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Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10

Nature Immunology volume 8, pages 1363–1371 (2007)Cite this article

Abstract

Interleukin 10 (IL-10) has a prominent function in regulating the balance between protective and pathological T cell responses. Consistent with that activity, many sources of this cytokine are found in vivo, including from myeloid cells and a variety of T cell subsets. However, although there are many pathways that regulate innate production of IL-10, the factors that govern its synthesis by the adaptive response are poorly understood. Here we report that IL-27 and IL-6 induced T helper type 1 and type 2 cells, as well as T helper cells that produce IL-17, to secrete IL-10. This effect was dependent on the transcription factors STAT1 and STAT3 for IL-27 and on STAT3 for IL-6. Our studies identify a previously unknown pathway that allows the immune system to temper inflammatory responses.

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Figure 1: IL-27 promotes the production of IL-10 by CD4+ and CD8+ T cells.
Figure 2: Cells produce less IL-10 in the absence of IL-27R signaling.
Figure 3: CD4+ T cells make IL-10 in response to IL-27 in TH1 and TH2 but not TH-17 conditions.
Figure 4: IL-27 induces the generation of IFN-γ+IL-10+ CD4+ T cells in TH1 conditions.
Figure 5: TGF-β augments the IL-27-driven production of IL-10 by CD4+ T cells.
Figure 6: IL-6 acts in synergy with TGF-β to promote IL-10 production.
Figure 7: STAT-dependent induction of IL-10.

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References

  1. Fiorentino, D.F., Bond, M.W. & Mosmann, T.R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 170, 2081–2095 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Moore, K.W. et al. Homology of Cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science 248, 1230–1234 (1990).

    Article  CAS  PubMed  Google Scholar 

  3. Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Yen, D. et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grunig, G. et al. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J. Exp. Med. 185, 1089–1099 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gazzinelli, R.T. et al. In the absence of endogenous IL-10, mice acutely infected with Toxoplasma gondii succumb to a lethal immune response dependent on CD4+ T cells and accompanied by overproduction of IL-12, IFN-γ and TNF-α. J. Immunol. 157, 798–805 (1996).

    CAS  PubMed  Google Scholar 

  8. Hunter, C.A. et al. IL-10 is required to prevent immune hyperactivity during infection with Trypanosoma cruzi. J. Immunol. 158, 3311–3316 (1997).

    CAS  PubMed  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. Suffia, I.J., Reckling, S.K., Piccirillo, C.A., Goldszmid, R.S. & Belkaid, Y. Infected site-restricted Foxp3+ natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 203, 777–788 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang, X. et al. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int. Immunol. 16, 249–256 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Jonuleit, H., Schmitt, E., Schuler, G., Knop, J. & Enk, A.H. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J. Exp. Med. 192, 1213–1222 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vieira, P.L. et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172, 5986–5993 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Del Prete, G. et al. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J. Immunol. 150, 353–360 (1993).

    CAS  PubMed  Google Scholar 

  15. Gerosa, F. et al. Interleukin-12 primes human CD4 and CD8 T cell clones for high production of both interferon-γ and interleukin-10. J. Exp. Med. 183, 2559–2569 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. O'Garra, A. & Vieira, P. TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Trinchieri, G. Interleukin-10 production by effector T cells: Th1 cells show self control. J. Exp. Med. 204, 239–243 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gerosa, F. et al. CD4+ T cell clones producing both interferon-γ and interleukin-10 predominate in bronchoalveolar lavages of active pulmonary tuberculosis patients. Clin. Immunol. 92, 224–234 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Pohl-Koppe, A., Balashov, K.E., Steere, A.C., Logigian, E.L. & Hafler, D.A. Identification of a T cell subset capable of both IFN-γ and IL-10 secretion in patients with chronic Borrelia burgdorferi infection. J. Immunol. 160, 1804–1810 (1998).

    CAS  PubMed  Google Scholar 

  20. Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D. CD4+CD25−Foxp3− Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jankovic, D. et al. Conventional T-bet+Foxp3− Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Chen, Q. et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat. Immunol. 7, 929–936 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Amadi-Obi, A. et al. TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1. Nat. Med. 13, 711–718 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  27. Villarino, A. et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19, 645–655 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. Villarino, A.V. et al. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J. Immunol. 174, 7684–7691 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Rich, S., Seelig, M., Lee, H.M. & Lin, J. Transforming growth factor β1 costimulated growth and regulatory function of staphylococcal enterotoxin B-responsive CD8+ T cells. J. Immunol. 155, 609–618 (1995).

