The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index.
Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa
Open accessAbstract
Recent studies have demonstrated dramatic shifts in metabolic supply-and-demand ratios during inflammation, a process resulting in localized tissue hypoxia within inflammatory lesions (“inflammatory hypoxia”). As part of the adaptive immune response, T cells are recruited to sites of inflammatory hypoxia. Given the profound effects of hypoxia on gene regulation, we hypothesized that T-cell differentiation is controlled by hypoxia. To pursue this hypothesis, we analyzed the transcriptional consequences of ambient hypoxia (1% oxygen) on a broad panel of T-cell differentiation factors. Surprisingly, these studies revealed selective, robust induction of FoxP3, a key transcriptional regulator for regulatory T cells (Tregs). Studies of promoter binding or loss- and gain-of-function implicated hypoxia-inducible factor (HIF)-1α in inducing FoxP3. Similarly, hypoxia enhanced Treg abundance in vitro and in vivo. Finally, Treg-intrinsic HIF-1α was required for optimal Treg function and Hif1a –deficient Tregs failed to control T-cell–mediated colitis. These studies demonstrate that hypoxia is an intrinsic molecular cue that promotes FoxP3 expression, in turn eliciting potent anti-inflammatory mechanisms to limit tissue damage in conditions of reduced oxygen availability.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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 source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“For instance, tumor hypoxia and/or HIFs can attract myeloid-derived suppressor cells (Corzo et al., 2010), regulatory T-cells (Clambey et al., 2012), and tumor-associated macrophages (Doedens et al., 2010;Imtiyaz et al., 2010) with immunosuppressive functions.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Clambey et al., 2012
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Ischemia and reperfusion—from mechanism to translation
Eltzschig, H. K., & Eckle, T. D. L. G. (2011) · Nature Medicine · doi:10.1038/nm.2507 · Cited by 3,468
Self-citationDeaglio, S., Dwyer, K. M., Gao, W., Friedman, D. J., Usheva, A., Erat, A., Chen, J., Enjyoji, K., Linden, J. M., Oukka, M., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062512 · Cited by 2,613
Eltzschig, H. K., & Carmeliet, P. (2011) · New England Journal of Medicine · doi:10.1056/nejmra0910283 · Cited by 2,061
Self-citationTGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function
Zhou, L., Lopes, J. E., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., Shen, Y., Du, J., Rubtsov, Y. P., Rudensky, A. Y., et al. (2008) · Nature · doi:10.1038/nature06878 · Cited by 1,928
Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H. (2011) · Journal of Experimental Medicine · doi:10.1084/jem.20110278 · Cited by 1,803
Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1
Dang, E. V., Barbi, J., Yang, H.-Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H.-R., et al. (2011) · Cell · doi:10.1016/j.cell.2011.07.033 · Cited by 1,595
Regulatory T Cell-Derived Interleukin-10 Limits Inflammation at Environmental Interfaces
Rubtsov, Y. P., Rasmussen, J. P., Chi, E. Y., Fontenot, J., Castelli, L., Ye, X., Treuting, P., Siewe, L., Roers, A., Henderson, W. R., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.02.017 · Cited by 1,586
Foxp3+ follicular regulatory T cells control the germinal center response
Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F., Srivastava, M., Divekar, D. P., Beaton, L., Hogan, J. J., et al. (2011) · Nature Medicine · doi:10.1038/nm.2425 · Cited by 1,292
Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009) · Nature Immunology · doi:10.1038/ni.1731 · Cited by 1,258
Research works printed but not linked: 3
- 10.1056/NEJMra0910283 · DOI · Paper page
- 10.1084/jem.20110278 · DOI · Paper page
- 10.1016/j.cell.2011.07.033 · DOI · Paper page
Cited by
Sorted by citations
Items 201–300 of 561
Targeting the metabolism of tumor-infiltrating regulatory T cells
Wang, Y., Huang, T., Gu, J., & Lu, L. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.06.001 · Cited by 54
Ratcliffe, P. P., & Bishop, T. (2014) · Hypoxia · doi:10.2147/hp.s47598 · Cited by 55
