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

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