HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T _H17 and T _reg cells

Abstract

HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of T _H17 and T _reg cells.

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 _H17 and Foxp3-expressing regulatory T cells (T _reg cells) and controls cell fate determination. T _H17 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 _H17 development while promoting T _reg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in T _H17 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 _H17 and T _reg cells. Lack of HIF1α resulted in diminished T _H17 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 _H17 and T _reg cells.

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (hwp): jem

Title: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 4 July 2011

Volume: 208

Issue: 7

Pages: 1367-1376

Affiliations

[1 ]Department of Immunology , [2 ]Department of Pathology , and [3 ]Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital, Memphis, TN 38105

Author notes

CORRESPONDENCE Douglas R. Green: douglas.green@ 123456stjude.org OR Hongbo Chi: chi@ 123456stjude.org

L.Z. Shi and R. Wang contributed equally to this paper.

Article

Publisher ID: 20110278

DOI: 10.1084/jem.20110278

PMC ID: 3135370

PubMed ID: 21708926

SO-VID: ff5ae6f5-7a0b-4aca-af14-31caf8aeda57

Copyright statement: © 2011 Shi et al.

License:

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Product

Categories

Subject: Brief Definitive Report