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A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17


Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-γ negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

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Figure 1: The generation of IL-17-producing T cells requires CD28 and ICOS costimulation.
Figure 2: Regulation of IL-17 expression by cytokines and transcriptional factors.
Figure 3: Regulation of IL-17 production by effector and memory T cells.
Figure 4: IL-17 regulates genes encoding inflammatory molecules.
Figure 5: IL-17 regulates chemokine expression in brain tissue during EAE.
Figure 6: Generation and analysis of Cc10-Il17–transgenic mice.


  1. 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 

  2. Lenschow, D.J., Walunas, T.L. & Bluestone, J.A. CD28/B7 system of T cell costimulation. Annu. Rev. Immunol. 14, 233–258 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Dong, C. & Nurieva, R.I. Regulation of immune and autoimmune responses by ICOS. J. Autoimmun. 21, 255–260 (2003).

    Article  PubMed  Google Scholar 

  4. Szabo, S.J., Sullivan, B.M., Peng, S.L. & Glimcher, L.H. Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Trinchieri, G., Pflanz, S. & Kastelein, R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 19, 641–644 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Robinson, D.S., O'Garra, A., Steinman, L. & Gijbels, K. Further checkpoints in Th1 development: CD4+ T-cell subsets in autoimmunity. Immunity 16, 755–758 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Murphy, C.A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Glimcher, L.H. & Murphy, K.M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14, 1693–1711 (2000).

    CAS  PubMed  Google Scholar 

  10. Zheng, W. & Flavell, R.A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–596 (1997).

    CAS  PubMed  Google Scholar 

  11. Ho, I.C., Hodge, M.R., Rooney, J.W. & Glimcher, L.H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85, 973–983 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. 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 

  13. Aggarwal, S. & Gurney, A.L. IL-17: prototype member of an emerging cytokine family. J. Leukoc. Biol. 71, 1–8 (2002).

    CAS  PubMed  Google Scholar 

  14. Moseley, T.A., Haudenschild, D.R., Rose, L. & Reddi, A.H. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155–174 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1240 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune iInduction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Bush, K.A., Farmer, K.M., Walker, J.S. & Kirkham, B.W. Reduction of joint inflammation and bone erosion in rat adjuvant arthritis by treatment with interleukin-17 receptor IgG1 Fc fusion protein. Arthritis Rheum. 46, 802–805 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Yao, Z. et al. Human IL-17: a novel cytokine derived from T cells. J. Immunol. 155, 5483–5486 (1995).

    CAS  PubMed  Google Scholar 

  22. Aggarwal, S., Ghilardi, N., Xie, M.H., De Sauvage, F.J. & Gurney, A.L. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J. Biol. Chem. 278, 1910–1914 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Seder, R.A. & Ahmed, R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat. Immunol. 4, 835–842 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Yang, J., Murphy, T.L., Ouyang, W. & Murphy, K.M. Induction of interferon-γ production in Th1 CD4+ T cells: evidence for two distinct pathways for promoter activation. Eur. J. Immunol. 29, 548–555 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Prasad, D.V., Richards, S., Mai, X.M. & Dong, C. B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18, 863–873 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Ruddy, M.J. et al. Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer-binding protein family members. J. Biol. Chem. 279, 2559–2567 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Sun, M. et al. Characterization of mouse and human B7–H3 genes. J. Immunol. 168, 6294–6297 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Ransohoff, R.M. The chemokine system in neuroinflammation: an update. J. Infect. Dis. 186, S152–S156 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Huang, D., Wang, J., Kivisakk, P., Rollins, B.J. & Ransohoff, R.M. Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 Immune response in experimental autoimmune encephalomyelitis. J. Exp. Med. 193, 713–726 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vignola, A.M. et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am. J. Respir. Crit. Care Med. 158, 1945–1950 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Beeh, K.M., Beier, J., Kornmann, O. & Buhl, R. Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and healthy subjects. Respir. Med. 97, 634–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Infante-Duarte, C., Horton, H.F., Byrne, M.C. & Kamradt, T. Microbial lipopeptides induce the production of IL-17 in Th cells. J. Immunol. 165, 6107–6115 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Linden, A. Role of interleukin-17 and the neutrophil in asthma. Int. Arch. Allergy Immunol. 126, 179–184 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Stark, M.A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Zhu, Z. et al. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J. Clin. Invest. 103, 779–788 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ideker, T., Thorsson, V., Siegel, A.F. & Hood, L.E. Testing for differentially-expressed genes by maximum-likelihood analysis of microarray data. J. Comput. Biol. 7, 805–817 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–102 (2001).

    Article  CAS  PubMed  Google Scholar 

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We thank L. Glimcher and I.-C. Ho for Maf-transgenic mice; L. Glimcher and C. Wilson for T-bet-deficient mice; J. Elias for the Cc10 promoter construct; A. Farr for guidance in animal work; and the Dong lab for help and discussions. Supported by the National Institutes of Health (C.D.), Arthritis Foundation (S.H.C., R.N. and C.D.), Cancer Research Institute (C.D.) and MD Anderson Cancer Center (C.D.).

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Correspondence to Chen Dong.

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Supplementary information

Supplementary Fig. 1

Anti-IL-17 antibody specifically blocks IL-17 biological activity. (PDF 11373 kb)

Supplementary Fig. 2

Blockage of IL-17 after disease onset reduces inflammation during EAE. (PDF 7419 kb)

Supplementary Fig. 3

Summary of TH differentiation. (PDF 3099 kb)

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Park, H., Li, Z., Yang, X. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6, 1133–1141 (2005).

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