• Franco Di Padova
  • Bernhard Ryffel
  • Valérie Quesniaux
Part of the Progress in Inflammation Research book series (PIR)


The identification of IL-17A and Th17 cells have modified the established Th1, Th2 paradigm, led to the definition of a new CD3+CD4+ Th17 cell subset and introduced a new paradigm to explain the origin of several autoimmune events. However, this paradigm shift tended also to identify the effects of IL-17A with those of Th17 cells and vice versa. This view might be insufficient to explain the role of IL-17A in several infection and autoimmune models. IL-17A is in fact produced by several other cell types involved in host defense, autoimmunity and inflammation. Overall, we favor the hypothesis that in an early phase of the immune response γ δ T cells are directly involved in the production of IL-17A. This is followed by the involvement of αβ Th17 cells. We cannot exclude that, in some human chronic diseases, other cell types like macrophages or astrocytes may also acquire the capacity to produce IL-17A and be involved in pathology.


Th17 Cell Experimental Autoimmune Encephalomyelitis iNKT Cell Programme Death Ligand Herpesvirus Saimiri 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Rouvier E, Luciani M-F, Mattei MG, Denizot F, 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: 5445–5456PubMedGoogle Scholar
  2. 2.
    Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ (1995) Cutting edge: Human IL-17: A novel cytokine derived from T cells. J Immunol 155: 5483–5486PubMedGoogle Scholar
  3. 3.
    Kennedy J, Rossi DL, Zurawski SM, Vega Jr F, Kastelein RA, Wagner JL, Hannum CH, Zlotnik A (1996) Mouse IL-17: A cytokine preferentially expressed by alpha beta TCR+ CD4-CD8-T cells. J Interferon Cytokine Res 16: 611–617PubMedCrossRefGoogle Scholar
  4. 4.
    Yao Z, Timour M, Painter S, Fanslow W, Spriggs M (1996) Complete nucleotide sequence of the mouse CTLA8 gene. Gene 168: 223–225PubMedCrossRefGoogle Scholar
  5. 5.
    Yao Z, Fanslow WC, Seldin MF, Rousseau A-M, Painter SL, Comeau MR, Cohen JI, Spriggs MK (1995) Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3: 811–821PubMedCrossRefGoogle Scholar
  6. 6.
    Yao Z, Spriggs MK, Derry JMJ, Strockbine L, Park LS, VandenBos T, Zappone JD, Painter SL, Armitage RJ (1997) Molecular characterization of the human interleukin-17 receptor. Cytokine 9: 794–800PubMedCrossRefGoogle Scholar
  7. 7.
    Shen F, Gaffen SL (2008) Structure-function relationships in the IL-17 receptor: Implications for signal transduction and therapy. Cytokine 41: 92–104PubMedCrossRefGoogle Scholar
  8. 8.
    Kuestner RE, Taft DW, Haran A, Brandt CS, Brender T, Lum K, Harder B, Okada S, Ostrander CD, Kreindler JL et al (2007) Identification of the IL-17 receptor related molecule IL-17RC as the receptor for IL-17F. J Immunol 179: 5462–5473PubMedGoogle Scholar
  9. 9.
    Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J et al (2001) 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: 519–527PubMedCrossRefGoogle Scholar
  10. 10.
    Ye P, Garvey PB, Zhang P, Nelson S, Bagby G, Summer WR, Schwarzenberger P, Shellito JE, Kolls JK (2001). Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol 25: 335–340PubMedGoogle Scholar
  11. 11.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25: 821–852PubMedCrossRefGoogle Scholar
  12. 12.
    Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W (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: 2832–2838PubMedGoogle Scholar
  13. 13.
    Tzartos JS, Friese MA, Craner M, Palace J, Newcombe J, Esiri MM, Fugger L (2007) Interleukin-17 production in CNS-infiltrating T-cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172: 146–155PubMedCrossRefGoogle Scholar
  14. 14.
