[HTML][HTML] Control of TH17/Treg balance by hypoxia-inducible factor 1

EV Dang, J Barbi, HY Yang, D Jinasena, H Yu… - Cell, 2011 - cell.com
EV Dang, J Barbi, HY Yang, D Jinasena, H Yu, Y Zheng, Z Bordman, J Fu, Y Kim, HR Yen
Cell, 2011cell.com
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 (T reg) and TH 17 differentiation. HIF-1 enhances TH 17
development through direct transcriptional activation of RORγt and via tertiary complex
formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating TH 17 …
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.
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