Seminars in Immunopathology

, Volume 34, Issue 6, pp 873–888 | Cite as

Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

  • Bridget M. Larkin
  • Patrick M. Smith
  • Holly E. Ponichtera
  • Mara G. Shainheit
  • Laura I. Rutitzky
  • Miguel J. Stadecker


Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to IL-17-producing CD4 T helper (Th17) cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a solely Th2-polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6. The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the production of IL-23 and IL-1β by antigen presenting cells following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with intestinal nematodes can also dampen pathogenic Th17 cell responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.


Helminth Schistosomes Parasite Immunopathology Immunoregulation Th17 response Genetics 



This work was supported by the National Institutes of Health grant R01-18919 to MJS. The authors declare no financial conflicts of interest.


  1. 1.
    Bica I, Hamer DH, Stadecker MJ (2000) Hepatic schistosomiasis. Infect Dis Clin North Am 14:583–604, viiiPubMedCrossRefGoogle Scholar
  2. 2.
    Fallon PG (2000) Immunopathology of schistosomiasis: a cautionary tale of mice and men. Immunol Today 21:29–35PubMedCrossRefGoogle Scholar
  3. 3.
    Pearce EJ, MacDonald AS (2002) The immunobiology of schistosomiasis. Nat Rev Immunol 2:499–511PubMedCrossRefGoogle Scholar
  4. 4.
    Wilson MS, Mentink-Kane MM, Pesce JT, Ramalingam TR, Thompson R, Wynn TA (2007) Immunopathology of schistosomiasis. Immunol Cell Biol 85:148–154PubMedCrossRefGoogle Scholar
  5. 5.
    Cheever A, Duvall R, Hallack T Jr, Minker R, Malley J, Malley K (1987) Variation of hepatic fibrosis and granuloma size among mouse strains infected with Schistosoma mansoni. Am J Trop Med Hyg 37:85–97PubMedGoogle Scholar
  6. 6.
    Hernandez HJ, Trzyna WC, Cordingley JS, Brodeur PH, Stadecker MJ (1997) Differential antigen recognition by T cell populations from strains of mice developing polar forms of granulomatous inflammation in response to eggs of Schistosoma mansoni. Eur J Immunol 27:666–670PubMedCrossRefGoogle Scholar
  7. 7.
    Bosshardt SC, Freeman GL Jr, Secor WE, Colley DG (1997) IL-10 deficit correlates with chronic, hypersplenomegaly syndrome in male CBA/J mice infected with Schistosoma mansoni. Parasite Immunol 19:347–353Google Scholar
  8. 8.
    Rutitzky LI, Bazzone L, Shainheit MG, Joyce-Shaikh B, Cua DJ, Stadecker MJ (2008) IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17. J Immunol 180:2486–2495PubMedGoogle Scholar
  9. 9.
    Dyer KD, Garcia-Crespo KE, Killoran KE, Rosenberg HF (2011) Antigen profiles for the quantitative assessment of eosinophils in mouse tissues by flow cytometry. J Immunol Methods 369:91–97PubMedCrossRefGoogle Scholar
  10. 10.
    Rutitzky LI, Hernandez HJ, Stadecker MJ (2001) Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection. Proc Natl Acad Sci USA 98:13243–13248PubMedCrossRefGoogle Scholar
  11. 11.
    Amiri P, Locksley RM, Parslow TG, Sadick M, Rector E, Ritter D, McKerrow JH (1992) Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature 356:604–607PubMedCrossRefGoogle Scholar
  12. 12.
    Freitas TC, Jung E, Pearce EJ (2007) TGF-beta signaling controls embryo development in the parasitic flatworm Schistosoma mansoni. PLoS Pathog 3:e52PubMedCrossRefGoogle Scholar
  13. 13.
