Advertisement

The IL23-Th17 Axis in Intestinal Inflammation

  • Kevin J. Maloy
Chapter

Abstract

Over the past 5 years, a wealth of data has emerged from experimental models linking the IL23/Th17 axis with chronic intestinal inflammation. Clinical studies have also reported elevated levels of IL23 and Th17 cytokines in the inflamed intestine of IBD patients, and recent GWAS have associated polymorphisms in IL23R, and in other Th17-related genes, with susceptibility to IBD. However, the precise mechanisms through which the IL23-Th17 axis contributes to intestinal homeostasis are not fully understood. Recent studies have revealed that IL23 drives intestinal inflammation by stimulating conserved effector responses, characterised by the production of IL-17A, IFN-γ and IL-22, from several populations of innate and adaptive intestinal leukocytes. However, the effects of individual Th17 cytokines are complex, ranging from disease protective to highly pathogenic, and are governed by the context in which they are expressed and by the presence of additional factors in the intestine. More recently, it has been shown that distinct members of the intestinal microbiota can modulate the Th17 axis and can regulate the balance between Th17 and Treg cells in the intestine. In addition, several approaches using pharmacological or biological inhibitors of the IL23/Th17 axis have been demonstrated to alleviate autoimmune pathology. These findings suggest that strategies targeting the IL23/Th17 axis could constitute novel therapies for IBD. However, a better understanding of how the IL23/Th17 axis interacts with host genetic factors and the intestinal microbiota in the normal and diseased intestine is necessary to ensure that these novel therapies are applied to appropriate patient cohorts.

Keywords

Inflammatory Bowel Disease Th17 Cell Treg Cell Inflammatory Bowel Disease Patient Dextran Sulphate Sodium 
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.

Notes

Acknowledgments

The author would like to acknowledge The Wellcome Trust and CRUK for research grants support and George Song-Zhao for help with preparing the figure.

