title: E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1α 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-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.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Jee H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Elly
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Park
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: yuncail@liai.org.
authors.forename: Yun-Cai
authors.initials: YC
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics; D003092:Colitis / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D007371:Interferon-gamma; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C494469:VHL protein, mouse