    Berriman M, Haas BJ, LoVerde PT, Wilson RA, Dillon GP, Cerqueira GC, Mashiyama ST, Al-Lazikani B, Andrade LF, Ashton PD, Aslett MA, Bartholomeu DC, Blandin G, Caffrey CR, Coghlan A, Coulson R, Day TA, Delcher A, DeMarco R, Djikeng A, Eyre T, Gamble JA, Ghedin E, Gu Y, Hertz-Fowler C, Hirai H, Hirai Y, Houston R, Ivens A, Johnston DA, Lacerda D, Macedo CD, McVeigh P, Ning Z, Oliveira G, Overington JP, Parkhill J, Pertea M, Pierce RJ, Protasio AV, Quail MA, Rajandream MA, Rogers J, Sajid M, Salzberg SL, Stanke M, Tivey AR, White O, Williams DL, Wortman J, Wu W, Zamanian M, Zerlotini A, Fraser-Liggett CM, Barrell BG, El-Sayed NM (2009) The genome of the blood fluke Schistosoma mansoni. Nature 460:352–358PubMedCrossRefGoogle Scholar
  14. 14.
    Cass CL, Johnson JR, Califf LL, Xu T, Hernandez HJ, Stadecker MJ, Yates JR 3rd, Williams DL (2007) Proteomic analysis of Schistosoma mansoni egg secretions. Mol Biochem Parasitol 155:84–93PubMedCrossRefGoogle Scholar
  15. 15.
    Williams DL, Asahi H, Oke TT, Lopes da Rosa J, Stadecker MJ (2005) Murine immune responses to a novel schistosome egg antigen, SmEP25. Int J Parasitol 35:875–882PubMedCrossRefGoogle Scholar
  16. 16.
    Schramm G, Falcone FH, Gronow A, Haisch K, Mamat U, Doenhoff MJ, Oliveira G, Galle J, Dahinden CA, Haas H (2003) Molecular characterization of an interleukin-4-inducing factor from Schistosoma mansoni eggs. J Biol Chem 278:18384–18392PubMedCrossRefGoogle Scholar
  17. 17.
    Steinfelder S, Andersen JF, Cannons JL, Feng CG, Joshi M, Dwyer D, Caspar P, Schwartzberg PL, Sher A, Jankovic D (2009) The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1). J Exp Med 206:1681–1690PubMedCrossRefGoogle Scholar
  18. 18.
    Everts B, Perona-Wright G, Smits HH, Hokke CH, van der Ham AJ, Fitzsimmons CM, Doenhoff MJ, van der Bosch J, Mohrs K, Haas H, Mohrs M, Yazdanbakhsh M, Schramm G (2009) Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses. J Exp Med 206:1673–1680PubMedCrossRefGoogle Scholar
  19. 19.
    Cai Y, Langley J, Smith D, Boros D (1996) A cloned major Schistosoma mansoni egg antigen with homologies to small heat shock proteins elicits Th1 responsiveness. Infect Immun 64:1750–1755PubMedGoogle Scholar
  20. 20.
    Nene V, Dunne D, Johnson K, Taylor D, Cordingley J (1986) Sequence and expression of a major egg antigen from Schistosoma mansoni. Homologies to heat shock proteins and alpha-crystallins. Mol Biochem Parasitol 21:179–188PubMedCrossRefGoogle Scholar
  21. 21.
    Cao M, Chao H, Doughty B (1993) Cloning of a cDNA encoding an egg antigen homologue from Schistosoma mansoni. Mol Biochem Parasitol 58:169–171PubMedCrossRefGoogle Scholar
  22. 22.
    Tiu WU, Davern KM, Wright MD, Board PG, Mitchell GF (1988) Molecular and serological characteristics of the glutathione S-transferases of Schistosoma japonicum and Schistosoma mansoni. Parasite Immunol 10:693–706PubMedCrossRefGoogle Scholar
  23. 23.
    Asahi H, Osman A, Cook RM, LoVerde PT, Stadecker MJ (2000) Schistosoma mansoni phosphoenolpyruvate carboxykinase, a novel egg antigen: immunological properties of the recombinant protein and identification of a T-cell epitope. Infect Immun 68:3385–3393PubMedCrossRefGoogle Scholar
  24. 24.
    Alger HM, Sayed AA, Stadecker MJ, Williams DL (2002) Molecular and enzymatic characterisation of Schistosoma mansoni thioredoxin. Int J Parasitol 32:1285–1292PubMedCrossRefGoogle Scholar
  25. 25.
    Williams DL, Asahi H, Botkin DJ, Stadecker MJ (2001) Schistosome infection stimulates host CD4(+) T helper cell and B-cell responses against a novel egg antigen, thioredoxin peroxidase. Infect Immun 69:1134–1141PubMedCrossRefGoogle Scholar
  26. 26.
    Schramm G, Hamilton JV, Balog CI, Wuhrer M, Gronow A, Beckmann S, Wippersteg V, Grevelding CG, Goldmann T, Weber E, Brattig NW, Deelder AM, Dunne DW, Hokke CH, Haas H, Doenhoff MJ (2009) Molecular characterisation of kappa-5, a major antigenic glycoprotein from Schistosoma mansoni eggs. Mol Biochem Parasitol 166:4–14PubMedCrossRefGoogle Scholar
  27. 27.
    Hokke CH, Deelder AM (2001) Schistosome glycoconjugates in host–parasite interplay. Glycoconj J 18:573–587PubMedCrossRefGoogle Scholar
  28. 28.
    Hokke CH, Yazdanbakhsh M (2005) Schistosome glycans and innate immunity. Parasite Immunol 27:257–264PubMedCrossRefGoogle Scholar
  29. 29.
    Cummings RD, Nyame AK (1999) Schistosome glycoconjugates. Biochim Biophys Acta 1455:363–374PubMedCrossRefGoogle Scholar
  30. 30.
    Wuhrer M, Balog CI, Catalina MI, Jones FM, Schramm G, Haas H, Doenhoff MJ, Dunne DW, Deelder AM, Hokke CH (2006) IPSE/alpha-1, a major secretory glycoprotein antigen from schistosome eggs, expresses the Lewis X motif on core-difucosylated N-glycans. FEBS J 273:2276–2292PubMedCrossRefGoogle Scholar
  31. 31.
    Shainheit MG, Lasocki KW, Finger E, Larkin BM, Smith PM, Sharpe AH, Dinarello CA, Rutitzky LI, Stadecker MJ (2011) The pathogenic Th17 cell response to major schistosome egg antigen is sequentially dependent on IL-23 and IL-1beta. J Immunol 187:5328–5335PubMedCrossRefGoogle Scholar
  32. 32.
    Hernandez HJ, Stadecker MJ (1999) Elucidation and role of critical residues of immunodominant peptide associated with T cell-mediated parasitic disease. J Immunol 163:3877–3882PubMedGoogle Scholar
  33. 33.
    Finger E, Brodeur PH, Hernandez HJ, Stadecker MJ (2005) Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis. Eur J Immunol 35:2659–2669PubMedCrossRefGoogle Scholar
  34. 34.
    Eberl M, Langermans JA, Vervenne RA, Nyame AK, Cummings RD, Thomas AW, Coulson PS, Wilson RA (2001) Antibodies to glycans dominate the host response to schistosome larvae and eggs: is their role protective or subversive? J Infect Dis 183:1238–1247PubMedCrossRefGoogle Scholar
  35. 35.
    Dunne DW, Butterworth AE, Fulford AJC, Curtis Kariuki H, Langley JG, Ouma JH, Capron A, Pierce RJ, Sturrock RF (1992) Immunity after treatment of human schistosomiasis: association between IgE antibodies to adult worm antigens and resistance to reinfection. Eur J Immunol 22:1483–1494PubMedCrossRefGoogle Scholar
  36. 36.
    King CL, Xianli J, Malhotra I, Liu S, Mahmoud AA, Oettgen HC (1997) Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with Schistosoma mansoni. J Immunol 158:294–300PubMedGoogle Scholar
  37. 37.
    Hernandez HJ, Wang Y, Stadecker MJ (1997) In infection with Schistosoma mansoni, B cells are required for T helper type 2 cell responses but not for granuloma formation. J Immunol 158:4832–4837PubMedGoogle Scholar
  38. 38.
    Zaretsky AG, Taylor JJ, King IL, Marshall FA, Mohrs M, Pearce EJ (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206:991–999PubMedCrossRefGoogle Scholar
  39. 39.
    Phillips SM, DiConza JJ, Gold JA, Reid WA (1977) Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. J Immunol 118:594–599PubMedGoogle Scholar
  40. 40.
    Iacomini J, Ricklan D, Stadecker M (1995) T cells expressing the γδ T cell receptor are not required for egg granuloma formation in schistosomiasis. Eur J Immunol 25:884–888Google Scholar
  41. 41.
    Hernandez HJ, Wang Y, Tzellas N, Stadecker MJ (1997) Expression of class II, but not class I, major histocompatibility complex molecules is required for granuloma formation in infection with Schistosoma mansoni. Eur J Immunol 27:1170–1176PubMedCrossRefGoogle Scholar
  42. 42.
