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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
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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
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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
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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
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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
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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
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“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
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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
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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
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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
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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
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In the paper
“T-HIF-1−/− mice had normal development of CD4+ and CD8+ T cells, B cells and dendritic cells (Figure S1).”
§ 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
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In the paper
“the expression of a HIF-1α mutant gene lacking the DNA binding domain failed to activate the wild type RORγt promoter (Figure 3B).”
§ 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
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In the paper
“We observed significant induction of IL-17A protein by WT T cells stimulated with TGF-β and IL-6 (Figure 2A).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“The ectopic expression of HIF-1α substantially increased the percentage of IL-17A+ cells even in the absence of the TH17-driving cytokines IL-6 and TGF-β (Figure 2C).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“This induction of IL-17A was associated with the upregulation of both RORγt mRNA and protein (Figure S2).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“The mutated constructs had much lower luciferase activity compared to that of a wild type RORγt promoter-driven luciferase reporter (Figure 3A).”
§ 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
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In the paper
“we also noted a dramatic increase in the proportion of Foxp3+ cells in HIF-1α −/− T cells (Figure 2A).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“This recruitment of HIF-1α was dependent on RORγt since it was abrogated in T cells from RORγt knockout mice (Figure S5A–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
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In the paper
“GST-HIF-1α (amino acids1–80), rather than GST alone, was bound to RORγt (Figure S4F).”
§ 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
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In the paper
“Immunoprecipitation and Western blot analysis of 293 T cells co-transfected with HIF-1α and Foxp3, in fact, demonstrated a physical interaction between these two molecules (Figure S7A).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“The expression of wild type HIF-1α in the presence of RORγt resulted in significantly increased reporter gene activity over that induced by RORγt alone (Figure 4A).”
§ 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
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In the paper
“T cells were thus cultured with TGF-β and IL-2 under hypoxic conditions. Foxp3+ cells were significantly decreased under these hypoxic conditions relative to normoxia (Figure 5D).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“Foxp3 mRNA levels in WT and HIF-1α −/− T cells stimulated under TH17 skewing conditions were essentially identical (Figure 5A).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“HIF-1α enhances TH17 development through direct transcriptional activation of RORvt, and via tertiary complex formation with RORvt and p300 recruitment to the IL17 promoter, thereby regulating TH17 signature genes.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > Abstract
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“a HIF-1α mutant with a C-terminal deletion of the p300 binding domain (Arany et al., 1996) failed to synergize with RORγt and p300 in the activation of the IL-17A promoter”
§ 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
What the sources say
- Not checked yetcites Arany et al., 1996 source
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In the paper
“Mice with HIF-1α deficient T cells are resistant to induction of TH17-dependent experimental autoimmune encephalitis associated with diminished TH17 and increased Treg cells.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > Abstract
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In the paper
“The HIF-1α binding domain was further mapped to the C-terminus of Foxp3 (Figure S7B)”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“ChIP analysis revealed that HIF-1α was recruited to several other putative RORγt binding regions, including CNS2.”
§ 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
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In the paper
“steady state levels of Foxp3+ cells in the lamina propria of the gut, which, as indicated above (Koch, 2002), is relatively hypoxic, are significantly increased in T-HIF-1−/− mice (Figure S6A–D).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“This binding, as analyzed by ChIP, was specific since no significant signal could be detected at a non-RORγt binding region within the IL-17A promoter.”
§ 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
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In the paper
“In HIF-1α+/+ T cells, retroviral RORγt expression induced a significantly higher proportion of IL-17A+ cells (45.7%) under non-skewing conditions, compared to control retrovirus recipients (0.72%) (Figure 3D and 3E, left panels).”
§ 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
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In the paper
“However, ectopic RORγt expression in HIF-1α−/− T cells induced a strikingly diminished population of IL-17A+ cells (1.33%) (Figure 3E, right panel).”
§ 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
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In the paper
“Only GST fusions of the HIF-1α N-terminus (1–80 aa), but not GST alone or other HIF-1α fragments, successfully pulled down RORγt (Figure 4C).”
§ 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
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In the paper
“ChIP assays revealed that histones H3 and H4 around the IL-17A promoter region were highly acetylated in WT compared to HIF-1−/−T cells under TH17-inducing conditions (Figure 4G).”
§ 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
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In the paper
“a HIF-1α mutant with a characterized DNA binding domain deletion (Arany et al., 1996) showed no defect in inducing reporter gene activity”
§ 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
What the sources say
- Not checked yetcites Arany et al., 1996 source
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In the paper
“Wild type p300, but not Δp300 could synergistically enhance IL-17A promoter activity in the presence of HIF-1α and RORγt (Figure S5E).”
