Clambey, Eric T. and McNamee, Eóin N. and Westrich, Joseph A. and Glover, Louise and Campbell, Eric L. and Jedlicka, Paul and de Zoeten, Edwin F. and Cambier, John C. and Stenmark, Kurt R. and Colgan, S.P. and Eltzschig, Holger K.
(2012)
Hypoxia-inducible factor-1 alpha–dependent induction
of FoxP3 drives regulatory T-cell abundance and
function during inflammatory hypoxia of the mucosa.
Proceedings of the National Academy of Sciences of the United States of America, 109 (41).
E2784-E2793.
ISSN 0027-8424
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 antiinflammatory mechanisms to limit tissue damage in conditions of
reduced oxygen availability.
| Item Type: |
Article
|
| Keywords: |
lymphocyte; metabolism; TGF-beta; |
| Academic Unit: |
Faculty of Science and Engineering > Biology |
| Item ID: |
12594 |
| Identification Number: |
https://doi.org/10.1073/pnas.1202366109 |
| Depositing User: |
Eoin McNamee
|
| Date Deposited: |
23 Mar 2020 12:22 |
| Journal or Publication Title: |
Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: |
National Academy of Sciences |
| Refereed: |
Yes |
| URI: |
|
| Use Licence: |
This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available
here |
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