Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 21, pages 638–646 (2015)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. MacIver, N.J., Michalek, R.D. & Rathmell, J.C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pearce, E.L., Poffenberger, M.C., Chang, C.H. & Jones, R.G. Fueling immunity: insights into metabolism and lymphocyte function. Science 342, 1242454 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pollizzi, K.N. & Powell, J.D. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14, 435–446 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Powell, J.D., Pollizzi, K.N., Heikamp, E.B. & Horton, M.R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).

    CAS  PubMed  Google Scholar 

  6. Dang, E.V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Doedens, A.L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim, J.S. et al. Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat. Immunol. 14, 611–618 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Michalek, R.D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

    CAS  PubMed  Google Scholar 

  10. Junger, W.G. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11, 201–212 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Quintana, F.J. & Sherr, D.H. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol. Rev. 65, 1148–1161 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Pot, C., Apetoh, L., Awasthi, A. & Kuchroo, V.K. Induction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27. Semin. Immunol. 23, 438–445 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Roncarolo, M.G. et al. Interleukin-10–secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).

    CAS  PubMed  Google Scholar 

  14. Roncarolo, M.G., Gregori, S., Bacchetta, R. & Battaglia, M. Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr. Top. Microbiol. Immunol. 380, 39–68 (2014).

    CAS  PubMed  Google Scholar 

  15. Awasthi, A. et al. A dominant function for interleukin 27 in generating interleukin 10–producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007).

    CAS  PubMed  Google Scholar 

  16. Stumhofer, J.S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

    CAS  PubMed  Google Scholar 

  17. Fitzgerald, D.C. et al. Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27–stimulated T cells. Nat. Immunol. 8, 1372–1379 (2007).

    CAS  PubMed  Google Scholar 

  18. Pot, C. et al. Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10–producing Tr1 cells. J. Immunol. 183, 797–801 (2009).

    CAS  PubMed  Google Scholar 

  19. Spolski, R., Kim, H.P., Zhu, W., Levy, D.E. & Leonard, W.J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol. 182, 2859–2867 (2009).

    CAS  PubMed  Google Scholar 

  20. Apetoh, L. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 11, 854–861 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gandhi, R. et al. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells. Nat. Immunol. 11, 846–853 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Eltzschig, H.K., Sitkovsky, M.V. & Robson, S.C. Purinergic signaling during inflammation. N. Engl. J. Med. 367, 2322–2333 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun, X. et al. CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. Gastroenterology 139, 1030–1040 (2010).

    CAS  PubMed  Google Scholar 

  24. Murugaiyan, G. et al. IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells. J. Immunol. 183, 2435–2443 (2009).

    CAS  PubMed  Google Scholar 

  25. Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).

    CAS  PubMed  Google Scholar 

  26. Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mills, J.H. et al. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 105, 9325–9330 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Quintana, F.J. et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol. 13, 770–777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Gagliani, N. et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746 (2013).

    CAS  PubMed  Google Scholar 

  31. Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knock-in tiger mouse. Immunity 25, 941–952 (2006).

    CAS  PubMed  Google Scholar 

  32. Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).

    CAS  PubMed  Google Scholar 

  33. Idzko, M., Ferrari, D. & Eltzschig, H.K. Nucleotide signalling during inflammation. Nature 509, 310–317 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Mascanfroni, I.D. et al. IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat. Immunol. 14, 1054–1063 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, C.M., Ploia, C., Anselmi, F., Sarukhan, A. & Viola, A. Adenosine triphosphate acts as a paracrine signaling molecule to reduce the motility of T cells. EMBO J. 33, 1354–1364 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Amoroso, F., Falzoni, S., Adinolfi, E., Ferrari, D. & Di Virgilio, F. The P2X7 receptor is a key modulator of aerobic glycolysis. Cell Death Dis. 3, e370 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun, X. et al. Disordered purinergic signaling and abnormal cellular metabolism are associated with development of liver cancer in Cd39/ENTPD1 null mice. Hepatology 57, 205–216 (2013).

    CAS  PubMed  Google Scholar 

  38. Semenza, G.L. Hypoxia-inducible factors in physiology and medicine. Cell 148, 399–408 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Semenza, G.L. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. 9, 47–71 (2014).

    CAS  PubMed  Google Scholar 

  40. Shi, L.Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Michalek, R.D. et al. Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc. Natl. Acad. Sci. USA 108, 18348–18353 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Eltzschig, H.K. & Carmeliet, P. Hypoxia and inflammation. N. Engl. J. Med. 364, 656–665 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Saraiva, M. et al. Interleukin-10 production by TH1 cells requires interleukin-12–induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209–219 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Chang, C.H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Ciofani, M. et al. A validated regulatory network for TH17 cell specification. Cell 151, 289–303 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Yosef, N. et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature 496, 461–468 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Enjyoji, K. et al. Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat. Med. 5, 1010–1017 (1999).

    CAS  PubMed  Google Scholar 

  49. Yeste, A. et al. IL-21 induces IL-22 production in CD4+ T cells. Nat. Commun. 5, 3753 (2014).

    CAS  PubMed  Google Scholar 

  50. Quintana, F.J. et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol. 13, 770–777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Wofford, J.A., Wieman, H.L., Jacobs, S.R., Zhao, Y. & Rathmell, J.C. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111, 2101–2111 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Feng, L. et al. Vascular CD39/ENTPD1 directly promotes tumor cell growth by scavenging extracellular adenosine triphosphate. Neoplasia 13, 206–216 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Author notes

  1. Ivan D Mascanfroni and Maisa C Takenaka: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Ivan D Mascanfroni, Maisa C Takenaka, Ada Yeste, Bonny Patel, Jessica E Kenison, Shafiuddin Siddiqui & Francisco J Quintana

  2. Division of Gastroenterology, Hepatology and Transplantation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Yan Wu, Leo E Otterbein & Simon C Robson

  3. Department of Microbiology, Immunology and Parasitology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil

    Alexandre S Basso

  4. Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Drew M Pardoll & Fan Pan

  5. Department of Physics, University of Alberta, Edmonton, Alberta, Canada

    Avner Priel

  6. Center for Proteomics, The Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA

    Clary B Clish

Authors
  1. Ivan D Mascanfroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maisa C Takenaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ada Yeste
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bonny Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jessica E Kenison
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shafiuddin Siddiqui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexandre S Basso
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Leo E Otterbein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Drew M Pardoll
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fan Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Avner Priel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Clary B Clish
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Simon C Robson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Francisco J Quintana
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Francisco J Quintana.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 3161 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3868

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing