Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α.

Nat Med
Authors
Keywords
Abstract

Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory T cell (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular ATP (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen-presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.

Year of Publication
2015
Journal
Nat Med
Volume
21
Issue
6
Pages
638-46
Date Published
2015 Jun
ISSN
1546-170X
URL
DOI
10.1038/nm.3868
PubMed ID
26005855
PubMed Central ID
PMC4476246
Links
Grant list
R21 CA164970 / CA / NCI NIH HHS / United States
K99 AI075285 / AI / NIAID NIH HHS / United States
NS087867 / NS / NINDS NIH HHS / United States
R21 NS087867 / NS / NINDS NIH HHS / United States
R01 AI099300 / AI / NIAID NIH HHS / United States
R01 AI093903 / AI / NIAID NIH HHS / United States
CA164970 / CA / NCI NIH HHS / United States
R00 AI075285 / AI / NIAID NIH HHS / United States
AI093903 / AI / NIAID NIH HHS / United States