References

  1. 1.
    Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621, Epub 2010/03/03PubMedGoogle Scholar
  2. 2.
    Khor B, Gardet A, Xavier RJ (2011) Genetics and pathogenesis of inflammatory bowel disease. Nature 474(7351):307–317, Epub 2011/06/17PubMedGoogle Scholar
  3. 3.
    Maloy KJ, Powrie F (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474(7351):298–306, Epub 2011/06/17PubMedGoogle Scholar
  4. 4.
    Melmed GY, Targan SR (2010) Future biologic targets for IBD: potentials and pitfalls. Nat Rev Gastroenterol Hepatol 7(2):110–117, Epub 2010/02/06PubMedGoogle Scholar
  5. 5.
    Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3(7):521–533PubMedGoogle Scholar
  6. 6.
    Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B 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(5):715–725PubMedGoogle Scholar
  7. 7.
    McGeachy MJ, Cua DJ (2007) The link between IL-23 and Th17 cell-mediated immune pathologies. Semin Immunol 19(6):372–376PubMedGoogle Scholar
  8. 8.
    Ouyang W, Kolls JK, Zheng Y (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28(4):454–467, Epub 2008/04/11PubMedGoogle Scholar
  9. 9.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517PubMedGoogle Scholar
  10. 10.
    Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B et al (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116(5):1310–1316PubMedGoogle Scholar
  11. 11.
    Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS et al (2006) Interleukin-23 drives innate and T cell-mediated intestinal inflammation. J Exp Med 203(11):2473–2483PubMedGoogle Scholar
  12. 12.
    Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS et al (2006) IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 203(11):2485–2494PubMedGoogle Scholar
  13. 13.
    Uhlig HH, McKenzie BS, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R et al (2006) Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity 25(2):309–318PubMedGoogle Scholar
  14. 14.
    Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y et al (2003) Increased expression of interleukin 17 in inflammatory bowel disease. Gut 52(1):65–70PubMedGoogle Scholar
  15. 15.
    Monteleone G, Monteleone I, Fina D, Vavassori P, Del Vecchio Blanco G, Caruso R et al (2005) Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn’s disease. Gastroenterology 128(3):687–694PubMedGoogle Scholar
  16. 16.
    Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM et al (2006) IL-22 is increased in active Crohn’s disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 290(4):G827–G838PubMedGoogle Scholar
  17. 17.
    Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314(5804):1461–1463, Epub 2006/10/28PubMedGoogle Scholar
  18. 18.
    Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447(7145):661–678, Epub 2007/06/08Google Scholar
  19. 19.
    Tremelling M, Cummings F, Fisher SA, Mansfield J, Gwilliam R, Keniry A et al (2007) IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 132(5):1657–1664PubMedGoogle Scholar
  20. 20.
    Franke A, Balschun T, Sina C, Ellinghaus D, Hasler R, Mayr G et al (2010) Genome-wide association study for ulcerative colitis identifies risk loci at 7q22 and 22q13 (IL17REL). Nat Genet 42(4):292–294, Epub 2010/03/17PubMedGoogle Scholar
  21. 21.
    Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD et al (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43(3):246–252, Epub 2011/02/08PubMedGoogle Scholar
  22. 22.
    Pidasheva S, Trifari S, Phillips A, Hackney JA, Ma Y, Smith A et al (2011) Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One 6(10):e25038, Epub 2011/10/25PubMedGoogle Scholar
  23. 23.
    Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L, Villanova F et al (2011) The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS One 6(2):e17160, Epub 2011/03/03PubMedGoogle Scholar
  24. 24.
    Yu RY, Gallagher G (2010) A naturally occurring, soluble antagonist of human IL-23 inhibits the development and in vitro function of human Th17 cells. J Immunol 185(12):7302–7308, Epub 2010/11/16PubMedGoogle Scholar
  25. 25.
    Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F et al (2006) Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis 12(1):9–15PubMedGoogle Scholar
  26. 26.
    Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T et al (2008) Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest 118(6):2269–2280, Epub 2008/05/24PubMedGoogle Scholar
  27. 27.
    Kastelein RA, Hunter CA, Cua DJ (2007) Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol 25:221–242PubMedGoogle Scholar
  28. 28.
    Langrish CL, McKenzie BS, Wilson NJ, de Waal Malefyt R, Kastelein RA, Cua DJ (2004) IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 202:96–105PubMedGoogle Scholar
  29. 29.
