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Nat Med DOI:10.1038/nm.3868

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

Publication TypeJournal Article
Year of Publication2015
AuthorsMascanfroni, ID, Takenaka, MC, Yeste, A, Patel, B, Wu, Y, Kenison, JE, Siddiqui, S, Basso, AS, Otterbein, LE, Pardoll, DM, Pan, F, Priel, A, Clish, CB, Robson, SC, Quintana, FJ
JournalNat Med
Volume21
Issue6
Pages638-46
Date Published2015 Jun
ISSN1546-170X
KeywordsAdult, Animals, Antigens, CD, Apyrase, Cell Differentiation, Female, Hematopoiesis, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Immunity, Cellular, Inflammation, Lymphocyte Activation, Mice, Receptors, Aryl Hydrocarbon, T-Lymphocytes, Regulatory
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.

URLhttp://dx.doi.org/10.1038/nm.3868
DOI10.1038/nm.3868
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26005855?dopt=Abstract

Alternate JournalNat. Med.
PubMed ID26005855
PubMed Central IDPMC4476246
Grant ListR21 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