Abstract
Tissue hypoxia can occur in physiological and pathological conditions. When O2 availability decreases, the transcription factor hypoxia-inducible factor (HIF)-1α is stabilized and regulates cellular adaptation to hypoxia. The objective of this study was to test whether HIF-1α regulates T cell fate and to define the molecular mechanisms of this control. Our data demonstrate that Th1 cells lose their capacity to produce IFN-γ when cultured under hypoxia. HIF-1α−/− Th1 cells were insensitive to hypoxia, underlining a critical role for HIF-1α. Our results point to a role for IL-10, as suggested by the increased IL-10 expression at low O2 levels and the unchanged IFN-γ production by IL-10–deficient Th1 cells stimulated in hypoxic conditions. Accordingly, STAT3 phosphorylation is increased in Th1 cells under hypoxia, leading to enhanced HIF-1α transcription, which, in turn, may inhibit suppressor of cytokine signaling 3 transcription. This positive-feedback loop reinforces STAT3 activation and downregulates Th1 responses that may cause collateral damage to the host.
Footnotes
↵1 M.M. and G.O. are cosenior authors.
This work was supported by grants from the Fonds National de la Recherche Scientifique/Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture, Wallonia, the Interuniversity Attraction Pole Programme, the Research Concerted Action, and the Fonds Jean Brachet.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- CA
- constitutively activated
- HA
- hemagglutinin
- HIF
- hypoxia-inducible factor
- KLH
- keyhole limpet hemocyanin
- ND
- nondegradable
- SOCS
- suppressor of cytokine signaling
- Treg
- regulatory T cell
- WT
- wild-type.
- Received October 15, 2014.
- Accepted June 23, 2015.
- Copyright © 2015 by The American Association of Immunologists, Inc.