The Inflammatory Tissue Microenvironment in IBD
Colgan, S. P., Curtis, V. F., & Campbell, E. L. (2013) · Inflammatory Bowel Diseases · doi:10.1097/mib.0b013e31828dcaaf · Cited by 52
Self-citationTuccitto, A., Shahaj, E., Vergani, E., Ferro, S., Huber, V., Rodolfo, M., Castelli, C., Rivoltini, L., & Vallacchi, V. (2018) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-018-2477-z · Cited by 54
Giatromanolaki, A. N., Harris, A. L., Banham, A. H., Contrafouris, C., & Koukourakis, M. I. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0756-3 · Cited by 51
Metabolic regulation of intestinal epithelial barrier during inflammation
Colgan, S. P., Curtis, V. F., Lanis, J. M., & Glover, L. E. (2014) · Tissue Barriers · doi:10.4161/21688362.2014.970936 · Cited by 51
Self-citationWang, X., Luo, X., Xiao, R., Liu, X., Zhou, F., Jiang, D., Bai, J., Cui, M., You, L., & Yupei, Z. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02334-4 · Cited by 59
Brose, S. A., Marquardt, A. L., & Golovko, M. Y. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12617 · Cited by 53
Intratumoral hypoxia and mechanisms of immune evasion mediated by hypoxia-inducible factors
Semenza, G. L. (2021) · Physiology · doi:10.1152/physiol.00034.2020 · Cited by 64
Metabolic reprogramming of T regulatory cells in the hypoxic tumor microenvironment
Nair, V. S., Saleh, R., Toor, S. M., Cyprian, F. S., & Elkord, E. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02842-y · Cited by 51
Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy
Mpekris, F., Panagi, M., Charalambous, A., Voutouri, C., & Stylianopoulos, T. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101626 · Cited by 55
The DEL-1/β3 integrin axis promotes regulatory T cell responses during inflammation resolution
Li, X., Colamatteo, A., Kalafati, L., Kajikawa, T., Wang, H., Lim, J., Bdeir, K., Chung, K., Yu, X., Fusco, C., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci137530 · Cited by 50
Determinants of Tissue-Specific Metabolic Adaptation of T Cells
Varanasi, S. K., Kumar, S. V., & Rouse, B. T. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.013 · Cited by 49
“This defective Treg cell migration and survival led to increased protective effector T cell responses within the colon during T cell-mediated colitis (Clambey et al., 2012) and in the brain during glioma (Miska et al.”
BackgroundLin, E., Liu, X., Liu, Y., Zhang, Z., Xie, L., Tian, K., Liu, J., & Yu, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.653358 · Cited by 51
“HIF-1α, which stably exists in the tumor microenvironment, could also facilitate the recruitment of Foxp3 Tregs by a TGFβ-independent mechanism (Figure 3A) (133).”
BackgroundHypoxia‐inducible factors in metabolic reprogramming during sepsis
Vanderhaeghen, T., Vandewalle, J., & Libert, C. (2020) · FEBS Journal · doi:10.1111/febs.15222 · Cited by 47
Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy
Xiao, C., Tian, H., Zheng, Y., Yang, Z., Li, S., Fan, T. T., Xu, J., Bai, G., Liu, J., Deng, Z., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1013885 · Cited by 50
“While under oxygen limitation, HIF-1α can be induced in Tregs, and bind to the promoter region of the FOXP3 to promote transcription (Clambey et al., 2012).”
BackgroundTumour hypoxia in driving genomic instability and tumour evolution
Suvac, A., Ashton, J., & Bristow, R. G. (2025) · Nature reviews. Cancer · doi:10.1038/s41568-024-00781-9 · Cited by 60
Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment
Schito, L. (2018) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00209.2018 · Cited by 49
“Importantly, HIF-1 selectively upregulates FoxP3, a master transcription factor that is essential for TR cell development and function (28, 50, 73) (Fig.”
BackgroundSpatial immune heterogeneity of hypoxia-induced exhausted features in high-grade glioma
Kim, A.-R., Choi, S. J., Park, J., Kwon, M., Chowdhury, T., Yu, H. J., Kim, S., Kang, H., Kim, K.-M., Park, S.-H., et al. (2022) · OncoImmunology · doi:10.1080/2162402x.2022.2026019 · Cited by 48
“Regarding the effect of hypoxia on TREG cells, conflicting results have been reported.(58,59) In the current study, we showed that hypoxia directly increased the frequency of CTLA-4 TREG cells.”
ResultHypoxia in bone metastasis and osteolysis
Todd, V. M., & Johnson, R. W. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.06.004 · Cited by 51
“Culturing T-cells in 1% O2 was found to induce the expression of FOXP3, a key regulator of Treg cell differentiation, in a HIF1α dependent manner [82].”
BackgroundGan, M., Liu, N., Li, W., Chen, M., Bai, Z., Liu, D., & Liu, S. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02193-7 · Cited by 50
Sun, L., Li, T., Tang, H., Yu, K., Ma, Y., Yu, M., Qiu, Y., Xu, P., Xiao, W., & Yang, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00806 · Cited by 47
“Recent studies demonstrated that HIF-1α also played an important role in the regulatory T cells (Tregs) (29, 30).”
BackgroundGong, P.-J., Shao, Y.-C., Huang, S., Zeng, Y., Yuan, X., Xu, J., Yin, W., Wei, L., & Zhang, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.579868 · Cited by 46
“In the presence of hypoxia and TGF-b, CD4+ T cells upregulated Foxp3 through the binding of HIF-1 to the promoter region of Foxp3, which induced the differentiation of Tregs and enhances immunosuppression (39).”
BackgroundTumor Vessel Normalization: A Window to Enhancing Cancer Immunotherapy
Li, S., Zhang, Q., & Hong, Y. (2020) · Technology in Cancer Research & Treatment · doi:10.1177/1533033820980116 · Cited by 52
“In particular, TGF-b reduces T lymphocyte activity and limits the ability of DCs to process tumor-associated antigens.(26,71,72) Furthermore, HIF-1 signaling promotes increased levels of PD-L1 expression by MDSCs, TAMs, DCs, and cancer cells, exerting an immunosuppressive effect on the TME.”
BackgroundRegulatory T Cell Metabolism: A Promising Therapeutic Target for Cancer Treatment?
Kim, J., Li, J., Wei, J., & Lim, S. A. (2025) · Immune Network · doi:10.4110/in.2025.25.e13 · Cited by 45
“Targeting HIF-1 α could disrupt Treg-mediated immunosuppression and enhance immune responses in glioblastoma (37,47).”
Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review
Haibe, Y., Husseini, Z. E., Sayed, R. E., & Shamseddine, A. I. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176176 · Cited by 45
Alpine altitude climate treatment for severe and uncontrolled asthma: An EAACI position paper
Fieten, K. B., Drijver‐Messelink, M. T., Cogo, A., Charpin, D., Sokolowska, M., Agache, I., Taborda‐Barata, L. M., Eguiluz‐Gracia, I., Braunstahl, G. J., Seys, S. F., et al. (2022) · Allergy · doi:10.1111/all.15242 · Cited by 45
“35,36 Hypoxia also alters function of the antigen-presenting cells, especially macrophages and their capacity to stimulate T cells.”
Schmidt, S. K., Ebel, S., Keil, E., Woite, C., Ernst, J. F., Benzin, A. E., Rupp, J., & Däubener, W. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063301 · Cited by 45
“have found a robust HIF1a-dependent induction of FoxP3 and therefore an enhanced abundance of regulatory T cells under hypoxia in vitro and in vivo [38].”
BackgroundIslam, S. M. T., Won, J., Khan, M., Mannie, M. D., & Singh, I. (2021) · Immunology · doi:10.1111/imm.13335 · Cited by 45
Iannitti, R. G., Casagrande, A., LUCA, A. D., Cunha, C., Sorci, G., Riuzzi, F., Borghi, M., Galosi, C., Massi-Benedetti, C., Oury, T. D., et al. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201305-0986oc · Cited by 43
“Thus, it is not surprising that hypoxia enhanced FoxP3(1) regulatory T-cells abundance and function to limit tissue damage in conditions of reduced oxygen availability (21).”
BackgroundA Window of Opportunity: Targeting Cancer Endothelium to Enhance Immunotherapy
Duru, G., van Egmond, M., & Heemskerk, N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.584723 · Cited by 44
“Hypoxic zones in tumors also attract MDSCs (21, 51, 52), tumor associated macrophages (TAMs) (22, 53) and regulatory T cells (Treg cells) (23, 54).”
