HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells
Open accessAbstract
Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory TH17 and Foxp3-expressing regulatory T cells (Treg cells) and controls cell fate determination. TH17 but not Treg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited TH17 development while promoting Treg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in TH17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between TH17 and Treg cells. Lack of HIF1α resulted in diminished TH17 development but enhanced Treg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.
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Genetic defects in the human IL-17/IL-17-receptor axis, STAT3, or RORγt that cause dysfunctional Th17 cells are associated with chronic mucocutaneous candidiasis and severe disease after BCG immunization.
“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 [67]
TH17 cell development is promoted by HIF-1α, which regulates glycolytic gene expression in TH17 cells.
“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 [35]
Blocking glycolysis during TH17 cell differentiation reduces TH17 development and favors Treg formation.
“Blocking glycolysis during TH17 cell differentiation reduced the development of TH17 cells and favored the formation of Tregs (35).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [35]
Loss of HIF-1α impairs TH17 expansion and induction of experimental autoimmune encephalitis.
“Loss of HIF-1α impairs TH17 expansion and induction of experimental autoimmune encephalitis (35)”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [35]
Different subsets of T cells and different stages following T cell activation are characterized by the use of different metabolic pathways.
“Different subsets of T cells, as well as different stages following T cell activation, are characterized by the use of different metabolic pathways [97, 108, 109].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [97]
T cells lacking Hif-1α have impaired Th17 differentiation and increased production of Tregs.
“T cells lacking Hif-1α had impaired Th17 differentiation and increased production of Tregs.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [97]
Hif-1α promotes production of pro-inflammatory Th17 cells while simultaneously limiting generation of Tregs.
“two recent reports identified an alternative role for Hif-1α in T cell differentiation in promoting the production of pro-inflammatory Th17 cells while simultaneously limiting the generation of Tregs [71, 97].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [97]
Hif-1α is required for the induction of experimental autoimmune encephalitis, a Th17-driven murine model of autoimmunity.
“both groups showed that Hif-1α was required for the induction of experimental autoimmune encephalitis, a Th17-driven murine model of autoimmunity.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [97]
Hif-1α can play an important role in promoting optimal metabolism in Th17 differentiation.
“it is clear that Hif-1α can play an important role in promoting optimal metabolism in the case of Th17 differentiation [97].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [97]
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- Authors
- Shi, L. Z., Wang, R., Huang, G., Vogel, P., Neale, G., Green, D. R., & Chi, H.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Green, Douglas R.
- Chi, Hongbo
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2011-06-27
- Volume
- 208
- Issue
- 7
- Pages
- 1367-1376
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3135370
- OpenAlex
- W2162873738
- Cited by
- 1,803
- References
- 36
- Citations by year
- 2026: 129 · 2025: 112 · 2024: 125 · 2023: 136 · 2022: 163 · 2021: 148 · 2020: 146 · 2019: 144 · 2018: 127 · 2017: 114 · 2016: 119 · 2015: 89 · 2014: 85 · 2013: 72 · 2012: 70
- FWCI
- 35.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- American Lebanese Syrian Associated Charities
- National Institutes of Health (AI44828)
- National Institute of General Medical Sciences (R37GM052735, R01GM052735, GM-52735)
- National Institute of Allergy and Infectious Diseases (R01AI044828, R01AI040646, AI47891, AI40646, AI44828, R01AI047891)
- National Institute of Neurological Disorders and Stroke (NS064599, R01NS064599)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR053573, AR053573)
- 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-1α, glycolysis, T cell metabolism, Th17 cell differentiation, regulatory T cells, Foxp3, mTOR signaling, hypoxia, autoimmune neuroinflammation, T cell energy metabolism
- MeSH terms
- Animals, Base Sequence, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Glycolysis, Mice, Inbred C57BL, Mice, Transgenic, Signal Transduction, Gene Expression, DNA Primers, T-Lymphocytes, Regulatory, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Forkhead Transcription Factors, Th17 Cells, TOR Serine-Threonine Kinases
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