The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index; none of the 33 sources its claims cite is checked for support yet.
Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1
Open accessAbstract
T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T(reg)) and T(H)17 differentiation. HIF-1 enhances T(H)17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating T(H)17 signature genes. Concurrently, HIF-1 attenuates T(reg) development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of T(H)17-dependent experimental autoimmune encephalitis associated with diminished T(H)17 and increased T(reg) cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.
Overview
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Written from the paper’s full text.
TL;DR
HIF-1α promotes TH17 differentiation by directly activating RORγt and cooperating with RORγt/p300 at IL-17A, while simultaneously attenuating Treg differentiation by targeting Foxp3 for proteasomal degradation. Mice with HIF-1α-deficient T cells are resistant to TH17-dependent EAE and show diminished TH17 and increased Treg responses.
Key findings
- HIF-1α expression is induced under TH17-skewing conditions in a Stat3-dependent manner; HIF-1α−/− T cells show minimal induction of IL-17A and RORγt transcripts and reduced IL-17A+ cells, with a dramatic increase in Foxp3+ cells.
- HIF-1α directly transactivates RORγt through a conserved HRE. RORγt overexpression induced IL-17A in 45.7% of HIF-1α+/+ T cells versus 0.72% with control retrovirus, but only 1.33% in HIF-1α−/− T cells. HIF-1α, RORγt, and p300 co-localize at IL-17A, IL-17F, and IL-23R promoters; triple co-expression increased IL-17A reporter activity more than 10-fold over any two factors, and hypoxia further enhanced IL-17A production.
- HIF-1α binds Foxp3 and mediates its ubiquitination and proteasomal degradation without changing Foxp3 mRNA; HIF-1α−/− T cells have higher Foxp3 protein under both TH17- and Treg-skewing conditions, and hypoxia decreases Foxp3+ cells. Degradation is blocked by proteasome inhibition and requires PHD2/proline hydroxylation of HIF-1α.
- In EAE, WT mice developed disease while T-HIF-1α−/− mice were highly resistant; at peak disease, WT lymph node, spleen, and CNS CD4+ T cells had higher IL-17+ proportions, and at day 21 T-HIF-1α−/− mice showed increased Foxp3+ and decreased IL-17+ CD4+ cells.
Methods
- Mice included T cell-specific HIF-1α knockout (CD4cre × HIF-1αflox/flox, T-HIF-1−/−), WT, Foxp3-GFP, and Rorc−/− mice. Naïve T cells were sorted and cultured under TH17, Treg, TH1, or TH2 conditions; hypoxia experiments used 1% O2.
- Molecular analyses included qRT-PCR, ChIP, luciferase reporter assays, co-immunoprecipitation, GST pull-down, Western blotting, and ubiquitination assays. EAE was induced with MOG35–55 in CFA plus pertussis toxin, with daily disease scoring.
- Statistical significance was determined by unpaired Student’s t test (*p<0.05).
Limitations
- The paper states that future studies are needed to delineate precisely how HIF-1α protein turnover dynamics in T cells modulate Foxp3 levels.
- The paper discusses a discrepancy with prior work suggesting HIF-1α is a general negative regulator of T cell activation, arguing that those experiments did not evaluate specific T cell differentiation decisions.
- Evident from the text: much of the mechanistic dissection relies on overexpression in Jurkat/293T cells and reporter assays, and the in vivo validation is limited to the MOG35–55 EAE model; no human data are presented.
