The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells
- Université Libre de Bruxelles, Belgium
Abstract
The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, in particular those characterized by IFN-γ production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2α axis in regulatory T cell phenotype and in vivo function.
Data availability
Sequencing data have been deposited in GEO under accession code GSE18458.Numerical data used to generate the figures have been provided for Figures 1-8 and S1-S8 (named Source data Figure 1 - Figure S8).
Article and author information
Author details
Funding
European Regional Development Fund
- Yousra Ajouaou
- Hind Hussein
- Fabienne Andris
- Muriel Moser
- Stanislas Goriely
- Oberdan Leo
Fond de la recherche scientifique
- Yousra Ajouaou
- Hind Hussein
Walloon region
- Fabienne Andris
- Muriel Moser
- Stanislas Goriely
- Oberdan Leo
Fond Jean Brachet
- Fabienne Andris
- Muriel Moser
- Stanislas Goriely
- Oberdan Leo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The experiments were performed in compliance with the relevant laws and institutional guidelines and were approved by the Local Ethic Committee. We received specific approval for this study from the Université Libre de Bruxelles Institutional Animal Care and Use Committee (protocol numbers CEBEA-4 and 31).
Copyright
© 2022, Ajouaou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,348
- views
-
- 195
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells
eLife 11:e70555.
https://doi.org/10.7554/eLife.70555
Further reading
-
- Immunology and Inflammation
Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
By altering which peptide antigens are presented to CD4+ T cells, adjuvants affect the specificity of the immune response.
