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

SummaryT 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.

Graphical AbstractFigure optionsDownload high-quality image (335 K)Download as PowerPoint slideHighlights
► 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