    Pène J, Chevalier S, Preisser L, Vénéreau E, Guilleux MH, Ghannam S, Molès JP, Danger Y, Ravon E, Lesaux S et al (2008) Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 180: 7423–7430PubMedGoogle Scholar
  15. 15.
    Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N, Olivenstein R, Elias J, Chakir J (2001) IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol 108: 430–438PubMedCrossRefGoogle Scholar
  16. 16.
    Infante-Duarte C, Horton HF, Byrne MC, Kamradt T (2000) Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 165: 6107–6115PubMedGoogle Scholar
  17. 17.
    Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6: 1123–1132PubMedCrossRefGoogle Scholar
  18. 18.
    Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6: 1133–1141PubMedCrossRefGoogle Scholar
  19. 19.
    Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441: 235–238PubMedCrossRefGoogle Scholar
  20. 20.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the TH17 lineage. Nature 441: 231–234PubMedCrossRefGoogle Scholar
  21. 21.
    Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B (2006) TGFß in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179–189PubMedCrossRefGoogle Scholar
  22. 22.
    McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-ß and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat Immunol 8: 1390–1397PubMedCrossRefGoogle Scholar
  23. 23.
    Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells Nature 448: 484–487PubMedCrossRefGoogle Scholar
  24. 24.
    Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448: 480–483PubMedCrossRefGoogle Scholar
  25. 25.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8: 967–974PubMedCrossRefGoogle Scholar
  26. 26.
    Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453: 236–240PubMedCrossRefGoogle Scholar
  27. 27.
    Gu Y, Yang J, Ouyang X, Liu W, Li H, Yang J, Bromberg J, Chen SH, Mayer L, Unkeless JC, Xiong H (2008) Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Eur J Immunol 38: 1807–1813PubMedCrossRefGoogle Scholar
  28. 28.
    Liu XK, Clements JL and Gaffen SL (2005) Signaling through the murine T cell receptor induces IL-17 production in the absence of costimulation, IL-23 or dendritic cells. Mol Cells 20: 339–347PubMedGoogle Scholar
  29. 29.
    Yoshiga Y, Goto D, Segawa S, Ohnishi Y, Matsumoto I, Ito S, Tsutsumi A, Taniguchi M, Sumida T (2008) Invariant NKT cells produce IL-17 through IL-23-dependent and-independent pathways with potential modulation of Th17 response in collageninduced arthritis. Int J Mol Med 22: 369–374PubMedGoogle Scholar
  30. 30.
    Ghilardi N, Kljavin N, Chen Q, Lucas S, Gurney AL, De Sauvage FJ (2004) Compromised humoral and delayed-type hypersensitivity responses in IL-23-deficient mice. J Immunol 172: 2827–2833PubMedGoogle Scholar
  31. 31.
    Ferretti S, Bonneau O, Dubois GR, Jones CE, Trifilieff A (2003) IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger. J Immunol 170: 2106–2112PubMedGoogle Scholar
  32. 32.
    Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278: 1910–1914PubMedCrossRefGoogle Scholar
  33. 33.
    Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201: 233–240PubMedCrossRefGoogle Scholar
  34. 34.
    Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26: 371–381PubMedCrossRefGoogle Scholar
  35. 35.
    Kleinschek MA, Owyang AM, Joyce-Shaikh B, Langrish CL, Chen Y, Gorman DM, Blumenschein WM, McClanahan T, Brombacher F, Hurst SD et al (2007) IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med 204: 161–170PubMedCrossRefGoogle Scholar
  36. 36.
    Stumhofer JS, Laurence A, Wilson EH, Huang E, Tato CM, Johnson LM, Villarino AV, Huang Q, Yoshimura A, Sehy D et al (2006). Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7: 937–945PubMedCrossRefGoogle Scholar
  37. 37.
    Jankovic D, Trinchieri G (2007) IL-10 or not IL-10: That is the question. Nat Immunol 8: 1281–1283PubMedCrossRefGoogle Scholar
  38. 38.
    Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J, O’Garra A, Stockinger B (2005). CD25+ CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction of IL-10 production. Int Immunol 17: 279–288PubMedCrossRefGoogle Scholar
  39. 39.
    Stockinger B (2007) Good for Goose, but not for Gander: IL-2 interferes with Th17 differentiation. Immunity 26: 278–279PubMedCrossRefGoogle Scholar
  40. 40.
    Nakae S, Iwakura Y, Suto H, Galli SJ (2007) Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol 81: 1258–1268PubMedCrossRefGoogle Scholar
  41. 41.
    Liang SC, Long AJ, Bennett F, Whitters MJ, Karim R, Collins M, Goldman SJ, Dunussi-Joannopoulos K, Williams CMM, Wright JF et al (2007) An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J Immunol 179: 7791–7799PubMedGoogle Scholar
  42. 42.
    Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L, Wang YH, Schluns KS, Broaddus RR, Zhu Z et al (2008) Regulation of inflammatory responses by IL-17F. J Exp Med 205: 1063–1075PubMedCrossRefGoogle Scholar
  43. 43.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, Fouser LA (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203: 2271–2279PubMedCrossRefGoogle Scholar
  44. 44.
    Page G, Miossec P (2005) RANK and RANKL expression as markers of dendritic cell-T cell interactions in paired samples of rheumatoid synovium and lymph nodes. Arthritis Rheum 52: 2307–2312PubMedCrossRefGoogle Scholar
  45. 45.
    Jensen KD, Su X, Shin S, Li L, Youssef S, Yamasaki S, Steinman L, Saito T, Locksley RM, Davis MM et al (2008) Thymic selection determines gammadelta T cell effector fate: Antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity 29: 90–100PubMedCrossRefGoogle Scholar
  46. 46.
    Michel ML, Keller AC, Paget C, Fujio M, Trottein F, Savage PB, Wong CH, Schneider E, Dy M, Leite-de-Moraes MC (2007) Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. J Exp Med 204: 995–1001PubMedCrossRefGoogle Scholar
  47. 47.
    Takahashi N, Vanlaere I, de Rycke R, Cauwels A, Joosten LA, Lubberts E, van den Berg WB, Libert C (2008) IL-17 produced by Paneth cells drives TNF-induced shock. J Exp Med 205: 1755–1761PubMedCrossRefGoogle Scholar
  48. 48.
    Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschei W et al (2006) IL-23 is essential for T cellmediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116: 1310–1316PubMedCrossRefGoogle Scholar
  49. 49.
    Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, Bamba T, Fujiyama Y (2003) Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52: 65–70PubMedCrossRefGoogle Scholar
  50. 50.
    Jandus C, Bioley G, Rivals JP, Dudler J, Speiser D, Romero P (2008) Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum 58: 2307–2317PubMedCrossRefGoogle Scholar
  51. 51.
    Cosmi L, De Palma R, Santarlasci V, Maggi L, Capone M, Frosali F, Rodolico G, Querci V, Abbate G, Angeli R et al (2008) Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J Exp Med 205: 1903–1916PubMedCrossRefGoogle Scholar
  52. 52.
    Coury F, Annels N, Rivollier A, Olsson S, Santoro A, Speziani C, Azocar O, Flacher M, Djebali S, Tebib J et al (2008) Langerhans cell histiocytosis reveals a new IL-17Adependent pathway of dendritic cell fusion. Nat Med 14: 81–87PubMedCrossRefGoogle Scholar
  53. 53.
    Zhou L, Peng S, Duan J, Zhou J, Wang L, Wang J (1998) A human B cell line AF10 expressing HIL-17. Biochem Mol Biol Int 45: 1113–1119PubMedGoogle Scholar
  54. 54.
    Steinman L (2008) A rush to judgment on Th17. J Exp Med 205: 1517–1522PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Franco Di Padova
    • 1
  • Bernhard Ryffel
    • 2
  • Valérie Quesniaux
    • 2
  1. 1.Novartis Institutes for Biomedical ResearchBaselSwitzerland
  2. 2.UMR6218 Molecular Immunology and EmbryologyUniversity of Orleans and CNRSOrleansFrance

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