BackgroundHypoxia-inducible factor as a bridge between healthy barrier function, wound healing, and fibrosis
Steiner, C. A., Cartwright, I. M., Taylor, C. T., & Colgan, S. P. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00227.2022 · Cited by 45
Self-citationYero, A., Bouassa, R. M., Ancuța, P., Estaquier, J., & Jenabian, M.-A. (2023) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2023.01.001 · Cited by 43
Burgers, F. H., van der Mijn, J. C., Seijkens, T. T. P., Jedema, I., Bex, A., & Haanen, J. B. A. G. (2025) · Nature Reviews Nephrology · doi:10.1038/s41581-025-00983-w · Cited by 49
Regulatory T Cells in Kidney Transplantation: New Directions?
Braza, F., Durand, M., Degauque, N., & Brouard, S. (2015) · American Journal of Transplantation · doi:10.1111/ajt.13395 · Cited by 44
“Foxp3 expression is enhanced under hypoxic conditions in a HIF1a-dependent manner (121).”
BackgroundHypoxia-inducible factor 1α plays a predominantly negative role in regulatory T cell functions
Hsu, T.-S., & Lai, M. (2018) · Journal of Leukocyte Biology · doi:10.1002/jlb.mr1217-481r · Cited by 43
Nagai, K., Ideguchi, H., Kajikawa, T., Li, X., Chavakis, T., Cheng, J., Messersmith, P. B., Heber‐Katz, E., & Hajishengallis, G. (2020) · The FASEB Journal · doi:10.1096/fj.202001248r · Cited by 40
Manipulating T-cell metabolism to enhance immunotherapy in solid tumor
Chen, C., Wang, Z., Ding, Y., & Qin, Y. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1090429 · Cited by 43
“However, there are contradictory views whether HIF-1a restrains Treg cell differentiation or prompt their immunosuppressive function in vivo (79, 80).”
BackgroundFoxP3, Helios, and SATB1: Roles and relationships in regulatory T cells
Grzanka, J., Leveson-Gower, D. B., Gołąb, K., Wang, X., Marek-Trzonkowska, N. M., Krzystyniak, A., Wardowska, A., Mills, J. M., Trzonkowski, P., & Witkowski, P. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.02.004 · Cited by 42
“Analysis of hypoxia-inducible factor (HIP)-1α demonstrated that it promotes FoxP3 expression, as an anti-inflammatory mechanism preventing tissue damage in low oxygen availability conditions [49].”
BackgroundNovak, S., Drenjančević, I., Vuković, R., Kellermayer, Z., Ćosić, A., Levak, M. T., Balogh, P., Čulo, F., & Mihalj, M. (2016) · Mediators of Inflammation · doi:10.1155/2016/7141430 · Cited by 41
Sox7 promotes high-grade glioma by increasing VEGFR2-mediated vascular abnormality
Kim, I., Kim, K., Lee, E., Oh, D. S., Park, C. S., Park, S., Yang, J. M., Kim, J.-H., Kim, H.-S., Shima, D. T., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20170123 · Cited by 40
“Several studies have reported that hypoxia and glucose shortage can exacerbate immune suppression in tumors (Clambey et al., 2012; Barsoum et al., 2014).”
Perspectives on Hypoxia Signaling in Tumor Stroma
Zhang, Y., Coleman, M., & Brekken, R. A. (2021) · Cancers · doi:10.3390/cancers13123070 · Cited by 39
Kheshtchin, N., & Hadjati, J. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30643 · Cited by 42
“Surprisingly, the addition of IL‐6 favors Th17 polarization due to the induction of Th17‐related transcription factor, ROR‐related orphan receptor γt (RORγt), and the proteasomal degradation of Foxp3 (Clambey et al., 2012; Dang et al., 2011).”
BackgroundMetabolic advantages of regulatory T cells dictated by cancer cells
Kondo, M., Kumagai, S., & Nishikawa, H. (2023) · International Immunology · doi:10.1093/intimm/dxad035 · Cited by 42
Immunometabolism of regulatory T cells in cancer
Saravia, J., & Chi, H. (2025) · Oncogene · doi:10.1038/s41388-025-03458-1 · Cited by 45
Hypoxia enhances indoleamine 2,3-dioxygenase production in dendritic cells
Song, X. H., Zhang, Y., Zhang, L., Song, W., & Shi, L. (2018) · Oncotarget · doi:10.18632/oncotarget.24098 · Cited by 40
“In contrast to effector T cells, CD4+CD25+ regulatory T cell potency is reportedly enhanced under hypoxic conditions [27, 28].”