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65 Own result · 33 Own interpretation · 23 Not checked yet · 5 No basis given · 1 Own method
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This increase was abrogated in HIF-1α −/− T cells (Figure 2D and S2E)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The IL-17A+ cell population was also significantly increased upon overexpression of HIF-1α under TH17 skewing conditions (Figure 2C, right panel).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Transfection of Jurkat cells with the RORγt promoter-driven reporter construct, together with increasing amounts of HIF-1α plasmid indeed caused corresponding increases in RORγt promoter activity, particularly upon PMA and ionomycin stimulation (Figure S3C).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α activates RORyt transcription and cooperates with RORyt and p300 to activate the IL-17A gene during TH17 development
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The mRNA expression of other TH17-related genes such as IL-17F and IL-23R was also much lower in HIF-1α −/− T cells than WT T cells”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“after TH17-skewing we observed a higher proportion of IL-17A+ cells in hypoxic compared to normoxic culture conditions.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“after isolating CD4+CD62LhighCD25-(naïve) Stat3-deficient T cells from CD4-cre x Stat3flox/flox mice and culturing them under TH17 skewing conditions for 4 days, very little HIF-1α protein was detected by Western blot (Figure 1E).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1γα expression is up-regulated in a Stat3-dependent manner in T cells under Th17 skewing conditions
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“no significant differences in IFN-γ or IL-4 were seen between WT and HIF-1α−/− T cells under TH1 or TH2 skewing conditions (Figure S2A)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these HIF-1 deficient T cells displayed a marked reduction in IL-17A+ cells.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Luciferase assays using the human sequence demonstrated that HIF-1α activates this promoter in a similar fashion to that of the mouse (Figure S3D and S3E).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α activates RORyt transcription and cooperates with RORyt and p300 to activate the IL-17A gene during TH17 development
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“CD4+ cells from both groups showed comparable proliferative capacity (Figure S2B).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plain- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 18
- Probably not a substantial claim. 15
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In the paper
“When naïve T cells were activated in the presence of TGF-β + IL-6 (TH17 skewing conditions), HIF-1α mRNA increased, peaked after 48 hours of culture and then began to decline (Figure 1B)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1γα expression is up-regulated in a Stat3-dependent manner in T cells under Th17 skewing conditions
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While HIF-1β expression was constitutive as expected under all treatments, both TGF-β and IL-6 alone induced HIF-1α and the combination of the two generated significantly higher levels of HIF-1α protei ven under normoxic conditions (Figure 1E).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1γα expression is up-regulated in a Stat3-dependent manner in T cells under Th17 skewing conditions
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Stat3 was directly associated with the promoter region of HIF-1α in the WT TH17-skewed T cells, but not at the promoter region of GAPDH (Figure 1F).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1γα expression is up-regulated in a Stat3-dependent manner in T cells under Th17 skewing conditions
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since the human and mouse RORγt promoter sequences share a high degree of identity as well as a conserved HRE (Figure S3A)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α activates RORyt transcription and cooperates with RORyt and p300 to activate the IL-17A gene during TH17 development
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“HIF-1α was found bind to several HREs located at the RORγt promoter, but not the promoter of the non-HIF-1α-regulated Gmpr gene (Figure 3C and Figure S4A–D).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α activates RORyt transcription and cooperates with RORyt and p300 to activate the IL-17A gene during TH17 development
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings support the idea that metabolic cues modulate T cell differentiation and that HIF-1α is an important mediator of this effect.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that HIF-1α deficiency specifically affects the TH17 pathway, as opposed to creating a global defect in T cell proliferation or differentiation capacity.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“On the other hand, pro-inflammatory cytokines such as IL-6 or IL-21 in the presence of low TGF-β activate Stat3, which overcomes Foxp3 inhibition of RORγt transcriptional activity. This leads to the up-regulation of the IL-23R, thus pushing T cell differentiation toward a TH17 fate (Zhou et al., 2008).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Zhou et al., 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these results demonstrate that HIF-1α plays a dual role in regulating IL-17A transcriptional activity by directly activating RORγt transcription and then associating with RORγt at the IL-17A promoter to recruit p300, thus generating a permissive chromatin structure.”