    Becker C, Wirtz S, Blessing M, Pirhonen J, Strand D, Bechthold O et al (2003) Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J Clin Invest 112(5):693–706PubMedGoogle Scholar
  30. 30.
    Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T (2009) Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn’s disease. Gastroenterology 137(5):1736–1745, Epub 2009/07/28PubMedGoogle Scholar
  31. 31.
    Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Kitazume MT et al (2009) Human CD14+ macrophages in intestinal lamina propria exhibit potent antigen-presenting ability. J Immunol 183(3):1724–1731, Epub 2009/07/14PubMedGoogle Scholar
  32. 32.
    Kinnebrew MA, Buffie CG, Diehl GE, Zenewicz LA, Leiner I, Hohl TM et al (2012) Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36(2):276–287, Epub 2012/02/07PubMedGoogle Scholar
  33. 33.
    Peters A, Lee Y, Kuchroo VK (2011) The many faces of Th17 cells. Curr Opin Immunol 23(6):702–706, Epub 2011/09/09PubMedGoogle Scholar
  34. 34.
    Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z et al (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30(1):155–167, Epub 2009/01/16PubMedGoogle Scholar
  35. 35.
    Mukasa R, Balasubramani A, Lee YK, Whitley SK, Weaver BT, Shibata Y et al (2010) Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32(5):616–627, Epub 2010/05/18PubMedGoogle Scholar
  36. 36.
    Littman DR, Rudensky AY (2010) Th17 and regulatory T cells in mediating and restraining inflammation. Cell 140(6):845–858, Epub 2010/03/23PubMedGoogle Scholar
  37. 37.
    Powrie F, Leach MW, Mauze S, Caddle LB, Coffman RL (1993) Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 5(11):1461–1471PubMedGoogle Scholar
  38. 38.
    Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, Turner SP et al (2009) Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med 206(3):525–534, Epub 2009/03/11PubMedGoogle Scholar
  39. 39.
    Ahern PP, Schiering C, Buonocore S, McGeachy MJ, Cua DJ, Maloy KJ et al (2010) Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33(2):279–288, Epub 2010/08/25PubMedGoogle Scholar
  40. 40.
    Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B et al (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204(8):1849–1861PubMedGoogle Scholar
  41. 41.
    Izcue A, Hue S, Buonocore S, Arancibia-Carcamo CV, Ahern PP, Iwakura Y et al (2008) Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28(4):559–570PubMedGoogle Scholar
  42. 42.
    Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ et al (2010) Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464(7293): 1371–1375, Epub 2010/04/16PubMedGoogle Scholar
  43. 43.
    Geremia A, Arancibia-Carcamo CV, Fleming MP, Rust N, Singh B, Mortensen NJ et al (2011) IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J Exp Med 208(6):1127–1133, Epub 2011/05/18PubMedGoogle Scholar
  44. 44.
    Cua DJ, Tato CM (2010) Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10(7):479–489, Epub 2010/06/19PubMedGoogle Scholar
  45. 45.
    Spits H, Di Santo JP (2011) The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 12(1):21–27, Epub 2010/11/30PubMedGoogle Scholar
  46. 46.
    Takayama T, Kamada N, Chinen H, Okamoto S, Kitazume MT, Chang J et al (2010) Imbalance of NKp44(+)NKp46(−) and NKp44(−)NKp46(+) natural killer cells in the intestinal mucosa of patients with Crohn’s disease. Gastroenterology 139(3):882–892, 892.e1-3. Epub 2010/07/20Google Scholar
  47. 47.
    Coccia M, Harrison OJ, Schiering C, Asquith MJ, Becher B, Powrie F et al (2012) IL-1beta mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells. J Exp Med 209(9):1595–1609, Epub 2012/08/15PubMedGoogle Scholar
  48. 48.
    Khader SA, Gaffen SL, Kolls JK (2009) Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol 2(5):403–411, Epub 2009/07/10PubMedGoogle Scholar
  49. 49.
    Maloy KJ, Kullberg MC (2008) IL-23 and Th17 cytokines in intestinal homeostasis. Mucosal Immunol 1(5):339–349, Epub 2008/12/17PubMedGoogle Scholar
  50. 50.
    Morrison PJ, Ballantyne SJ, Kullberg MC (2011) Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity. Immunology 133(4):397–408, Epub 2011/06/03PubMedGoogle Scholar
  51. 51.
    Mundy R, MacDonald TT, Dougan G, Frankel G, Wiles S (2005) Citrobacter rodentium of mice and man. Cell Microbiol 7(12):1697–1706, Epub 2005/11/29PubMedGoogle Scholar
  52. 52.
    Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441(7090):231–234PubMedGoogle Scholar
  53. 53.
    Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, Komiyama Y et al (2009) Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30(1):108–119, Epub 2009/01/16PubMedGoogle Scholar
  54. 54.
    Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q et al (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14(3):282–289PubMedGoogle Scholar
  55. 55.
    Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M et al (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203(10):2271–2279PubMedGoogle Scholar
