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PMID: 21708926 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells.

The Journal of experimental medicine ·Vol. 208 ·No. 7 ·2011-07-04 ·Pages 1367-76

Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H

Abstract

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 T(H)17 and Foxp3-expressing regulatory T cells (T(reg) cells) and controls cell fate determination. T(H)17 but not T(reg) cell-inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited T(H)17 development while promoting T(reg) cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in T(H)17 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 T(H)17 and T(reg) cells. Lack of HIF1α resulted in diminished T(H)17 development but enhanced T(reg) cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T(H)17 and T(reg) cells.

MeSH Terms
Animals Base Sequence Cell Differentiation/genetics,physiology DNA Primers/genetics Encephalomyelitis, Autoimmune, Experimental/genetics,metabolism,prevention & control Forkhead Transcription Factors/metabolism Gene Expression Glycolysis/genetics,physiology Hypoxia-Inducible Factor 1, alpha Subunit/deficiency,genetics,metabolism Mice Mice, Inbred C57BL Mice, Transgenic Signal Transduction T-Lymphocytes, Regulatory/cytology,metabolism TOR Serine-Threonine Kinases/metabolism Th17 Cells/cytology,metabolism
Chemicals
DNA Primers Forkhead Transcription Factors Foxp3 protein, mouse Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit mTOR protein, mouse TOR Serine-Threonine Kinases
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Shi Lewis Z
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Wang Ruoning
Huang Gonghua
Vogel Peter
Neale Geoffrey
Green Douglas R
Chi Hongbo
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20110278
Published
2011-07-04
Epub
2011-00-27
Pages
1367-76
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC3135370
Subset
IM
Grants
NIAID NIH HHS · AI44828 · United States
NIAID NIH HHS · R01 AI047891 · United States
NINDS NIH HHS · NS064599 · United States
NIGMS NIH HHS · R37 GM052735 · United States
NIAID NIH HHS · AI40646 · United States
NIGMS NIH HHS · GM52735 · United States
NINDS NIH HHS · R01 NS064599 · United States
NIAID NIH HHS · R01 AI044828 · United States
NIAID NIH HHS · AI47891 · United States
NIAID NIH HHS · R01 AI040646 · United States
NIGMS NIH HHS · R01 GM052735 · United States
NIAMS NIH HHS · K01 AR053573 · United States
NIAMS NIH HHS · AR053573 · United States
Corrections
CommentIn
PMID: 21785454
External Links
PubMed source DOI: 10.1084/jem.20110278 PMC Full Text View journal details
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