BackgroundMechanisms of TREG cell adaptation to inflammation
Alvarez, F., Al-Aubodah, T.-A., Yang, Y. H., & Piccirillo, C. A. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1mr0120-196r · Cited by 41
T Lymphocyte Exhaustion During Human and Experimental Visceral Leishmaniasis
Costa-Madeira, J. C., Trindade, G. B., Almeida, P. H. P., Silva, J. S., & Carregaro, V. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.835711 · Cited by 40
“The FOXP3 gene promoter in HIF1-a Tregs fails to protect the animal from colitis caused by effector T cells, further demonstrating the role of HIF1-a in the suppressive functions of Tregs (109, 112).”
BackgroundRegulatory Cells and Transplantation TolerancePreprint
Cobbold, S. P., & Waldmann, H. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a015545 · Cited by 38
The Interplay between T Cells and Cancer: The Basis of Immunotherapy
Chen, C., Liu, X., Chang, C., Wang, H. Y., & Wang, R. (2023) · Genes · doi:10.3390/genes14051008 · Cited by 42
Giudice, A., Crispo, A., Grimaldi, M., Polo, A., Bimonte, S., Capunzo, M., Amore, A., D'Arena, G. F., Cerino, P., Budillon, A., et al. (2018) · Molecules · doi:10.3390/molecules23061308 · Cited by 40
“Specifically, these authors demonstrated that hypoxia increases the abundance and function of Tregs by stimulating Foxp3 expression without acting on the pre-existing Tregs and that HIF-1α suppresses inflammation and tissue damage in conditions of reduced oxygen availability [107].”
BackgroundCopper-Fructose Interactions: A Novel Mechanism in the Pathogenesis of NAFLD
Song, M., Vos, M. B., & McClain, C. J. (2018) · Nutrients · doi:10.3390/nu10111815 · Cited by 40
“HIF-1 is a transcription factor which plays a central role in the protection of gut barrier function in multiple ways, including transcriptional regulation of tight junction protein expression [179,180], induction of Tregs activation [181], and differentiation via transcriptional regulation of FoxP3 [182].”
BackgroundHypoxia-inducible factor-1α: a promising therapeutic target for autoimmune diseases
Guan, S., Leng, R., Tao, J.-H., Li, X.-P., Ye, D., Olsen, N. J., Zheng, S. G., & Pan, H. (2017) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2017.1336539 · Cited by 43
“[60] verified that under hypoxic condition, hypoxia increased Treg relative abundance in vitro and in”
BackgroundRegulatory T Cell Metabolism in the Hepatic Microenvironment
Wawman, R. E., Bartlett, H., & Oo, Y. H. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01889 · Cited by 40
“HIF-1α-deficient Treg cells fail to control T-cell-mediated colitis (84).”
BackgroundOxygen-dependent regulation of immune checkpoint mechanisms
Ohta, A. (2018) · International Immunology · doi:10.1093/intimm/dxy038 · Cited by 38
Li, Y., Wang, J., Ma, Y., Du, W., Feng, K., & Wang, S. (2021) · Journal of Cellular Physiology · doi:10.1002/jcp.30027 · Cited by 39
“Moreover, existing studies have documented that the transcription factor HIF1α facilitates the expression of forkhead box P3 (FOXP3) in T cells leading to potent anti‐ inflammatory mechanisms to limit tissue damage (Clambey et al., 2012).”
BackgroundModulating T regulatory cells in cancer: how close are we?
Banerjee, A., Vasanthakumar, A., & Grigoriadis, G. (2013) · Immunology and Cell Biology · doi:10.1038/icb.2013.12 · Cited by 38
Adenosine A2A receptor (A2AR) is a fine-tune regulator of the collagen1:collagen3 balance
Pérez‐Aso, M., Mediero, A., & Cronstein, B. N. (2013) · Purinergic Signalling · doi:10.1007/s11302-013-9368-1 · Cited by 37
Oxygen sensing in intestinal mucosal inflammation
Flück, K., & Fandrey, J. (2015) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-015-1722-4 · Cited by 36
Kouidhi, S., Noman, M. Z., Kiéda, C., Elgaaïed, A. B., & Chouaïb, S. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00114 · Cited by 39
“Moreover, under hypoxic conditions, TCR activation results in an increase in FOXP3 on CD4 T cells in a TGF-β-dependent manner, thereby impacting the differentiation toward Tregs (39).”
