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

Ivan D. Mascanfroni, Maisa C. Takenaka, Ada Yeste, Bonny Patel, Yan Wu, Jessica E. Kenison, Shafiuddin Siddiqui, Alexandre S. Basso, Leo E. Otterbein, Andrew Mark Pardoll, Fan Pan, Avner Priel, Clary B. Clish, Simon C. Robson, Francisco J. Quintana

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)638-646
Number of pages9
JournalNature Medicine
Volume21
Issue number6
DOIs
StatePublished - Jun 9 2015

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Aryl Hydrocarbon Receptors
T-cells
Regulatory T-Lymphocytes
Cell Differentiation
Metabolism
Adenosine Triphosphate
Hypoxia-Inducible Factor 1
Lymphocytes
Adenosine
Transcription Factors
Viral Tumor Antigens
Antigen-Presenting Cells
Degradation
Inflammation
T-Lymphocytes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mascanfroni, I. D., Takenaka, M. C., Yeste, A., Patel, B., Wu, Y., Kenison, J. E., ... Quintana, F. J. (2015). Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nature Medicine, 21(6), 638-646. https://doi.org/10.1038/nm.3868

Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. / Mascanfroni, Ivan D.; Takenaka, Maisa C.; Yeste, Ada; Patel, Bonny; Wu, Yan; Kenison, Jessica E.; Siddiqui, Shafiuddin; Basso, Alexandre S.; Otterbein, Leo E.; Pardoll, Andrew Mark; Pan, Fan; Priel, Avner; Clish, Clary B.; Robson, Simon C.; Quintana, Francisco J.

In: Nature Medicine, Vol. 21, No. 6, 09.06.2015, p. 638-646.

Research output: Contribution to journalArticle

Mascanfroni, ID, Takenaka, MC, Yeste, A, Patel, B, Wu, Y, Kenison, JE, Siddiqui, S, Basso, AS, Otterbein, LE, Pardoll, AM, Pan, F, Priel, A, Clish, CB, Robson, SC & Quintana, FJ 2015, 'Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α', Nature Medicine, vol. 21, no. 6, pp. 638-646. https://doi.org/10.1038/nm.3868
Mascanfroni ID, Takenaka MC, Yeste A, Patel B, Wu Y, Kenison JE et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nature Medicine. 2015 Jun 9;21(6):638-646. https://doi.org/10.1038/nm.3868
Mascanfroni, Ivan D. ; Takenaka, Maisa C. ; Yeste, Ada ; Patel, Bonny ; Wu, Yan ; Kenison, Jessica E. ; Siddiqui, Shafiuddin ; Basso, Alexandre S. ; Otterbein, Leo E. ; Pardoll, Andrew Mark ; Pan, Fan ; Priel, Avner ; Clish, Clary B. ; Robson, Simon C. ; Quintana, Francisco J. / Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. In: Nature Medicine. 2015 ; Vol. 21, No. 6. pp. 638-646.
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