- Also stated in: § INTRODUCTION · boosted
“Specifically, we have discovered that HIF-1α promotes TH17 differentiation by directly inducing RORγt transcription and subsequently collaborates with RORγt to regulate downstream TH17 genes.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α activates RORyt transcription and cooperates with RORyt and p300 to activate the IL-17A gene during TH17 development
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § INTRODUCTION · boosted
In the paper
“Interestingly, the defect in TH17 differentiation seen in the absence of Stat3 can be only partially rescued by RORγt overexpression (Yang et al., 2008b).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Yang et al., 2008b
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, IL-6, IL-21 and IL-23 all activate Stat3, which is critical for the effects of these cytokines on TH17 cell differentiation (Zhou et al., 2007; (Harris et al., 2007).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Zhou et al., 2007
- Not checked yetcites Harris et al., 2007
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“High TGF-β levels in the absence of IL-6 induce Foxp3 and repress IL-23R transcription.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, accumulating evidence suggests that TH17 and iTreg arise from a common precursor.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“hypoxia-inducible factor 1α (HIF-1α), the transcription factor that mediates the metabolic switch from oxidative phosphorylation to aerobic glycolysis in response to hypoxia (Semenza, 2007)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Semenza, 2007
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Both iTreg and nTreg express Foxp3 as a core subset-specific transcription factor, which activates a large bank of genes that mediate the suppressive phenotype of Treg and also silences many effector T cell genes (Getnet et al., 2010; Pan et al., 2009; Sakaguchi et al., 2008).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Getnet et al., 2010
- Not checked yetcites Pan et al., 2009
- Not checked yetcites Sakaguchi et al., 2008
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“TH17 cells are induced by IL-6 and TGF-p and propagated by IL-23 and IL-21.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“HIF-1α expression in T cells can be induced both by hypoxic and non-hypoxic stimuli, including TCR-triggered and PI3K–mediated pathways, that result in mRNA up-regulation and protein stabilization (Lukashev et al., 2006).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1γα expression is up-regulated in a Stat3-dependent manner in T cells under Th17 skewing conditions
What the sources say
- Not checked yetcites Lukashev et al., 2006 source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“TGF-β induces Foxp3 expression in peripheral naïve T cells leading to the differentiation of iTregs, which exhibit a suppressive phenotype similar to that seen in nTreg cells (Sakaguchi et al., 2008).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Sakaguchi et al., 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Tregs can be induced from naïve T cells upon exposure to TGF-β and are propagated by IL-2 (Chen et al., 2003; Davidson et al., 2007; Rajewsky and von Boehmer, 2008).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Chen et al., 2003
- Not checked yetcites Davidson et al., 2007
- Not checked yetcites Rajewsky and von Boehmer, 2008
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that HIF-1α not only directly mediates RORγt gene expression, but also is required for the full function of RORγt in IL-17A gene transcription.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α activates RORyt transcription and cooperates with RORyt and p300 to activate the IL-17A gene during TH17 development
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“our previous observation that HIF-1α is a target gene for activated Stat3 in tumor cells (Harris et al., 2007; Xu et al., 2005)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1γα expression is up-regulated in a Stat3-dependent manner in T cells under Th17 skewing conditions
What the sources say
- Not checked yetcites Harris et al., 2007
- Not checked yetcites Xu et al., 2005
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“While it is now known that Stat3 induces RORyt gene expression (Harris et al., 2007; Yang et al., 2007) - the key transcription factor required for TH17 development (Ivanov et al., 2006)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Harris et al., 2007
- Not checked yetcites Yang et al., 2007
- Not checked yetcites Ivanov et al., 2006 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these results support the notion that HIF-1α plays a role in setting the TH17/Treg balance in a TH17-dependent disease model and that the mechanisms defined in the in vitro differentiation assays are also operative in vivo (Figure 7).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > Mice with HIF-1α-deficient T cells fail to mount a strong TH17 response, have increased Treg numbers and are resistant to EAE
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, degradation of Foxp3 in TH17/Treg progenitors mediated by HIF-1α would be expected to eventually diminish Foxp3 gene transcriptional activity thereby antagonizing stable Foxp3 autoregulation and consequent Treg lineage commitment.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Sitkovsky and colleagues have suggested that HIF-1α activity in T cells is a general negative regulator of T cell activation (Lukashev et al., 2006).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
What the sources say
- Not checked yetcites Lukashev et al., 2006 source
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
In the paper
“a TH17-dependent disease whose remission is dependent upon Treg cells (Schraml et al., 2009).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
What the sources say
- Not checked yetcites Schraml et al., 2009
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Animal protocols were approved by the Johns Hopkins Animal Care and Use Committee.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > EXPERIMENTAL PROCEDURES > Mice
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Rudensky and colleagues have recently proposed that conserved noncoding sequence 2 (CNS2) in the Foxp3 gene represents a site for positive transcriptional autoregulation of Foxp3, providing a mechanism for the protein to maintain its own expression levels (Zheng et al., 2010).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
What the sources say
- Not checked yetcites Zheng et al., 2010
hedgeddirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true.
In the paper
“Because TH17 cytokines can inhibit Th1/IFN-γ development in some circumstances (Luger et al., 2008)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
What the sources say
- Not checked yetcites Luger et al., 2008
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper relies on this without support.
p300 is critical for HIF-1α-mediated gene activation under hypoxic conditions.
“Because it has been shown that the transcription factor p300 is critical for HIF-1α-mediated gene activation under hypoxic conditions, we hypothesized that HIF-1α might function in a complex with RORγt by recruiting p300 to activate target genes such as IL-17A.”
The paper relies on this without support.
Inflammatory environments are relatively hypoxic.
“a number of studies have demonstrated that inflammatory environments are, relatively hypoxic.”
The paper relies on this without support.
TH17 cells are the major pathogenic population in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis.
“TH17 cells are the major pathogenic population in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, although factors besides IL-17A and IL-17F can contribute to the disease.”
The paper relies on this without support.
Immunization of B6 mice with MOG35–55 in complete Freund’s adjuvant (CFA) induces a TH17-dependent response that induces encephalitis.
“Immunization of B6 mice with myelin oligodendrocyte glycoprotein peptide (MOG35–55) in complete Freund’s adjuvant (CFA) induces a TH17-dependent response that induces encephalitis.”
The paper relies on this without support.
After a peak of encephalitis, the disease remits, concomitant with expansion of Tregs that can silence the TH17 encephalitic process.
“After a peak of encephalitis, clinically discernible by various gradable neurologic signs (including tail paralysis, progressing to hind and front limb paralysis) the disease remits, concomitant with expansion of Tregs that can silence the TH17 encephalitic process.”
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?
The cited source says what the claim attributes to it.
In the citing paper
“T cells lacking Hif-1α had impaired Th17 differentiation and increased production of Tregs.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [71]
In the citing paper
“genetic defects in humans in the IL-17/IL-17-receptor axis, STAT3, and RORγt, resulting in dysfunctional Th17 cells, are associated with chronic mucocutaneous candidiasis and severe disease following BCG immunization”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [68]
In the citing paper
“TH17 cell development is promoted by hypoxia inducible factor–1α (HIF-1α) (35, 36), an oxygen-sensitive transcription factor that regulates glycolytic gene expression in TH17 cells.”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [36]
In the citing paper
“While HIF-1α has been shown to be involved in degradation of Foxp3 and induce the Th17 phenotype (26)”
From Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues (2022) · cites this paper as [26]
In the citing paper
“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].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [71]
In the citing paper
“In T cells, HIF-1α is transiently stabilized in T cells following TCR activation (41), and plays an important role in regulating Treg and Th17 balance (26).”
From Targeting HIF-1α abrogates PD-L1–mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues (2022) · cites this paper as [26]
In the citing paper
“both groups showed that Hif-1α was required for the induction of experimental autoimmune encephalitis, a Th17-driven murine model of autoimmunity.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [71]
In the citing paper
“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].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [71]
Citations
Cites
Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., & Kuchroo, V. K. (2006) · Nature · doi:10.1038/nature04753 · Cited by 6,992
Regulatory T Cells and Immune Tolerance
Sakaguchi, S., Yamaguchi, T., Nomura, T., & Ono, M. (2008) · Cell · doi:10.1016/j.cell.2008.05.009 · Cited by 5,485
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., & Littman, D. R. (2006) · Cell · doi:10.1016/j.cell.2006.07.035 · Cited by 5,145
Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132710 · Cited by 4,873
Chen, W., Jin, W., Hardegen, N. J., Lei, K.-J., Li, L., Marinos, N. J., McGrady, G., & Wahl, S. M. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030152 · Cited by 4,678
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M., & Stockinger, B. (2006) · Immunity · doi:10.1016/j.immuni.2006.01.001 · Cited by 3,605 · cited 2×
“In response toTGF-b in vitro as well as in vivo, many T cells coexpress RORgt and Foxp3 (Veldhoen et al., 2006; Yang et al., 2008a).”