BackgroundInfluentialCell Intrinsic and Systemic Metabolism in Tumor Immunity and Immunotherapy
Coleman, M. F., Cozzo, A. J., Pfeil, A. J., Etigunta, S. K., & Hursting, S. D. (2020) · Cancers · doi:10.3390/cancers12040852 · Cited by 37
Immunologic Consequences of Hypoxia during Critical Illness
Kiers, H. D., Scheffer, G., van der Hoeven, J. G., Eltzschig, H. K., Pickkers, P., & Kox, M. (2016) · Anesthesiology · doi:10.1097/aln.0000000000001163 · Cited by 37
Self-citationSurvival of the fittest: Cancer challenges T cell metabolism
Franchina, D. G., HeFeng, F. Q., & Brenner, D. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.10.014 · Cited by 34
Frias, A. B., Hyzny, E. J., Buechel, H. M., Beppu, L. Y., Xie, B., Jurczak, M. J., & D’Cruz, L. M. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900358 · Cited by 34
“Hif1a has previously been described as upregulated in adipocytes under HFD conditions (27, 28), presumably to influence survival under increasing hypoxic conditions, and its expression is also associated with induction of Foxp3, increasing abundance and function of Tregs (29).”
BackgroundHIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?
Gaete, D., Rodriguez, D., Watts, D., Sormendi, S., Chavakis, T., & Wielockx, B. (2021) · Cancers · doi:10.3390/cancers13050988 · Cited by 35
“Moreover, a hypoxic environment increases HIF1α-induced expression of the distinct Treg marker and master regulator forkhead box P3 (Foxp3) [82,83].”
BackgroundStudy on hypoxia-inducible factor and its roles in immune system
Kiani, A. A., Elyasi, H., Ghoreyshi, S., Nouri, N., Safarzadeh, A., & Nafari, A. (2021) · Immunological Medicine · doi:10.1080/25785826.2021.1910187 · Cited by 38
HIF-1α modulates sex-specific Th17/Treg responses during hepatic amoebiasis
Groneberg, M., Hoenow, S., Marggraff, C., Fehling, H., Metwally, N. G., Hansen, C. S., Bruchhaus, I., Tiegs, G., Sellau, J., & Lotter, H. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.09.020 · Cited by 38
Danese, S., Levesque, B. G., Feagan, B. G., Jucov, A., Bhandari, B. R., Pai, R. K., Meadows, K. T., Kirby, B. J., Bruey, J., Olson, A. D., et al. (2022) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.16753 · Cited by 34
Peréz-Chanona, E., Mühlbauer, M., & Jobin, C. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2014.07.014 · Cited by 33
The Impact of Smoking on Sentinel Node Metastasis of Primary Cutaneous Melanoma
Jones, M. S., Jones, P. C., Stern, S. L., Elashoff, D. A., Hoon, D. S. �., Thompson, J. F., Mozzillo, N., Nieweg, O. E., Noyes, D. R., Hoekstra, H. J., et al. (2017) · Annals of Surgical Oncology · doi:10.1245/s10434-017-5775-9 · Cited by 34
Mirlekar, B. (2020) · Immunology Letters · doi:10.1016/j.imlet.2020.03.007 · Cited by 36
Metabolic profiles of regulatory T cells in the tumour microenvironment
Rao, D., Verburg, F., Renner, K., Peeper, D. S., Lacroix, R., & Blank, C. U. (2021) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-021-02881-z · Cited by 43
Mitochondrial dysfunctions in T cells: focus on inflammatory bowel disease
Lee, H., Jeon, J., & Kim, E. S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1219422 · Cited by 33
Hyperbaric oxygen therapy ameliorates TNBS-induced acute distal colitis in rats
Parra, R. S., Lopes, A. H., Carreira, E. U., Feitosa, M. R., Cunha, F. Q., Garcia, S. B., Cunha, T. M., da Rocha, J. J. R., & Féres, O. (2015) · Medical Gas Research · doi:10.1186/s13618-015-0026-2 · Cited by 32
“In the context of inflammatory diseases, hypoxia has been shown to activate multiple inflammatory mechanisms that are associated with inflammation [8].”
