73).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [73]
Activated T cells cultured in standard medium experience 25 mM glucose (five times standard blood glucose of 5 mM), 4 mM glutamine (eight times the standard concentration of 0.5 mM in blood), and 20% O2 [two to four times the oxygen tension in blood, which varies depending on tissue type].
“Activated T cells cultured in standard medium (Iscove’s modified Dulbecco medium plus 10% serum) experience 25 mM glucose (five times standard blood glucose of 5 mM), 4 mM glutamine (eight times the standard concentration of 0.5 mM in blood), and 20% O2 [two to four times the oxygen tension in blood, which varies depending on tissue type (73)].”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [73]
The citation lists haven’t been fetched yet
References 130 · Cited by 234
- Authors
- McNamee, E. N., Korns Johnson, D., Homann, D., & Clambey, E. T.
- Affiliations
- University of Colorado Anschutz (US)
- National Jewish Health (US)
- Corresponding author
- Clambey, Eric T.
- Venue
- Immunologic Research
- Published
- 2012-09-09
- Volume
- 55
- Issue
- 1-3
- Pages
- 58-70
- ISSN
- 0257-277X (ISSN-L)
- 1559-0755
- PMC
- PMC3919451
- OpenAlex
- W2021947467
- Cited by
- 234
- References
- 130
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 12 · 2023: 17 · 2022: 19 · 2021: 23 · 2020: 29 · 2019: 25 · 2018: 18 · 2017: 16 · 2016: 15 · 2015: 14 · 2014: 13 · 2013: 5 · 2012: 1
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Immunologic Research (publishedVersion)
- PubMed (publishedVersion)
- Maynooth University ePrints and eTheses Archive (Maynooth University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (U19AI050864, R01AI093637)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- hypoxia, hypoxia-inducible factor, T cell development, T cell differentiation, T cell function, oxygen availability, hypoxia signaling, cellular respiration, adaptive immunity
- MeSH terms
- Animals, Hypoxia, Cell Differentiation, Humans, Oxygen, T-Lymphocytes, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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