§ 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
“This interaction between HIF-1α and Foxp3 was further confirmed by endogenous co-IP in iTreg cells (Figure 5E).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“We found that, under steady state conditions, T-HIF-1−/− mice had reduced proportions of IL-17A+ cells in the lamina propria (Figure S6A–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
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In the paper
“HIF-1α −/− T cells cultured under Treg conditions also expressed substantially more Foxp3 than did WT T cells (Figure 5B and 5C).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“Importantly this regulation occurs under both normoxic and hypoxic conditions.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > Abstract
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In the paper
“we observed similar co-localized binding of RORγt, HIF-1α and p300 at the promoters of the TH17 signature genes IL-17F and IL-23R (Figure 4E).”
§ 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
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In the paper
“Furthermore, a HIF-1α mutant with a deletion in its p300 binding domain (Arany et al., 1996) fails to activate the IL-17A promoter.”
§ 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
What the sources say
- Not checked yetcites Arany et al., 1996 source
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In the paper
“we detected localized binding of RORγt, HIF-1α and p300 to the IL-17A promoter determined using primers flanking the RORγt-binding site located at the IL-17A promoter region (Figure 4D).”
- Also stated in: § Abstract · plain
“HIF-1α enhances TH17 development through direct transcriptional activation of RORvt, and via tertiary complex formation with RORvt and p300 recruitment to the IL17 promoter, thereby regulating TH17 signature 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
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- Also stated in: § Abstract · plain
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In the paper
“HIF-1α was found to co-immunoprecipitate (co-IP) with RORγt (Figure S4E).”
§ 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
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In the paper
“Similarly, hyper-acetylated histones H3 and H4 were associated with the promoter of TH17 signature genes IL-17F and IL-23R in WT, but not in HIF-1α −/−, TH17 cells (Figure S6E and S6F).”
§ 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
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In the paper
“IL-17A production in Jurkat T cells co-transfected with RORγt, HIF-1α and p300 was further increased under hypoxic conditions (Figure 4F).”
§ 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
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In the paper
“The association between HIF-1α and RORyt was further confirmed by co-IP of endogenous HIF-1α and RORyt in T cells cultured under TH17-skewing conditions (Figure 4B).”
§ 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
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In the paper
“we found that TH17 differentiation is enhanced under hypoxia in a HIF-1α-dependent manner.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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In the paper
“RORγt protein levels remained unchanged upon co-transfection with HIF-1α (Figure S7D).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“At peak disease, lymph node-, spleen- and central nervous system (CNS)-infiltrating CD4+ T cells from WT mice contained higher proportions of IL-17+ cells compared to those of T-HIF-1α −/− mice (Figure 6B and 6C).”
§ 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
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In the paper
“HIF-1α protein is readily detectable in TH17 cells under normoxia”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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In the paper
“WT mice immunized with MOG35–55 developed EAE, while T-HIF-1α −/− mice were highly resistant (Figure 6A).”
- Also stated in: § DISCUSSION · boosted
“Our in vivo findings demonstrate that mice with HIF-1α−/− T cells are resistant to induction of EAE, 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 > RESULTS > Mice with HIF-1α-deficient T cells fail to mount a strong TH17 response, have increased Treg numbers and are resistant to EAE
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In the paper
“the experiments utilizing HIF-1α−/− T cells confirm that under such conditions TH17 differentiation is significantly impaired without HIF-1α.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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In the paper
“Hypoxic culture significantly enhanced both Foxp3 ubiquitination and degradation in these cells (Figure 5I and 5J).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“HIF-1α mediated Foxp3 degradation was completely inhibited in the presence of a proteasome inhibitor (Figure S8B).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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
“Hypoxic culture significantly enhanced both Foxp3 ubiquitination and degradation in these cells (Figure 5I and 5J).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“this ubiquitin-mediated Foxp3 degradation process could be prevented by addition of the proteasomal inhibitor MG132 to iTreg cells under hypoxia.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“T-HIF-1−/− mice showed a significant increase in the percentage of CD4+ Foxp3+ cells during the recovery phase of disease (21 days post-injection), concomitant with a decrease in the proportion of IL-17+ CD4+ cells in T-HIF-1−/−animals (Figure 6D and 6E).”
§ 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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the Foxp3 binding domain in HIF-1α was found to be within the N-terminal 80 amino acids by GST pull-down experiments (Figure S7C).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Knockdown of PHD2 with siRNA also eliminated the ability of wild type HIF-1α to mediate the degradation of Foxp3 (Figure S8A).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Similar co-transfection assays using a HIF-1α plasmid containing an oxygen dependent domain (ODD) deletion (CA5-HIF-1α) further demonstrated that a non-proline hydroxylatable HIF-1α was incapable of mediating Foxp3 degradation (Figure 5G and 5H).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“The expression of P402A and P564A HIF-1α failed to induce Foxp3 degradation (Figure 5G and 5H).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“T-HIF-1−/− mice showed a significant increase in the percentage of CD4+ Foxp3+ cells during the recovery phase of disease (21 days post-injection), concomitant with a decrease in the proportion of IL-17+ CD4+ cells in T-HIF-1−/−animals (Figure 6D and 6E).”
§ 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that neither IFN-y nor IL-4 production was significantly affected by the absence of HIF-1 in T cells cultured under Th1 or Th2 conditions, Respectively.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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In the paper
“upon co-transfection of 293T cells with Foxp3 and increasing amounts of Flag-tagged HIF-1α, Foxp3 protein levels progressively decreased (Figure 5F).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These results support the notion that HIF-1α might facilitate TH17 development through the upregulation of RORγt.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“indicating that the hypoxia-induced enhancement of TH17 differentiation is HIF-1α-dependent.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“indicating that HIF-1α regulates multiple genes in the TH17 program (Figure 2B).”
- Also stated in: § Abstract · plain
“HIF-1α enhances TH17 development through direct transcriptional activation of RORvt, and via tertiary complex formation with RORvt and p300 recruitment to the IL17 promoter, thereby regulating TH17 signature genes.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α positively regulates TH17 development at multiple levels
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In the paper
“These findings confirm that HIF-1α expression is induced in T cells during TH17 differentiation in a Stat3-dependent manner.”
§ 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
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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
“which implies that DNA binding is dispensable for HIF-1α-mediated IL-17A expression.”
§ 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
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“This implies that HIF-1α might be involved in Foxp3 protein modulation in addition to its role in the transcriptional activation of the TH17 pathway.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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In the paper
“Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between T regulatory (Treg) and TH17 differentiation.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > Abstract
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In the paper
“Concurrently, HIF-1α attenuates Treg development by binding Foxp3 and targeting it for proteasomal degradation.”
- Also stated in: § INTRODUCTION · plain
“In addition, HIF-1α inhibits Treg differentiation through an active process that targets Foxp3 protein for degradation.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > Abstract
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- Also stated in: § INTRODUCTION · plain
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
“Foxp3 can in turn bind to the RORγt protein and antagonize its ability to bind DNA, thus pushing T cell differentiation away from the TH17 transcriptional program and towards the Treg lineage.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
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In the paper
“These results suggest that, while active under normoxic conditions, HIF-1α’s ability to promote IL-17A production is indeed modulated by oxygen tension.”
§ 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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
“implying that p300 is required for the full function of RORγt and HIF-1α in the regulation of IL-17A gene expression (Figure S5E).”
§ 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
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In the paper
“p300 possesses histone acetyltransferase (HAT) activity (Thompson et al., 2004).”
§ 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
What the sources say
- Not checked yetcites Thompson et al., 2004 source
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In the paper
“These results collectively indicate that HIF-1α directly transactivates RORγt gene expression.”
- Also stated in: § Abstract · plain
“HIF-1α enhances TH17 development through direct transcriptional activation of RORvt, and via tertiary complex formation with RORvt and p300 recruitment to the IL17 promoter, thereby regulating TH17 signature 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Abstract · plain
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 indicate that RORγt and HIF-1α, through recruitment of p300 to the IL-17A promoter, acetylate histones to “open” the chromatin structure and facilitate gene expression.”
§ 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.
- 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.
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 suggested a direct interaction between the two proteins in vitro.”
§ 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
hedgedcorrelational- 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.
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
“indicating a potential role for HIF-1α in promoting TH17 development in the context of microbial influences.”
§ 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
hedgedconditional- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“TH17 and Treg cells share a common requirement for TGF-p in their differentiation requirements despite expressing distinct transcriptional regulators (RORγt vs. Foxp3 respectively) and demonstrating opposing functions (inflammatory vs. anti-inflammatory)(Bettelli et al., 2006; Dong, 2008; Littman and Rudensky, 2010; Mangan et al., 2006; O'Quinn et al., 2008; Veldhoen et al., 2006).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
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.
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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, hypoxi culture conditions have opposite effects on IL-17 and Foxp3 induction.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
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.
