title: Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1.
abstract: T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T(reg)) and T(H)17 differentiation. HIF-1 enhances T(H)17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating T(H)17 signature genes. Concurrently, HIF-1 attenuates T(reg) development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of T(H)17-dependent experimental autoimmune encephalitis associated with diminished T(H)17 and increased T(reg) cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.
authors.affiliation: Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Maryland 21231, USA.
authors.forename: Eric V
authors.initials: EV
authors.lastname: Dang
authors.forename: Joseph
authors.initials: J
authors.lastname: Barbi
authors.forename: Huang-Yu
authors.initials: HY
authors.lastname: Yang
authors.forename: Dilini
authors.initials: D
authors.lastname: Jinasena
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zachary
authors.initials: Z
authors.lastname: Bordman
authors.forename: Juan
authors.initials: J
authors.lastname: Fu
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
authors.forename: Hung-Rong
authors.initials: HR
authors.lastname: Yen
authors.forename: Weibo
authors.initials: W
authors.lastname: Luo
authors.forename: Karen
authors.initials: K
authors.lastname: Zeller
authors.forename: Larissa
authors.initials: L
authors.lastname: Shimoda
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Fan
authors.initials: F
authors.lastname: Pan
mesh_terms: D000818:Animals; D001483:Base Sequence; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D051379:Mice; D008969:Molecular Sequence Data; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016415:Sequence Alignment; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D050796:STAT3 Transcription Factor; D050880:p300-CBP Transcription Factors