BackgroundFungal Colonization and Infections—Interactions with Other Human Diseases
Mahalingam, S. S., Jayaraman, S., & Pandiyan, P. (2022) · Pathogens · doi:10.3390/pathogens11020212 · Cited by 34
“Moreover, HIF-1α is known to regulate FOXP3+-regulatory-T-cell (Treg) differentiation and accumulation [81,82].”
BackgroundHIF-1α- and hypoxia-dependent immune responses in human CD4+CD25high T cells and T helper 17 cells
Bollinger, T., Gies, S. E., Naujoks, J., Feldhoff, L., Bollinger, A., Solbach, W., & Rupp, J. (2014) · Journal of Leukocyte Biology · doi:10.1189/jlb.3a0813-426rr · Cited by 33
“[29] described a correlation between HIF-1 and/or Hox and increased FOXP3 levels in the murine system.”
BackgroundResultHypoxic culture conditions enhance the generation of regulatory T cells
Neildez‐Nguyen, T. M. A., Bigot, J., Rocha, S. D., Corre, G., Boisgérault, F., Páldi, A., & Galy, A. H. M. (2014) · Immunology · doi:10.1111/imm.12388 · Cited by 36
Singh, Y., Garden, O. A., Lang, F., & Cobb, B. S. (2016) · Immunology · doi:10.1111/imm.12631 · Cited by 37
Immune consequences of exercise in hypoxia: A narrative review
Burtscher, J., Pasha, Q., Chanana, N., Millet, G. P., Burtscher, M., & Strasser, B. (2023) · Journal of sport and health science/Journal of Sport and Health Science · doi:10.1016/j.jshs.2023.09.007 · Cited by 34
Zhang, T., Lv, Q., & Jin, W. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189137 · Cited by 36
Systemic silencing of Phd2 causes reversible immune regulatory dysfunction
Yamamoto, A., Hester, J., Macklin, P. S., Kawai, K., Uchiyama, M., Biggs, D., Bishop, T., Bull, K. R., Cheng, X., Cawthorne, E., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124099 · Cited by 31
Endogenous antisense RNA curbs CD39 expression in Crohn’s disease
Harshe, R. P., Xie, A., Vuerich, M., Frank, L. A., Gromová, B., Zhang, H., Robles, R. J., Mukherjee, S., Csizmadia, E., Kokkotou, E. G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19692-y · Cited by 31
Liu, Z., Tang, Q., Qi, T., Othmane, B., Yang, Z., Chen, J., Hu, J., & Zu, X. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.725223 · Cited by 34
“Hypoxia upregulates the infiltration levels of Treg cells by increasing the expression of the FOXP3 transcription factor, TGF-b, and CCL28, which may inhibit the anti-cancer immune responses (41, 42).”
BackgroundLi, Z., Deng, Y., Sun, H., Tan, C., Li, H., Mo, F., Wang, Y., Li, J., Zhou, Z., & Sun, M. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.05.013 · Cited by 30
Increased expression of surface CD44 in hypoxia-DCs skews helper T cells toward a Th2 polarization
Yang, M., Liu, Y., Ren, G., Shao, Q., Gao, W., Sun, J., Wang, H., Ji, C., Li, X., Zhang, Y., et al. (2015) · Scientific Reports · doi:10.1038/srep13674 · Cited by 29
Ning, F., Takeda, K., Schedel, M., Domenico, J. M., Joetham, A., & Gelfand, E. W. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.11.049 · Cited by 30
Regulatory T Cells in the Tumor Microenvironment
Dadey, R., Workman, C. J., & Vignali, D. A. A. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-49270-0_6 · Cited by 32
Xiao, J., Guo, X., & Wang, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1385907 · Cited by 31
Regulatory T Cell Metabolism in Atherosclerosis
Baardman, J., & Lutgens, E. (2020) · Metabolites · doi:10.3390/metabo10070279 · Cited by 32
“Hypoxic conditions were found to promote the expression of Foxp3 in T cells [72,73].”