In the paper
“the gut, which is known to be relatively hypoxic under physiologic conditions (Koch, 2002)”
§ 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
What the sources say
- Not checked yetcites Koch, 2002 source
boosted- 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.
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 suggest that under both Treg- and TH17-skewing conditions, HIF-1α down-regulates Foxp3 protein levels despite demonstrating no effect on Foxp3 mRNA levels (Figure 5A).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
hedgeddirect- 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.
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 can regulate RORγt gene expression.”
§ 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.
- 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.
None of the sources cited for this claim have been checked yet.
In the paper
“In response to TGF-β in vitro as well as in vivo, many T cells co-express RORγt and Foxp3 (Veldhoen et al., 2006; Yang et al., 2008a).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > INTRODUCTION
What the sources say
- Not checked yetcites Veldhoen et al., 2006 source
- Not checked yetcites Yang et al., 2008a
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.
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
“Collectively, these in vitro differentiation studies, alongside our transcriptional and biochemical analyses, suggest a model in which HIF-1α is transcriptionally activated via Stat3 signaling in differentiating T cells, resulting in the enhancement of the TH17 genetic program via a RORγt/p300-dependent mechanism and repression of the Treg transcriptional program through induced degradation of Fox”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
hedgeddirect- 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.
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
“Collectively, these results are compatible with a scenario in which HIF-1α mediates Foxp3 degradation via PHD-VHL-Ubiquitin-mediated proteasomal degradation, although future studies are needed to delineate precisely how HIF-1α protein turnover dynamics in T cells modulate Foxp3 levels.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
hedgeddirect- 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.
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
“Collectively, these in vitro differentiation studies, alongside our transcriptional and biochemical analyses, suggest a model in which HIF-1α is transcriptionally activated via Stat3 signaling in differentiating T cells, resulting in the enhancement of the TH17 genetic program via a RORγt/p300-dependent mechanism and repression of the Treg transcriptional program through induced degradation of Fox”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
hedgeddirect- 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.
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
“Collectively, these in vitro differentiation studies, alongside our transcriptional and biochemical analyses, suggest a model in which HIF-1α is transcriptionally activated via Stat3 signaling in differentiating T cells, resulting in the enhancement of the TH17 genetic program via a RORγt/p300-dependent mechanism and repression of the Treg transcriptional program through induced degradation of Fox”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
hedgeddirect- 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.
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 experiments validate the role of HIF-1α identified by our in vitro studies and further suggest the possibility for metabolic modulation of autoimmune diseases.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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.
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
“Specifically, HIF-1α promotes TH17 development through: a) direct transcriptional activation of RORγt, the major TH17 transcription factor, and b) direct collaboration with RORγt to activate TH17 signature genes, such as IL-17A, through mechanisms involving p300 recruitment and histone acetylation.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
boosteddirect- 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.
In the paper
“the lamina propria of the gut, which, as indicated above (Koch, 2002), is relatively hypoxic”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > RESULTS > HIF-1α mediates Foxp3 protein degradation during TH17 development
What the sources say
- Not checked yetcites Koch, 2002 source
hedged- 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.
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
“This altered balance between Treg cells and TH17 cells exactly parallels our in vitro culture studies and suggests that HIF-1α indeed plays a role in modulating the TH17/Treg balance.”
§ 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
hedgedconditional- 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.
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
“Specifically, HIF-1α promotes TH17 development through: a) direct transcriptional activation of RORγt, the major TH17 transcription factor, and b) direct collaboration with RORγt to activate TH17 signature genes, such as IL-17A, through mechanisms involving p300 recruitment and histone acetylation.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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.
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
“HIF-1α inhibits differentiation toward the Treg lineage through a distinct, non-transcriptional mechanism.”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
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.
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
“We show that HIF-1 targets Foxp3 for ubiquitination and proteasomal degradation, using the same ubiquitin ligase system that is responsible for degradation of HIF-1α itself (Figure 7).”
§ Control of TH17/Treg Balance by Hypoxia-inducible Factor 1 > DISCUSSION
boosteddirect- 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. 18
- Probably not a substantial claim. 15
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
“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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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.
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.
- 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.
- 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.
- 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.
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.
- 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. 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.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether 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.
None of the sources cited for this claim have been checked yet.
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.
- 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
“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.
- 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.
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.
- 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.
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.
- 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. 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.
- 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. 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.
- 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.
None of the sources cited for this claim have been checked yet.
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.
- 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. 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.
- 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.
None of the sources cited for this claim have been checked yet.
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.
- 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.
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.
- 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.
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.
- 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.
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.
- 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.
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?
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
“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
“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 5,475
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
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