| First Author | Lee JH | Year | 2015 |
| Journal | Immunity | Volume | 42 |
| Issue | 6 | Pages | 1062-74 |
| PubMed ID | 26084024 | Mgi Jnum | J:229111 |
| Mgi Id | MGI:5750819 | Doi | 10.1016/j.immuni.2015.05.016 |
| Citation | Lee JH, et al. (2015) E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1alpha to Maintain Regulatory T Cell Stability and Suppressive Capacity. Immunity 42(6):1062-74 |
| abstractText | 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 1alpha (HIF-1alpha)-induced glycolytic reprogramming was required for IFN-gamma production. Furthermore, HIF-1alpha bound directly to the Ifng promoter. HIF-1alpha 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-1alpha pathway by VHL is crucial to maintain the stability and suppressive function of Foxp3(+) T cells. |