    Karanja DM, Colley DG, Nahlen BL, Ouma JH, Secor WE (1997) Studies on schistosomiasis in western Kenya: I. Evidence for immune-facilitated excretion of schistosome eggs from patients with Schistosoma mansoni and human immunodeficiency virus coinfections. Am J Trop Med Hyg 56:515–521PubMedGoogle Scholar
  43. 43.
    Mathew RC, Boros DL (1986) Anti-L3T4 antibody treatment suppresses hepatic granuloma formation and abrogates antigen-induced interleukin-2 production in Schistosoma mansoni infection. Infect Immun 54:820–826PubMedGoogle Scholar
  44. 44.
    Pearce E, Caspar P, Grzych J, Lewis F, Sher A (1991) Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med 173:159–166PubMedCrossRefGoogle Scholar
  45. 45.
    MacDonald AS, Patton EA, La Flamme AC, Araujo MI, Huxtable CR, Bauman B, Pearce EJ (2002) Impaired Th2 development and increased mortality during Schistosoma mansoni Infection in the absence of CD40/CD154 interaction. J Immunol 168:4643–4649Google Scholar
  46. 46.
    Hernandez HJ, Sharpe AH, Stadecker MJ (1999) Experimental murine schistosomiasis in the absence of B7 costimulatory molecules: reversal of elicited T cell cytokine profile and partial inhibition of egg granuloma formation. J Immunol 162:2884–2889PubMedGoogle Scholar
  47. 47.
    Rutitzky LI, Ozkaynak E, Rottman JB, Stadecker MJ (2003) Disruption of the ICOS-B7RP-1 costimulatory pathway leads to enhanced hepatic immunopathology and increased gamma interferon production by CD4 T cells in murine schistosomiasis. Infect Immun 71:4040–4044PubMedCrossRefGoogle Scholar
  48. 48.
    Brunet LR, Finkelman FD, Cheever AW, Kopf MA, Pearce EJ (1997) IL-4 protects against TNF-alpha-mediated cachexia and death during acute schistosomiasis. J Immunol 159:777–785PubMedGoogle Scholar
  49. 49.
    Herbert DR, Holscher C, Mohrs M, Arendse B, Schwegmann A, Radwanska M, Leeto M, Kirsch R, Hall P, Mossmann H, Claussen B, Forster I, Brombacher F (2004) Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20:623–635PubMedCrossRefGoogle Scholar
  50. 50.
    Chiaramonte MG, Donaldson DD, Cheever AW, Wynn TA (1999) An IL-13 inhibitor blocks the development of hepatic fibrosis during a T-helper type 2-dominated inflammatory response. J Clin Invest 104:777–785PubMedCrossRefGoogle Scholar
  51. 51.
    Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN (2000) Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol 164:2585–2591PubMedGoogle Scholar
  52. 52.
    Araujo MI, de Jesus AR, Bacellar O, Sabin E, Pearce E, Carvalho EM (1996) Evidence of a T helper type 2 activation in human schistosomiasis. Eur J Immunol 26:1399–1403PubMedCrossRefGoogle Scholar
  53. 53.
    Joseph AL, Boros DL (1993) Tumor necrosis factor plays a role in Schistosoma mansoni egg-induced granulomatous inflammation. J Immunol 151:5461–5471PubMedGoogle Scholar
  54. 54.
    Flores-Villanueva PO, Zheng XX, Strom TB, Stadecker MJ (1996) Recombinant IL-10 and IL-10/Fc treatment down-regulate egg antigen- specific delayed hypersensitivity reactions and egg granuloma formation in schistosomiasis. J Immunol 156:3315–3320PubMedGoogle Scholar
  55. 55.
    Hoffmann KF, Cheever AW, Wynn TA (2000) IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis. J Immunol 164:6406–6416PubMedGoogle Scholar
  56. 56.
    Sadler CH, Rutitzky LI, Stadecker MJ, Wilson RA (2003) IL-10 is crucial for the transition from acute to chronic disease state during infection of mice with Schistosoma mansoni. Eur J Immunol 33:880–888PubMedCrossRefGoogle Scholar
  57. 57.