  56. 56.
    Sonnenberg GF, Monticelli LA, Elloso MM, Fouser LA, Artis D (2011) CD4(+) lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34(1):122–134, Epub 2011/01/05PubMedGoogle Scholar
  57. 57.
    Ogawa A, Andoh A, Araki Y, Bamba T, Fujiyama Y (2004) Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol 110(1):55–62PubMedGoogle Scholar
  58. 58.
    Yang XO, Chang SH, Park H, Nurieva R, Shah B, Acero L et al (2008) Regulation of inflammatory responses by IL-17F. J Exp Med 205(5):1063–1075PubMedGoogle Scholar
  59. 59.
    Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA (2008) Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29(6):947–957, Epub 2008/12/23PubMedGoogle Scholar
  60. 60.
    Kinugasa T, Sakaguchi T, Gu X, Reinecker HC (2000) Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118(6):1001–1011PubMedGoogle Scholar
  61. 61.
    Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, Warntjen M et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206(7): 1465–1472PubMedGoogle Scholar
  62. 62.
    Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK et al (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118(2):534–544PubMedGoogle Scholar
  63. 63.
    Iwakura Y, Ishigame H, Saijo S, Nakae S (2011) Functional specialization of interleukin-17 family members. Immunity 34(2):149–162, Epub 2011/02/26PubMedGoogle Scholar
  64. 64.
    Gaffen SL (2009) Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9(8):556–567, Epub 2009/07/04PubMedGoogle Scholar
  65. 65.
    Liang SC, Long AJ, Bennett F, Whitters MJ, Karim R, Collins M et al (2007) An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J Immunol 179(11):7791–7799PubMedGoogle Scholar
  66. 66.
    Wright JF, Guo Y, Quazi A, Luxenberg DP, Bennett F, Ross JF et al (2007) Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J Biol Chem 282(18): 13447–13455PubMedGoogle Scholar
  67. 67.
    Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK (2006) Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 12(5):382–388PubMedGoogle Scholar
  68. 68.
    Fina D, Sarra M, Fantini MC, Rizzo A, Caruso R, Caprioli F et al (2008) Regulation of gut inflammation and th17 cell response by interleukin-21. Gastroenterology 134(4):1038–1048PubMedGoogle Scholar
  69. 69.
    Caruso R, Fina D, Peluso I, Stolfi C, Fantini MC, Gioia V et al (2007) A functional role for interleukin-21 in promoting the synthesis of the T-cell chemoattractant, MIP-3alpha, by gut epithelial cells. Gastroenterology 132(1):166–175PubMedGoogle Scholar
  70. 70.
    Monteleone G, Caruso R, Fina D, Peluso I, Gioia V, Stolfi C et al (2006) Control of matrix metalloproteinase production in human intestinal fibroblasts by interleukin 21. Gut 55(12): 1774–1780PubMedGoogle Scholar
  71. 71.
    Strengell M, Matikainen S, Siren J, Lehtonen A, Foster D, Julkunen I et al (2003) IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol 170(11):5464–5469PubMedGoogle Scholar
  72. 72.
    Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB et al (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448(7152):484–487PubMedGoogle Scholar
  73. 73.
    Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152):480–483PubMedGoogle Scholar
  74. 74.
    Fantini MC, Rizzo A, Fina D, Caruso R, Becker C, Neurath MF et al (2007) IL-21 regulates experimental colitis by modulating the balance between Treg and Th17 cells. Eur J Immunol 37(11):3155–3163PubMedGoogle Scholar
  75. 75.
    Peluso I, Fantini MC, Fina D, Caruso R, Boirivant M, MacDonald TT et al (2007) IL-21 counteracts the regulatory T cell-mediated suppression of human CD4+ T lymphocytes. J Immunol 178(2):732–739PubMedGoogle Scholar
  76. 76.
    Noguchi D, Wakita D, Tajima M, Ashino S, Iwakura Y, Zhang Y et al (2007) Blocking of IL-6 signaling pathway prevents CD4+ T cell-mediated colitis in a T(h)17-independent manner. Int Immunol 19(12):1431–1440PubMedGoogle Scholar
  77. 77.
    Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C et al (2009) RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136(1):257–267PubMedGoogle Scholar
  78. 78.
    Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB et al (2007) Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132(7):2359–2370PubMedGoogle Scholar
  79. 79.
    Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15(9):1016–1022, Epub 2009/08/25PubMedGoogle Scholar
  80. 80.
    Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A et al (2009) CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326(5955):986–991, Epub 2009/10/03PubMedGoogle Scholar
  81. 81.
    Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM et al (2011) Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34(4):566–578, Epub 2011/04/23PubMedGoogle Scholar
  82. 82.
