HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

Lewis Z. Shi, Ruoning Wang, Gonghua Huang, Peter Vogel, Geoffrey Neale, Douglas R. Green, Hongbo Chi

Research output: Contribution to journalArticle

743 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1367-1376
Number of pages10
JournalJournal of Experimental Medicine
Volume208
Issue number7
DOIs
StatePublished - Jul 4 2011

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Hypoxia-Inducible Factor 1
Regulatory T-Lymphocytes
Glycolysis
T-Lymphocytes
Th17 Cells
Enzyme Induction
Cell Lineage
Energy Metabolism
Cell Differentiation
Transcription Factors
Up-Regulation
Cell Proliferation
Antigens
Growth

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. / Shi, Lewis Z.; Wang, Ruoning; Huang, Gonghua; Vogel, Peter; Neale, Geoffrey; Green, Douglas R.; Chi, Hongbo.

In: Journal of Experimental Medicine, Vol. 208, No. 7, 04.07.2011, p. 1367-1376.

Research output: Contribution to journalArticle

Shi, Lewis Z. ; Wang, Ruoning ; Huang, Gonghua ; Vogel, Peter ; Neale, Geoffrey ; Green, Douglas R. ; Chi, Hongbo. / HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 7. pp. 1367-1376.
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