    Stadecker MJ, Asahi H, Finger E, Hernandez HJ, Rutitzky LI, Sun J (2004) The immunobiology of Th1 polarization in high-pathology schistosomiasis. Immunol Rev 201:168–179PubMedCrossRefGoogle Scholar
  58. 58.
    Rutitzky LI, Mirkin GA, Stadecker MJ (2003) Apoptosis by neglect of CD4+ Th cells in granulomas: a novel effector mechanism involved in the control of egg-induced immunopathology in murine schistosomiasis. J Immunol 171:1859–1867PubMedGoogle Scholar
  59. 59.
    Stadecker MJ, Kamisato JK, Chikunguwo SM (1990) Induction of T helper cell unresponsiveness to antigen by macrophages from schistosomal egg granulomas. A basis for immunomodulation in schistosomiasis? J Immunol 145:2697–2700PubMedGoogle Scholar
  60. 60.
    Colley DG, Montesano MA, Freeman GL, Secor WE (1999) Infection-stimulated or perinatally initiated idiotypic interactions can direct differential morbidity and mortality in schistosomiasis. Microbes Infect 1:517–524PubMedCrossRefGoogle Scholar
  61. 61.
    Taylor JJ, Krawczyk CM, Mohrs M, Pearce EJ (2009) Th2 cell hyporesponsiveness during chronic murine schistosomiasis is cell intrinsic and linked to GRAIL expression. J Clin Invest 119:1019–1028PubMedCrossRefGoogle Scholar
  62. 62.
    Mossmann T, Coffman R (1989) TH-1 and TH-2 cells: different patterns of lymphokine secretion lead to different properties. Ann Rev Immunol 7:145–173CrossRefGoogle Scholar
  63. 63.
    Dong C (2006) Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 6:329–333PubMedCrossRefGoogle Scholar
  64. 64.
    Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19:281–286PubMedCrossRefGoogle Scholar
  65. 65.
    Bettelli E, Korn T, Kuchroo VK (2007) Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 19:652–657PubMedCrossRefGoogle Scholar
  66. 66.
    Iwakura Y, Nakae S, Saijo S, Ishigame H (2008) The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 226:57–79PubMedCrossRefGoogle Scholar
  67. 67.
    McGeachy MJ, Cua DJ (2008) Th17 cell differentiation: the long and winding road. Immunity 28:445–453PubMedCrossRefGoogle Scholar
  68. 68.
    Mills KH (2008) Induction, function and regulation of IL-17-producing T cells. Eur J Immunol 38:2636–2649PubMedCrossRefGoogle Scholar
  69. 69.
    Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476PubMedCrossRefGoogle Scholar
  70. 70.
    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
  71. 71.
    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
  72. 72.
    Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421:744–748PubMedCrossRefGoogle Scholar
  73. 73.
    Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ (2003) Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 198:1951–1957PubMedCrossRefGoogle Scholar
  74. 74.
    Nakae S, Nambu A, Sudo K, Iwakura Y (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173–6177PubMedGoogle Scholar
  75. 75.
    Sonderegger I, Rohn TA, Kurrer MO, Iezzi G, Zou Y, Kastelein RA, Bachmann MF, Kopf M (2006) Neutralization of IL-17 by active vaccination inhibits IL-23-dependent autoimmune myocarditis. Eur J Immunol 36:2849–2856PubMedCrossRefGoogle Scholar
  76. 76.
    Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D (2006) IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 116:1310–1316PubMedCrossRefGoogle Scholar
  77. 77.
    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
  78. 78.
    Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, Odden AR, Shellito JE, Bagby GJ, Nelson S, Kolls JK (2005) Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 202:761–769PubMedCrossRefGoogle Scholar
  79. 79.
    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 T(H)17 lineage. Nature 441:231–234PubMedCrossRefGoogle Scholar
  80. 80.
    Huang W, Na L, Fidel PL, Schwarzenberger P (2004) Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190:624–631PubMedCrossRefGoogle Scholar
  81. 81.
    Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, Akitsu A, Fujikado N, Kusaka T, Kubo S, Chung SH, Komatsu R, Miura N, Adachi Y, Ohno N, Shibuya K, Yamamoto N, Kawakami K, Yamasaki S, Saito T, Akira S, Iwakura Y (2010) Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 32:681–691PubMedCrossRefGoogle Scholar
  82. 82.
    Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487PubMedCrossRefGoogle Scholar
  83. 83.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967–974PubMedCrossRefGoogle Scholar
  84. 84.
