Cell
Volume 146, Issue 5, 2 September 2011, Pages 772-784
Journal home page for Cell

Article
Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1

https://doi.org/10.1016/j.cell.2011.07.033Get rights and content
Under an Elsevier user license
open archive

Summary

T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (Treg) and TH17 differentiation. HIF-1 enhances TH17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating TH17 signature genes. Concurrently, HIF-1 attenuates Treg development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of TH17-dependent experimental autoimmune encephalitis associated with diminished TH17 and increased Treg cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.

Highlights

► HIF-1 is induced by TH17 promoting signals in a Stat3-dependent manner ► HIF-1 cooperates with RORγt, Stat3, and p300 to drive transcription of TH17 genes ► HIF-1 negatively regulates Treg development by mediating Foxp3 protein degradation ► In vitro and in vivo TH17 differentiation is deficient in T cells lacking HIF-1

Cited by (0)

9

These authors contributed equally to this work