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

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.

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Figure 1: CD39 is expressed in Tr1 cells.
Figure 2: CD39 contributes to the suppressive function of Tr1 cells.
Figure 3: CD39 promotes Tr1 cell differentiation by limiting eATP levels.
Figure 4: HIF1-α antagonizes AHR during Tr1 cell differentiation.
Figure 5: HIF1-α controls the early metabolic reprogramming of Tr1 cells.
Figure 6: AHR maintains the metabolic program of Tr1 cells.

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Acknowledgements

We thank D. Frank (Dana-Farber Cancer Institute) for STAT3C plasmid. This work was supported by grants AI093903 and NS087867 from the US National Institutes of Health and RG4111A1 from the National Multiple Sclerosis Society to F.J.Q., and by grant CA164970 from the US National Institutes of Health to S.C.R. I.D.M. received support from an educational grant from Questcor (A219074) and by a postdoctoral fellowship (FG 2036-A1/1) from the National Multiple Sclerosis Society. M.C.T. is a graduate student in the Ph.D. program of the Federal University of São Paulo, and was supported by fellowship 246252/2012-0 from Ciências sem Fronteiras CNPq, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil.

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I.D.M., M.C.T., A.Y., Y.W., J.E.K. and C.B.C. performed in vitro and in vivo experiments; B.P. performed bioinformatics analysis; A.P. developed mathematical models; S.C.R., A.S.B., S.S., L.E.O., D.M.P. and F.P. provided unique reagents and discussed and/or interpreted findings; I.D.M. and F.J.Q. wrote the manuscript; and F.J.Q. designed and supervised the study and edited the manuscript.

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Correspondence to Francisco J Quintana.

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Mascanfroni, I., Takenaka, M., Yeste, A. et al. Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-α. Nat Med 21, 638–646 (2015). https://doi.org/10.1038/nm.3868

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