    Matsuki T, Nakae S, Sudo K, Horai R, Iwakura Y (2006) Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int Immunol 18:399–407PubMedCrossRefGoogle Scholar
  85. 85.
    Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203:1685–1691PubMedCrossRefGoogle Scholar
  86. 86.
    Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133PubMedCrossRefGoogle Scholar
  87. 87.
    Rutitzky LI, Lopes da Rosa JR, Stadecker MJ (2005) Severe CD4 T cell-mediated immunopathology in murine schistosomiasis is dependent on IL-12p40 and correlates with high levels of IL-17. J Immunol 175:3920–3926PubMedGoogle Scholar
  88. 88.
    Shainheit MG, Saraceno R, Bazzone LE, Rutitzky LI, Stadecker MJ (2007) Disruption of interleukin-27 signaling results in impaired gamma interferon production but does not significantly affect immunopathology in murine schistosome infection. Infect Immun 75:3169–3177PubMedCrossRefGoogle Scholar
  89. 89.
    Rutitzky LI, Smith PM, Stadecker MJ (2009) T-bet protects against exacerbation of schistosome egg-induced immunopathology by regulating Th17-mediated inflammation. Eur J Immunol 39:2470–2481PubMedCrossRefGoogle Scholar
  90. 90.
    Rutitzky LI, Stadecker MJ (2011) Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL-17 and restrained by IFN-gamma. Eur J Immunol 41:2677–2687PubMedCrossRefGoogle Scholar
  91. 91.
    Shainheit MG, Smith PM, Bazzone LE, Wang AC, Rutitzky LI, Stadecker MJ (2008) Dendritic cell IL-23 and IL-1 production in response to schistosome eggs induces Th17 cells in a mouse strain prone to severe immunopathology. J Immunol 181:8559–8567PubMedGoogle Scholar
  92. 92.
    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
  93. 93.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189PubMedCrossRefGoogle Scholar
  94. 94.
    Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949PubMedCrossRefGoogle Scholar
  95. 95.
    van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, Kapsenberg ML, de Jong EC (2007) Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. Immunity 27:660–669PubMedCrossRefGoogle Scholar
  96. 96.
    Ghoreschi K, Laurence A, Yang XP, Tato CM, McGeachy MJ, Konkel JE, Ramos HL, Wei L, Davidson TS, Bouladoux N, Grainger JR, Chen Q, Kanno Y, Watford WT, Sun HW, Eberl G, Shevach EM, Belkaid Y, Cua DJ, Chen W, O’Shea JJ (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971PubMedCrossRefGoogle Scholar
  97. 97.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517PubMedCrossRefGoogle Scholar
  98. 98.
    Sacks D, Noben-Trauth N (2002) The immunology of susceptibility and resistance to Leishmania major in mice. Nat Rev Immunol 2:845–858PubMedCrossRefGoogle Scholar
  99. 99.
    Locksley RM, Heinzel FP, Sadick MD, Holaday BJ, Gardner KD Jr (1987) Murine cutaneous leishmaniasis: susceptibility correlates with differential expansion of helper T-cell subsets. Ann Inst Pasteur Immunol 138:744–749PubMedCrossRefGoogle Scholar
  100. 100.
    van Die I, van Vliet SJ, Nyame AK, Cummings RD, Bank CM, Appelmelk B, Geijtenbeek TB, van Kooyk Y (2003) The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x. Glycobiology 13:471–478Google Scholar
  101. 101.
    van Liempt E, van Vliet SJ, Engering A, Garcia Vallejo JJ, Bank CM, Sanchez-Hernandez M, van Kooyk Y, van Die I (2007) Schistosoma mansoni soluble egg antigens are internalized by human dendritic cells through multiple C-type lectins and suppress TLR-induced dendritic cell activation. Mol Immunol 44:2605–2615PubMedCrossRefGoogle Scholar
  102. 102.
    Zhang Y, Chen L, Gao W, Hou X, Gu Y, Gui L, Huang D, Liu M, Ren C, Wang S, Shen J (2012) IL-17 neutralization significantly ameliorates hepatic granulomatous inflammation and liver damage in Schistosoma japonicum infected mice. Eur J Immunol 42:1523–1535PubMedCrossRefGoogle Scholar
  103. 103.
