Signaling Through the Murine T Cell Receptor Induces IL-17 Production in the Absence of Costimulation, IL-23 or Dendritic Cells

  • Liu, Xikui K. (Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York) ;
  • Clements, James L. (Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York) ;
  • Gaffen, Sarah L. (Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York)
  • Received : 2005.05.31
  • Accepted : 2005.08.11
  • Published : 2005.12.31


IL-17 (IL-17A or CTLA-8) is the founding member of a novel family of inflammatory cytokines, and emerging evidence indicates that it plays a central role in inflammation and autoimmunity. IL-17 is made primarily, if not exclusively by T cells, but relatively little is known about how its expression is regulated. In the present study, we examined the requirements and mechanisms for IL-17 expression in primary mouse lymphocytes. Like many cytokines, IL-17 is induced rapidly in primary T cells after stimulation of the T cell receptor (TCR) through CD3 crossinking. Surprisingly, however, the pattern of regulation of IL-17 is different in mice than in humans, because "costimulation" of T cells through CD28 only mildly enhanced IL-17 expression, whereas levels of IL-2 were dramatically enhanced. Similarly, several other costimulatory molecules such as ICOS, 4-1BB and CD40L exerted only very weak enhancing effects on IL-17 production. In agreement with other reports, IL-23 enhanced CD3-induced IL-17 expression. However, IL-17 production can occur autonomously in T cells, as neither dendritic cells nor IL-23 were necessary for promoting short-term production of IL-17. Finally, to begin to characterize the TCR-mediated signaling pathway(s) required for IL-17 production, we showed that IL-17 expression is sensitive to cyclosporin-A and MAPK inhibitors, suggesting the involvement of the calcineurin/NFAT and MAPK signaling pathways.


