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; Drew M. Pardoll; Fan Pan; Avner Priel; Clary B. Clish; Simon C. Robson; Francisco J. Quintana

doi:10.1038/nm.3868

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, Drew M. Pardoll, Fan Pan, Avner Priel, Clary B. Clish, Simon C. Robson, Francisco J. Quintana

Research output: Contribution to journal › Article › peer-review

372 Scopus citations

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 language	English
Pages (from-to)	638-646
Number of pages	9
Journal	Nature Medicine
Volume	21
Issue number	6
DOIs	https://doi.org/10.1038/nm.3868
State	Published - 9 Jun 2015
Externally published	Yes

Bibliographical note

Funding Information:
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.

Funding

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.

Funders	Funder number
Federal University of São Paulo	246252/2012-0
National Institutes of Health	RG4111A1
National Institute of Neurological Disorders and Stroke	R21NS087867
National Multiple Sclerosis Society	A219074, CA164970, FG 2036-A1/1
Conselho Nacional de Desenvolvimento Científico e Tecnológico

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title = "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.",

author = "Mascanfroni, {Ivan D.} and Takenaka, {Maisa C.} and Ada Yeste and Bonny Patel and Yan Wu and Kenison, {Jessica E.} and Shafiuddin Siddiqui and Basso, {Alexandre S.} and Otterbein, {Leo E.} and Pardoll, {Drew M.} and Fan Pan and Avner Priel and Clish, {Clary B.} and Robson, {Simon C.} and Quintana, {Francisco J.}",

note = "Funding Information: 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 S{\~a}o Paulo, and was supported by fellowship 246252/2012-0 from Ci{\^e}ncias sem Fronteiras CNPq, Conselho Nacional de Desenvolvimento Cient{\'i}fico e Tecnol{\'o}gico, Brazil.",

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AU - Takenaka, Maisa C.

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AU - Wu, Yan

AU - Kenison, Jessica E.

AU - Siddiqui, Shafiuddin

AU - Basso, Alexandre S.

AU - Otterbein, Leo E.

AU - Pardoll, Drew M.

AU - Pan, Fan

AU - Priel, Avner

AU - Clish, Clary B.

AU - Robson, Simon C.

AU - Quintana, Francisco J.

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PY - 2015/6/9

Y1 - 2015/6/9

N2 - 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.

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

Abstract

Bibliographical note

Funding

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