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Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells

Abstract

The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells (Treg cells) and interleukin 17 (IL-17)-producing helper T cells (TH17 cells), but its role in human T cell differentiation is unknown. We investigated the role of AhR in the differentiation of human induced Treg cells (iTreg cells). We found that AhR activation promoted the differentiation of CD4+Foxp3 T cells, which produce IL-10 and control responder T cells through granzyme B. However, activation of AhR in the presence of transforming growth factor-β1 induced Foxp3+ iTreg cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional Foxp3+ iTreg cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iTreg cells could be induced in human autoimmune disorders.

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Figure 1: AhR activation induces T cells that produce IL-10.
Figure 2: AhR activation induces human Tr1-like cells.
Figure 3: The suppressive activity of Tr1-like cells induced by AhR activation is mediated by granzyme B.
Figure 4: AhR activation plus TGF-β1 induces Foxp3+ T cells.
Figure 5: AhR activation plus TGF-β1 induces functional human Foxp3+ Treg cells.
Figure 6: AhR activation plus TGF-β1 induce the expression of Smad1 and Aiolos.
Figure 7: Smad1 regulates FOXP3 enhancer activity.
Figure 8: Aiolos interacts with Foxp3 to silence IL2 expression.

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References

  1. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Allan, S.E. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 19, 345–354 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Wang, J., Ioan-Facsinay, A., van der Voort, E.I., Huizinga, T.W. & Toes, R.E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37, 129–138 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Allan, S.E. et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276–3284 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tran, D.Q., Ramsey, H. & Shevach, E.M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-β dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol 10, 170–181 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Baecher-Allan, C. & Hafler, D.A. Human regulatory T cells and their role in autoimmune disease. Immunol. Rev. 212, 203–216 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Tran, D.Q. & Shevach, E.M. Therapeutic potential of FOXP3+ regulatory T cells and their interactions with dendritic cells. Hum. Immunol. 70, 294–299 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 23, 65–71 (2008).

    Article  Google Scholar 

  15. Hauben, E. et al. Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell-mediated effects on regulatory T cells. Blood 112, 1214–1222 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Kimura, A., Naka, T., Nohara, K., Fujii-Kuriyama, Y. & Kishimoto, T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc. Natl. Acad. Sci. USA 105, 9721–9726 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Vogel, C.F., Goth, S.R., Dong, B., Pessah, I.N. & Matsumura, F. Aryl hydrocarbon receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem. Biophys. Res. Commun. 375, 331–335 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang, L. et al. Suppression of experimental autoimmune uveoretinitis by inducing differentiation of regulatory T cells via activation of aryl hydrocarbon receptor. Invest. Ophthalmol. Vis. Sci. 51, 2109–2117 (2010).

    Article  PubMed  Google Scholar 

  19. Veldhoen, M., Hirota, K., Christensen, J., O′Garra, A. & Stockinger, B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med. 206, 43–49 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Kerkvliet, N.I. et al. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 1, 539–547 (2009).

    CAS  PubMed  Google Scholar 

  22. Jones, P.B., Galeazzi, D.R., Fisher, J.M. & Whitlock, J.P. Jr. Control of cytochrome P1–450 gene expression by dioxin. Science 227, 1499–1502 (1985).

    Article  CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Xu, J. et al. c-Maf regulates IL-10 expression during Th17 polarization. J. Immunol. 182, 6226–6236 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Kim, J.I., Ho, I.C., Grusby, M.J. & Glimcher, L.H. The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 10, 745–751 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Planque, N. et al. Interaction of Maf transcription factors with Pax-6 results in synergistic activation of the glucagon promoter. J. Biol. Chem. 276, 35751–35760 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Vignali, D.A., Collison, L.W. & Workman, C.J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grossman, W.J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Thomas, D.A., Du, C., Xu, M., Wang, X. & Ley, T.J. DFF45/ICAD can be directly processed by granzyme B during the induction of apoptosis. Immunity 12, 621–632 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Rubtsov, Y.P. & Rudensky, A.Y. TGF-β signalling in control of T-cell-mediated self-reactivity. Nat. Rev. Immunol. 7, 443–453 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Bynoe, M.S. & Viret, C. Foxp3+CD4+ T cell-mediated immunosuppression involves extracellular nucleotide catabolism. Trends Immunol. 29, 99–102 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes Dev. 19, 2783–2810 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Georgopoulos, K. Haematopoietic cell-fate decisions, chromatin regulation and ikaros. Nat. Rev. Immunol. 2, 162–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Pan, F. et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325, 1142–1146 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Morgan, B. et al. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 16, 2004–2013 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Caballero, R. et al. Combinatorial effects of splice variants modulate function of Aiolos. J. Cell Sci. 120, 2619–2630 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. 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., advance online publication 1 August 2010 (doi:10.1038/ni.1912).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+IL-10+Foxp3 effector T cells. Nat. Immunol. 9, 1347–1355 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Marshall, N.B., Vorachek, W.R., Steppan, L.B., Mourich, D.V. & Kerkvliet, N.I. Functional characterization and gene expression analysis of CD4+CD25+ regulatory T cells generated in mice treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. Immunol. 181, 2382–2391 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ruan, Q. et al. Development of Foxp3+ regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31, 932–940 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kim, J. et al. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. Immunity 10, 345–355 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Thompson, E.C. et al. Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits. Immunity 26, 335–344 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Denison, M.S. & Nagy, S.R. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu. Rev. Pharmacol. Toxicol. 43, 309–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Perdew, G.H. & Babbs, C.F. Production of Ah receptor ligands in rat fecal suspensions containing tryptophan or indole-3-carbinol. Nutr. Cancer 16, 209–218 (1991).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank V. Kuchroo (Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School) for discussions and the IL10 promoter reporter construct; Y. Tone and M. Tone (Cedars-Sinai Medical Center) for reporter constructs for FOXP3 +2079 to +2198; and E. Ballestar (Bellvitge Biomedical Research Institute) for vectors encoding Aiolos and its isoforms. Supported by the US National Institutes of Health (AI435801 and NS38037 to H.L.W. and 1K99AI075285 to F.J.Q.), the National Multiple Sclerosis Society (RG4151A12 to H.L.W. and RG4111A1 to F.J.Q.) and the Harvard Medical School Office for Diversity and Community Partnership (to F.J.Q.).

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R.G., D.K., E.J.B., M.N. and A.L. did experiments; D.K. sorted cells by flow cytometry; B.D. provided advice; R.G., D.K., E.J.B., H.L.W. and F.J.Q. analyzed data; R.G. and F.J.Q. wrote the manuscript; and H.L.W. and F.J.Q. supervised the study and edited the manuscript.

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Correspondence to Francisco J Quintana.

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Gandhi, R., Kumar, D., Burns, E. 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). https://doi.org/10.1038/ni.1915

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