    CAS  PubMed  Google Scholar 

  32. Fontenot, J.D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Neufert, C. et al. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. Eur. J. Immunol. 37, 1809–1816 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chiarle, R. et al. Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. Nat. Med. 11, 623–629 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hamano, S. et al. WSX-1 is required for resistance to Trypanosoma cruzi infection by regulation of proinflammatory cytokine production. Immunity 19, 657–667 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Rosas, L.E. et al. Interleukin-27R (WSX-1/T-cell cytokine receptor) gene-deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am. J. Pathol. 168, 158–169 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilson, E.H., Wille-Reece, U., Dzierszinski, F. & Hunter, C.A. A critical role for IL-10 in limiting inflammation during toxoplasmic encephalitis. J. Neuroimmunol. 165, 63–74 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Hunter, C.A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat. Rev. Immunol. 5, 521–531 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Brightbill, H.D., Plevy, S.E., Modlin, R.L. & Smale, S.T. A prominent role for Sp1 during lipopolysaccharide-mediated induction of the IL-10 promoter in macrophages. J. Immunol. 164, 1940–1951 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Liu, Y.W., Chen, C.C., Tseng, H.P. & Chang, W.C. Lipopolysaccharide-induced transcriptional activation of interleukin-10 is mediated by MAPK- and NF-κB-induced CCAAT/enhancer-binding protein δ in mouse macrophages. Cell. Signal. 18, 1492–1500 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Lucas, M., Zhang, X., Prasanna, V. & Mosser, D.M. ERK activation following macrophage FcγR ligation leads to chromatin modifications at the IL-10 locus. J. Immunol. 175, 469–477 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Shoemaker, J., Saraiva, M. & O'Garra, A. GATA-3 directly remodels the IL-10 locus independently of IL-4 in CD4+ T cells. J. Immunol. 176, 3470–3479 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Lucas, S., Ghilardi, N., Li, J. & de Sauvage, F.J. IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc. Natl. Acad. Sci. USA 100, 15047–15052 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ziegler-Heitbrock, L. et al. IFN-α induces the human IL-10 gene by recruiting both IFN regulatory factor 1 and Stat3. J. Immunol. 171, 285–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Hou, J. et al. An interleukin-4-induced transcription factor: IL-4. Stat. Sci. 265, 1701–1706 (1994).

    CAS  Google Scholar 

  48. Jacobson, N.G. et al. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J. Exp. Med. 181, 1755–1762 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103, 8137–8142 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mathur, A.N. et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J. Immunol. 178, 4901–4907 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Shull, M.M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Espevik, T. et al. Inhibition of cytokine production by cyclosporin A and transforming growth factor β. J. Exp. Med. 166, 571–576 (1987).

    Article  CAS  PubMed  Google Scholar 

  53. Silva, J.S., Twardzik, D.R. & Reed, S.G. Regulation of Trypanosoma cruzi infections in vitro and in vivo by transforming growth factor β (TGF-β). J. Exp. Med. 174, 539–545 (1991).

    Article  CAS  PubMed  Google Scholar 

  54. Hunter, C.A., Bermudez, L., Beernink, H., Waegell, W. & Remington, J.S. Transforming growth factor-β inhibits interleukin-12-induced production of interferon-γ by natural killer cells: a role for transforming growth factor-β in the regulation of T cell-independent resistance to Toxoplasma gondii. Eur. J. Immunol. 25, 994–1000 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Mosmann, T.R. & Coffman, R.L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    Article  CAS  PubMed  Google Scholar 

  56. Cohen, S.B. et al. High level of interleukin-10 production by the activated T cell population within the rheumatoid synovial membrane. Arthritis Rheum. 38, 946–952 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Lee, C.K. et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17, 63–72 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Sharma, S.D., Mullenax, J., Araujo, F.G., Erlich, H.A. & Remington, J.S. Western blot analysis of the antigens of Toxoplasma gondii recognized by human IgM and IgG antibodies. J. Immunol. 131, 977–983 (1983).

    CAS  PubMed  Google Scholar 

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Acknowledgements

WSX-1-deficient (Il27ra−/−) mice were provided by C. Saris (Amgen); BALB/c Il10−/− mice were originally obtained from R. Coffman (DNAX); Stat1−/− mice were provided by P. Scott (University of Pennsylvania); Foxp3GFP mice were provided by L. Turka (University of Pennsylvania); and CD4-Cre–Stat3−/− mice were provided by J.J. O′Shea (National Institutes of Health). Supported by the National Institutes of Health (AI42334 and AI41158 to C.H.; AI 43620 to L.T.; 1-T32-AI-055428 to J.S.S.; and 1-T32-AI-07532 to J.S.), the Scholler Foundation, the State of Pennsylvania, and the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Jason S Stumhofer, Jonathan S Silver, Tajie H Harris & Christopher A Hunter

  2. Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Muskoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland

    Arian Laurence & John J O'Shea

  3. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Paige M Porrett & Laurence A Turka

  4. Ludwig Institute for Cancer Research, Parkville, 3050, Victoria, Australia

    Matthias Ernst

  5. Department of Inflammation Research, Amgen, Thousand Oaks, 91320, California, USA

    Christiaan J M Saris

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Contributions

J.S.S. and C.A.H. contributed to all studies; J.S. and M.E. were involved in the analysis and interpretation of the p-STAT1 and p-STAT3 signaling experiments; T.H.H. was involved in the analysis of IL-10 expression by real-time quantitative PCR; A.L. and J.J.O. contributed to the studies of Stat3−/− CD4+ T cells; and P.M.P. and L.A.T. contributed to the studies of the Foxp3GFP mice.

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Correspondence to Christopher A Hunter.

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The authors have patents related to the use of IL-27.

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Stumhofer, J., Silver, J., Laurence, A. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat Immunol 8, 1363–1371 (2007). https://doi.org/10.1038/ni1537

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