    Kamanaka M, Huber S, Zenewicz LA, Gagliani N, Rathinam C, O’Connor W Jr et al (2011) Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med 208(5):1027–1040, Epub 2011/04/27PubMedGoogle Scholar
  83. 83.
    Sonnenberg GF, Nair MG, Kirn TJ, Zaph C, Fouser LA, Artis D (2010) Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J Exp Med 207(6):1293–1305, Epub 2010/05/26PubMedGoogle Scholar
  84. 84.
    Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ et al (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263, Epub 2011/02/01PubMedGoogle Scholar
  85. 85.
    Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L et al (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12(6):560–567, Epub 2011/04/26PubMedGoogle Scholar
  86. 86.
    El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F et al (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12(6):568–575, Epub 2011/04/26PubMedGoogle Scholar
  87. 87.
    Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M et al (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature 455(7214):808–812, Epub 2008/08/22PubMedGoogle Scholar
  88. 88.
    Hall JA, Bouladoux N, Sun CM, Wohlfert EA, Blank RB, Zhu Q et al (2008) Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29(4):637–649, Epub 2008/10/07PubMedGoogle Scholar
  89. 89.
    Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB et al (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4(4):337–349, Epub 2008/10/16PubMedGoogle Scholar
  90. 90.
    Niess JH, Leithauser F, Adler G, Reimann J (2008) Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions. J Immunol 180(1):559–568, Epub 2007/12/22PubMedGoogle Scholar
  91. 91.
    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U et al (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139(3):485–498, Epub 2009/10/20PubMedGoogle Scholar
  92. 92.
    Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C et al (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31(4):677–689, Epub 2009/10/17PubMedGoogle Scholar
  93. 93.
    Prakash T, Oshima K, Morita H, Fukuda S, Imaoka A, Kumar N et al (2011) Complete genome sequences of rat and mouse segmented filamentous bacteria, a potent inducer of th17 cell differentiation. Cell Host Microbe 10(3):273–284, Epub 2011/09/20PubMedGoogle Scholar
  94. 94.
    Sczesnak A, Segata N, Qin X, Gevers D, Petrosino JF, Huttenhower C et al (2011) The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10(3):260–272, Epub 2011/09/20PubMedGoogle Scholar
  95. 95.
    Cerf-Bensussan N, Gaboriau-Routhiau V (2010) The immune system and the gut microbiota: friends or foes? Nat Rev Immunol 10(10):735–744, Epub 2010/09/25PubMedGoogle Scholar
  96. 96.
    Wu HJ, Ivanov II, Darce J, Hattori K, Shima T, Umesaki Y et al (2010) Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32(6):815–827, Epub 2010/07/14PubMedGoogle Scholar
  97. 97.
    Lee YK, Menezes JS, Umesaki Y, Mazmanian SK (2011) Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 108(Suppl 1):4615–4622, Epub 2010/07/28PubMedGoogle Scholar
  98. 98.
    Hernandez-Santos N, Gaffen SL (2012) Th17 cells in immunity to Candida albicans. Cell Host Microbe 11(5):425–435, Epub 2012/05/23PubMedGoogle Scholar
  99. 99.
    Round JL, Mazmanian SK (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 107(27):12204–12209, Epub 2010/06/23PubMedGoogle Scholar
  100. 100.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y et al (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341, Epub 2011/01/06PubMedGoogle Scholar
  101. 101.
    Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104(34):13780–13785, Epub 2007/08/19PubMedGoogle Scholar
  102. 102.
    Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermudez-Humaran LG, Gratadoux JJ et al (2008) Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A 105(43):16731–16736, Epub 2008/10/22PubMedGoogle Scholar
  103. 103.
    Willing BP, Dicksved J, Halfvarson J, Andersson AF, Lucio M, Zheng Z et al (2010) A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology 139(6):1844–1854.e1. Epub 2010/09/08Google Scholar
  104. 104.
    Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S et al (2011) Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34(5):794–806, Epub 2011/05/21PubMedGoogle Scholar
  105. 105.
    Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N et al (2011) Peripheral education of the immune system by colonic commensal microbiota. Nature 478(7368):250–254, Epub 2011/09/23PubMedGoogle Scholar
  106. 106.
    Cho JH, Gregersen PK (2011) Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med 365(17):1612–1623, Epub 2011/10/28PubMedGoogle Scholar
  107. 107.
    Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S et al (2008) A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology 135(4):1130–1141PubMedGoogle Scholar
  108. 108.
    Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y et al (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371(9625):1665–1674, Epub 2008/05/20PubMedGoogle Scholar
  109. 109.
    Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N et al (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371(9625):1675–1684, Epub 2008/05/20PubMedGoogle Scholar
  110. 110.
    Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G et al (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2(52):52ra72, Epub 2010/10/12PubMedGoogle Scholar
  111. 111.
    Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P et al (2010) LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 62(4):929–939, Epub 2010/02/05PubMedGoogle Scholar
  112. 112.
    Gabay C, Lamacchia C, Palmer G (2010) IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 6(4):232–241, Epub 2010/02/24PubMedGoogle Scholar
  113. 113.
    Schmechel S, Konrad A, Diegelmann J, Glas J, Wetzke M, Paschos E et al (2008) Linking genetic susceptibility to Crohn’s disease with Th17 cell function: IL-22 serum levels are increased in Crohn’s disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis 14(2):204–212PubMedGoogle Scholar
  114. 114.
    Klotz L, Burgdorf S, Dani I, Saijo K, Flossdorf J, Hucke S et al (2009) The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med 206(10):2079–2089, Epub 2009/09/10PubMedGoogle Scholar
  115. 115.
    Huh JR, Leung MW, Huang P, Ryan DA, Krout MR, Malapaka RR et al (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472(7344):486–490, Epub 2011/03/29PubMedGoogle Scholar
  116. 116.
    Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J et al (2011) Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472(7344):491–494, Epub 2011/04/19PubMedGoogle Scholar
  117. 117.
    Kitabayashi C, Fukada T, Kanamoto M, Ohashi W, Hojyo S, Atsumi T et al (2010) Zinc suppresses Th17 development via inhibition of STAT3 activation. Int Immunol 22(5):375–386, Epub 2010/03/11PubMedGoogle Scholar
  118. 118.
    Cantorna MT (2012) Vitamin D, multiple sclerosis and inflammatory bowel disease. Arch Biochem Biophys 523(1):103–106, Epub 2011/11/17PubMedGoogle Scholar
  119. 119.
    Simmons JD, Mullighan C, Welsh KI, Jewell DP (2000) Vitamin D receptor gene polymorphism: association with Crohn’s disease susceptibility. Gut 47(2):211–214, Epub 2000/07/18PubMedGoogle Scholar
  120. 120.
    Joshi S, Pantalena LC, Liu XK, Gaffen SL, Liu H, Rohowsky-Kochan C et al (2011) 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol 31(17):3653–3669, Epub 2011/07/13PubMedGoogle Scholar
  121. 121.
    Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338, Epub 2009/03/24PubMedGoogle Scholar
  122. 122.
    Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X et al (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28(4):546–558, Epub 2008/04/05PubMedGoogle Scholar
  123. 123.
    Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ, Chaudhry A et al (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3(−) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34(4):554–565, Epub 2011/04/23PubMedGoogle Scholar
  124. 124.
    Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F et al (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361(21):2033–2045, Epub 2009/11/06PubMedGoogle Scholar
  125. 125.
    Glocker EO, Frede N, Perro M, Sebire N, Elawad M, Shah N et al (2010) Infant colitis—it’s in the genes. Lancet 376(9748):1272, Epub 2010/10/12PubMedGoogle Scholar
  126. 126.
    McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T et al (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397PubMedGoogle Scholar
  127. 127.
    Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM et al (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452(7188):773–776, Epub 2008/03/14PubMedGoogle Scholar
  128. 128.
    Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U et al (2009) A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 361(18):1727–1735, Epub 2009/10/30PubMedGoogle Scholar
  129. 129.
    Ferwerda B, Ferwerda G, Plantinga TS, Willment JA, van Spriel AB, Venselaar H et al (2009) Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 361(18): 1760–1767, Epub 2009/10/30PubMedGoogle Scholar
  130. 130.
    Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV et al (2010) Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 207(2):299–308, Epub 2010/02/04PubMedGoogle Scholar
  131. 131.
    Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C et al (2010) Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 207(2):291–297, Epub 2010/02/04PubMedGoogle Scholar
  132. 132.
    Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK et al (2011) Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332(6025):65–68, Epub 2011/02/26PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Sir William Dunn School of PathologyUniversity of OxfordOxfordUK

Personalised recommendations