Differentiation of Effector CD4 T Cell Populations
Zhu, J., Yamane, H., & Paul, W. E. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101212 · Cited by 3,452
Transforming growth factor-β induces development of the TH17 lineage
Mangan, P. R., Harrington, L. E., O'Quinn, D. B., Helms, W. S., Bullard, D. C., Elson, C. O., Hatton, R. D., Wahl, S. M., Schoeb, T. R., & Weaver, C. T. (2006) · Nature · doi:10.1038/nature04754 · Cited by 3,087
Regulatory T Cell Lineage Specification by the Forkhead Transcription Factor Foxp3
Fontenot, J. D., Rasmussen, J. P., Williams, L. M., Dooley, J., Farr, A. G., & Rudensky, A. Y. (2005) · Immunity · doi:10.1016/j.immuni.2005.01.016 · Cited by 2,302
TGF-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
Research works printed but not linked: 4
- Harris, T.J., Grosso, J.F., Yen, H.R., Xin, H., Kortylewski, M., Albesiano, E., Hipkiss, E.L., Getnet, D., Goldberg, M.V., Maris, C.H., et al. (2007). Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179, 4313–4317. · DOI
- Pan, F., Means, A.R., and Liu, J.O. (2005). Calmodulin-dependent protein kinase IV regulates nuclear export of Cabin1 during T-cell activation. EMBO J. 24, 2104–2113. · DOI
- Schraml, B.U., Hildner, K., Ise, W., Lee, W.L., Smith, W.A., Solomon, B., Sahota, G., Sim, J., Mukasa, R., Cemerski, S., et al. (2009). The AP-1 transcription factor Batf controls T(H)17 differentiation. Nature 460, 405–409. · DOI
- Wu, S., Rhee, K.J., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H.R., Huso, D.L., Brancati, F.L., Wick, E., McAllister, F., et al. (2009). A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022. · DOI · Paper page
Cited by
Sorted by citations
Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645
Self-citationDang, C. V. (2012) · Cell · doi:10.1016/j.cell.2012.03.003 · Cited by 3,390
Self-citationThe IL-23-IL-17 immune axis: from mechanisms to therapeutic testing
Gaffen, S. L., Jain, R., Garg, A. V., & Cua, D. J. (2014) · Nature reviews. Immunology · doi:10.1038/nri3707 · Cited by 1,585
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612
Regulatory T cells in cancer immunosuppression — implications for anticancer therapy
Togashi, Y., Shitara, K., & Nishikawa, H. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0175-7 · Cited by 1,620
Metadata
- Authors
- Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., Luo, W., Zeller, K., Shimoda, L., Topalian, S. L., Semenza, G. L., Dang, C. V., Pardoll, D. M., & Pan, F.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Pardoll, Drew M.
- Pan, Fan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 146
- Issue
- 5
- Pages
- 772-784
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3387678
- OpenAlex
- W2134053452
- Cited by
- 1,595
- References
- 49
- Citations by year
- 2026: 89 · 2025: 105 · 2024: 107 · 2023: 117 · 2022: 133 · 2021: 136 · 2020: 130 · 2019: 106 · 2018: 100 · 2017: 107 · 2016: 107 · 2015: 97 · 2014: 88 · 2013: 84 · 2012: 81
- FWCI
- 36.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 685 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alexander and Margaret Stewart Trust
- Melanoma Research Alliance
- Memorial Sloan-Kettering Cancer Center
- Johns Hopkins University
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI089830)
- 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
- HIF-1, HIF-1α, Th17 cells, regulatory T cells, T cell differentiation, RORγt, Foxp3, P300, proteasomal degradation, T cell metabolism, experimental autoimmune encephalitis, T cell fate determination
- MeSH terms
- Animals, Base Sequence, Encephalomyelitis, Autoimmune, Experimental, Humans, Molecular Sequence Data, Sequence Alignment, Jurkat Cells, Interleukin-17, T-Lymphocytes, Regulatory, STAT3 Transcription Factor, p300-CBP Transcription Factors, Mice, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Forkhead Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells
About these checks
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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