BackgroundRiaz, F., Wei, P. Y., & Pan, F. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.949603 · Cited by 31
“HIF-1α plays a vital role in enhancing the population and suppressive roles of thymic Treg (Ben-Shoshan et al., 2008; Clambey et al., 2012) by directly binding the promoter region”
BackgroundPositron emission tomography imaging sheds new light on hypoxia and antitumor therapies
Fang, H., Wang, X., Lan, X., & Jiang, D. (2023) · Interdisciplinary medicine · doi:10.1002/inmd.20230002 · Cited by 29
Metabolism of T Lymphocytes in Health and Disease
Gaber, T., Chen, Y., Krauß, P.-L., & Buttgereit, F. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.06.002 · Cited by 32
Shafqat, A., Omer, M. H., Ahmed, E. N., Mushtaq, A. H., Ijaz, E., Ahmed, Z., AlKattan, K. M., & Yaqinuddin, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1200941 · Cited by 32
“The upregulation of HIF-1a in naïve T-cells favors Treg differentiation (57) and indirectly augments Treg recruitment through CCL28 and TGF-b production in the TME (58, 59).”
BackgroundImmune regulation by protein ubiquitination: roles of the E3 ligases VHL and Itch
Aki, D., Li, Q., Li, H., Liu, Y., & Lee, J. H. (2018) · Protein & Cell · doi:10.1007/s13238-018-0586-8 · Cited by 27
Wang, S., Kuang, Y., Liang, L., Sun, B., Zhao, X., Zhang, L., & Chang, Y. (2021) · Scientific Reports · doi:10.1038/s41598-021-84652-5 · Cited by 28
Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy
Gao, R., Shi, G., & Wang, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.833667 · Cited by 29
Chen, Q., Cui, K., Zhao, Z., Xu, X., Liu, Y., Shen, Y., Chen, F., Mai, K., & Ai, Q. (2022) · The FASEB Journal · doi:10.1096/fj.202200256r · Cited by 28
Chen, L., Yang, J., Zhang, M., Fu, D., Luo, H., & Yang, X. (2023) · Cytokine · doi:10.1016/j.cyto.2022.156107 · Cited by 28
Bowker, R. M., Yan, X., Managlia, E. Z., Liu, S. X. L., Marek, C., Tan, X., & Plaen, I. G. D. (2017) · Pediatric Research · doi:10.1038/pr.2017.219 · Cited by 28
“Although the role of HIFs in neonatal NEC is not well understood, there is accumulating evidence that hypoxia-induced changes in HIF-mediated genes are important in intestinal diseases characterized by ischemia and inflammation (33,34).”
BackgroundImmunotherapeutic Targeting of Tumor-Associated Blood Vessels
Fabian, K. P., & Storkus, W. J. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-67577-0_13 · Cited by 29
Metadata
- Authors
- Clambey, E. T., McNamee, E. N., Westrich, J. A., Glover, L. E., Campbell, E. L., Jedlicka, P., de Zoeten, E. F., Cambier, J. C., Stenmark, K. R., Colgan, S. P., & Eltzschig, H. K.
- Affiliations
- Mucosal Inflammation Program,
- Department of Anesthesiology, Departments of bMedicine,
- Pathology, and
- Pediatrics and Genetics (US)
- Integrated Department of Immunology, and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-09-17
- Volume
- 109
- Issue
- 41
- Pages
- E2784-93
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3478644
- OpenAlex
- W1986925527
- Cited by
- 560
- References
- 71
- Citations by year
- 2026: 28 · 2025: 31 · 2024: 35 · 2023: 43 · 2022: 60 · 2021: 49 · 2020: 62 · 2019: 44 · 2018: 39 · 2017: 35 · 2016: 38 · 2015: 35 · 2014: 34 · 2013: 25 · 2012: 2
- FWCI
- 13.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Maynooth University ePrints and eTheses Archive (Maynooth University) (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL60569, R01HL060569, R01HL098294, R01HL092188, R01‑HL0921)
- National Institute of Diabetes and Digestive and Kidney Diseases (R0-1 DK50189, R01DK050189, R37DK050189, R01DK083385, R01DK095491)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- hypoxia-inducible factor-1α, Foxp3, regulatory T cells, mucosal inflammation, T cell differentiation, transcriptional regulation, T cell-mediated colitis, anti-inflammatory mechanism, oxygen availability
- MeSH terms
- Animals, Hypoxia, Cells, Cultured, Colitis, Female, Flow Cytometry, Gene Expression Regulation, Humans, Inflammation, Interleukin-1, Intestinal Mucosa, Male, Mice, Inbred C57BL, Mice, Transgenic, Cell Hypoxia, Transforming Growth Factor beta, Mice, Knockout, Jurkat Cells, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Forkhead Transcription Factors
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.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
