E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1? to Maintain Regulatory T Cell Stability and Suppressive Capacity.

ABSTRACT: 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-? (IFN-?) 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-? deficiency. Augmented hypoxia-inducible factor 1? (HIF-1?)-induced glycolytic reprogramming was required for IFN-? production. Furthermore, HIF-1? bound directly to the Ifng promoter. HIF-1? knockdown or knockout could reverse the increased IFN-? by VHL-deficient Treg cells and restore their suppressive function in vivo. These findings indicate that regulation of HIF-1? pathway by VHL is crucial to maintain the stability and suppressive function of Foxp3(+) T cells.

SUBMITTER: Lee JH 

PROVIDER: S-EPMC4498255 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature