Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa

Eric T. Clambey*, Eóin N. McNamee, Joseph A. Westrich, Louise E. Glover, Eric L. Campbell, Paul Jedlicka, Edwin F. De Zoeten, John C. Cambier, Kurt R. Stenmark, Sean P. Colgan, Holger K. Eltzschig

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

308 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)E2784-E2793
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number41
DOIs
Publication statusPublished - 09 Oct 2012
Externally publishedYes

Keywords

  • Lymphocyte
  • Metabolism
  • TGF-beta

ASJC Scopus subject areas

  • General

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