[PDF][PDF] E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T cell stability and suppressive capacity

JH Lee, C Elly, Y Park, YC Liu - Immunity, 2015 - cell.com
JH Lee, C Elly, Y Park, YC Liu
Immunity, 2015cell.com
Summary Foxp3+ regulatory T (Treg) cells play a critical role in immune homeostasis;
however, the mechanisms to maintain their function remain unclear. Here, we report that the
E3 ubiquitin ligase VHL is essential for Treg cell function. Mice with Foxp3-restricted VHL
deletion displayed massive inflammation associated with excessive Treg cell interferon-γ
(IFN-γ) production. VHL-deficient Treg cells failed to prevent colitis induction, but converted
into Th1-like effector T cells. VHL intrinsically orchestrated such conversion under both …
Summary
Foxp3+ regulatory T (Treg) cells play a critical role in immune homeostasis; however, the mechanisms to maintain their function remain unclear. Here, we report that the E3 ubiquitin ligase VHL is essential for Treg cell function. Mice with Foxp3-restricted VHL deletion displayed massive inflammation associated with excessive Treg cell interferon-γ (IFN-γ) production. VHL-deficient Treg cells failed to prevent colitis induction, but converted into Th1-like effector T cells. VHL intrinsically orchestrated such conversion under both steady and inflammatory conditions followed by Foxp3 downregulation, which was reversed by IFN-γ deficiency. Augmented hypoxia-inducible factor 1α (HIF-1α)-induced glycolytic reprogramming was required for IFN-γ production. Furthermore, HIF-1α bound directly to the Ifng promoter. HIF-1α knockdown or knockout could reverse the increased IFN-γ by VHL-deficient Treg cells and restore their suppressive function in vivo. These findings indicate that regulation of HIF-1α pathway by VHL is crucial to maintain the stability and suppressive function of Foxp3+ T cells.
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