title: Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa.
abstract: Recent studies have demonstrated dramatic shifts in metabolic supply-and-demand ratios during inflammation, a process resulting in localized tissue hypoxia within inflammatory lesions ("inflammatory hypoxia"). As part of the adaptive immune response, T cells are recruited to sites of inflammatory hypoxia. Given the profound effects of hypoxia on gene regulation, we hypothesized that T-cell differentiation is controlled by hypoxia. To pursue this hypothesis, we analyzed the transcriptional consequences of ambient hypoxia (1% oxygen) on a broad panel of T-cell differentiation factors. Surprisingly, these studies revealed selective, robust induction of FoxP3, a key transcriptional regulator for regulatory T cells (Tregs). Studies of promoter binding or loss- and gain-of-function implicated hypoxia-inducible factor (HIF)-1α in inducing FoxP3. Similarly, hypoxia enhanced Treg abundance in vitro and in vivo. Finally, Treg-intrinsic HIF-1α was required for optimal Treg function and Hif1a-deficient Tregs failed to control T-cell-mediated colitis. These studies demonstrate that hypoxia is an intrinsic molecular cue that promotes FoxP3 expression, in turn eliciting potent anti-inflammatory mechanisms to limit tissue damage in conditions of reduced oxygen availability.
authors.affiliation: Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. Eric.Clambey@ucdenver.edu
authors.forename: Eric T
authors.initials: ET
authors.lastname: Clambey
authors.forename: Eóin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Westrich
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.forename: Edwin F
authors.initials: EF
authors.lastname: de Zoeten
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007375:Interleukin-1; D016212:Transforming Growth Factor beta