Costimulation;Cytokine;Dendritic Cells;IL-17;T Cell Receptor


Supported by : NIH


  1. Bettelli, E. and Kuchroo, V. K. (2005) IL-12- and IL-23- induced T helper cell subsets: birds of the same feather flock together. J. Exp. Med. 201, 169-171
  2. Gaffen, S. L. (2004) Interleukin-17: a unique inflammatory cytokine with roles in bone biology and arthritis. Arth. Res. Ther. 6, 240-247
  3. Ghilardi, N., Kljavin, N., Chen, Q., Lucas, S., Gurney, A. L., et al. (2004) Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J. Immunol. 172, 2827-2833
  4. Hsieh, C. S., Macatonia, S. E., O'garra, A., and Murphy, K. M. (1995) T cell genetic background determines default T helper phenotype development in vitro. J. Exp. Med. 181, 713-721
  5. Linden, A. and Adachi, M. (2002) Neutrophilic airway inflammation and IL-17. Allergy 2002. 57, 769-775
  6. Liu, X., Lin, X., and Gaffen, S. L. (2004) Crucial role for nucelar factor of activated T cells (NFAT) in T cell receptormediated regulation of the human interleukin-17 gene. J. Biol. Chem. 279, 52762-52771
  7. Matusevicius, D., Kivisakk, P., He, B., Kostulas, N., Ozenci V., et al. (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101-104
  8. Oppmann, B., Lesley, R., Blom, B., Timans, J. C., Xu, Y., et al. (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715-725
  9. Shen, F., Ruddy, M. J., Plamondon, P., and Gaffen, S. L. (2005) Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-alpha-induced genes in bone cells. J. Leukoc. Biol. 77, 388-399
  10. Stark, M. A., Huo, Y., Burcin, T. L., Morris, M. A., Olson, T. S., et al. (2005) Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285-294
  11. Tartour, E., Fossiez, F., Joyeux, I., Galinha, A., Gey, A., et al. (1999) Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice. Cancer Res. 59, 3698-3704
  12. Yao, Z., Fanslow, W. C., Seldin, M. F., Rousseau, A. M., Painter, S. L., et al. (1995a) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811-821
  13. Fossiez, F., Djossou, O., Chomarat, P., Flores-Romo, L., Ait- Yahia, S., et al. (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593-2603
  14. Ruddy, M. J., Shen, F., Smith, J., Sharma, A., and Gaffen, S. L. (2004) Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment. J. Leukoc. Biol. 76, 135-144
  15. Zhou, L., Wang, J., Peng, S., Duan, J., Cai, X., et al. (1998) High-level expression of human interleukin-17 in the yeast Pichia pastoris. Biochem. Mol. Biol. Int. 46, 1109-1116
  16. Rouvier, E., Luciani, M.-F., Mattei, M.-G., Denizot, F., and Golstein, P. (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J. Immunol. 150, 5445-5456
  17. Ziolkowska, M., Koc, A., Luszczykiewicz, G., Ksiezopolska- Pietrzak, K., Klimczak, E., et al. (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J. Immunol. 164, 2832-2838
  18. Hogan, P. G., Chen, L., Nardone, J., and Rao, A. (2003) Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205-2232
  19. Kelly, M. N., Kolls, J. K., Happel, K., Schwartzman, J. D.,Schwarzenberger, P., et al. (2005) Interleukin-17/interleukin- 17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infect Immun. 73, 617-621
  20. Shin, H. C., Benbernou, N., Esnault, S., and Guenounou, M. (1999) Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway. Cytokine 11, 257-266
  21. Moseley, T. A., Haudenschild, D. R., Rose, L., and Reddi, A. H. (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155-174
  22. Dong, C. and Nurieva, R. I. (2003) Regulation of immune and autoimmune responses by ICOS. J. Autoimmunity 21, 255-260
  23. Jain, J., Loh, C., and Rao, A. (1995) Transcriptional regulation of the IL-2 gene. Cur. Opin. Immunol. 7, 333-342
  24. Nakae, S., Komiyama, Y., Nambu, A., Sudo, K., Iwase, M., et al. (2002) Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375-387
  25. Ye, P., Garvey, P. B., Zhang, P., Nelson, S., Bagby, G., et al. (2001) Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am. J. Respir. Cell Mol. Biol. 25, 335-340
  26. Aggarwal, S., Ghilardi, N., Xie, M. H., De Sauvage, F. J., and Gurney, A. L. (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin- 17. J. Biol. Chem. 278, 1910-1914
  27. Frucht, D. M. (2002) IL-23: a cytokine that acts on memory T cells. Sci. STKE 2002, E1
  28. Teunissen, M. B., Koomen, C. W., De Waal Malefyt, R., Wierenga, E. A., and Bos, J. D. (1998) Interleukin-17 and interferon- g synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J. Invest. Dermatol. 111, 645-649
  29. Yao, Z., Painter, S. L., Fanslow, W. C., Ulrich, D., Macduff, B. M., et al. (1995b) Human IL-17: a novel cytokine derived from T cells. J. Immunol. 155, 5483-5486
  30. Albanesi, C., Cavani, A., and Girolomoni, G. (1999) IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonistic effects with IFN-${\gamma}$ and TNF-${\alpha}$. J. Immunol. 162, 494-502
  31. Kostulas, N., Pelidou, S. H., Kivisakk, P., Kostulas, V., and Link, H. (1999) Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke 30, 2174-2179
  32. Langrish, C. L., McKenzie, B. S., Wilson, N. J., de Waal Malefyt, R., Kastelein, R. A., et al. (2004) IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol. Rev. 202, 96-105
  33. Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., et al. (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233-240
  34. Nakae, S., Saijo, S., Horai, R., Sudo, K., Mori, S., et al. (2003) IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc. Natl. Acad. Sci. USA 100, 5986-5990
  35. Gaffen, S. and Liu, K. D. (2004) Overview of interleukin-2 function, production and clinical applications. Cytokine 28, 109-123
  36. Happel, K. I., Zheng, M., Young, E., Quinton, L. J., Lockhart, E., et al. (2003) Cutting edge: roles of toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 170, 4432-4436
  37. Kolls, J. K. and Linden, A. (2004) Interleukin-17 family members and inflammation. Immunity 21, 467-476
  38. Kennedy, J., Rossi, D. L., Zurawski, S. M., Vega, F. Jr, Kastelein, R. A., et al. (1996) Mouse IL-17: a cytokine preferentially expressed by ab TCR + CD4-CD8-T cells. J. Interferon Cytokine Res. 16, 611-617