    Mbow M, Larkin BM, Meurs L, Wammes LJ, de Jong SE, Labuda LA, Camara M, Smits HH, Polman K, Dieye TN, Mboup S, Stadecker MJ, Yazdanbakhsh M (2012) Th17 cells are associated with pathology in human schistosomiasis. J Infect Dis (in press)Google Scholar
  104. 104.
    Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564PubMedCrossRefGoogle Scholar
  105. 105.
    Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787PubMedCrossRefGoogle Scholar
  106. 106.
    Goerdt S, Orfanos CE (1999) Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 10:137–142PubMedCrossRefGoogle Scholar
  107. 107.
    Anthony RM, Rutitzky LI, Urban JF Jr, Stadecker MJ, Gause WC (2007) Protective immune mechanisms in helminth infection. Nat Rev Immunol 7:975–987PubMedCrossRefGoogle Scholar
  108. 108.
    Nair MG, Cochrane DW, Allen JE (2003) Macrophages in chronic type 2 inflammation have a novel phenotype characterized by the abundant expression of Ym1 and Fizz1 that can be partly replicated in vitro. Immunol Lett 85:173–180PubMedCrossRefGoogle Scholar
  109. 109.
    Hesse M, Piccirillo CA, Belkaid Y, Prufer J, Mentink-Kane M, Leusink M, Cheever AW, Shevach EM, Wynn TA (2004) The pathogenesis of schistosomiasis is controlled by cooperating IL-10-producing innate effector and regulatory T cells. J Immunol 172:3157–3166PubMedGoogle Scholar
  110. 110.
    McKee AS, Pearce EJ (2004) CD25+ CD4+ cells contribute to Th2 polarization during helminth infection by suppressing Th1 response development. J Immunol 173:1224–1231PubMedGoogle Scholar
  111. 111.
    Baumgart M, Tompkins F, Leng J, Hesse M (2006) Naturally occurring CD4+ Foxp3+ regulatory T cells are an essential, IL-10-independent part of the immunoregulatory network in Schistosoma mansoni egg-induced inflammation. J Immunol 176:5374–5387PubMedGoogle Scholar
  112. 112.
    Bazzone LE, Smith PM, Rutitzky LI, Shainheit MG, Urban JF, Setiawan T, Blum AM, Weinstock JV, Stadecker MJ (2008) Coinfection with the intestinal nematode Heligmosomoides polygyrus markedly reduces hepatic egg-induced immunopathology and proinflammatory cytokines in mouse models of severe schistosomiasis. Infect Immun 76:5164–5172PubMedCrossRefGoogle Scholar
  113. 113.
    McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (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 8:1390–1397PubMedCrossRefGoogle Scholar
  114. 114.
    Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109PubMedCrossRefGoogle Scholar
  115. 115.
    Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777PubMedGoogle Scholar
  116. 116.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704PubMedCrossRefGoogle Scholar
  117. 117.
    Colley DG, Sasser LE, Reed AM (2005) PD-L2+ dendritic cells and PD-1+ CD4+ T cells in schistosomiasis correlate with morbidity. Parasite Immunol 27:45–53PubMedCrossRefGoogle Scholar
  118. 118.
    Maizels RM, Yazdanbakhsh M (2008) T-cell regulation in helminth parasite infections: implications for inflammatory diseases. Chem Immunol Allergy 94:112–123PubMedCrossRefGoogle Scholar
  119. 119.
    Jackson JA, Friberg IM, Little S, Bradley JE (2009) Review series on helminths, immune modulation and the hygiene hypothesis: immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies? Immunology 126:18–27PubMedCrossRefGoogle Scholar
  120. 120.
    Maizels RM (2005) Infections and allergy—helminths, hygiene and host immune regulation. Curr Opin Immunol 17:656–661PubMedCrossRefGoogle Scholar
  121. 121.
    Wilson MS, Taylor MD, O’Gorman MT, Balic A, Barr TA, Filbey K, Anderton SM, Maizels RM (2010) Helminth-induced CD19+ CD23hi B cells modulate experimental allergic and autoimmune inflammation. Eur J Immunol 40:1682–1696PubMedCrossRefGoogle Scholar
  122. 122.
    Hubner MP, Shi Y, Torrero MN, Mueller E, Larson D, Soloviova K, Gondorf F, Hoerauf A, Killoran KE, Stocker JT, Davies SJ, Tarbell KV, Mitre E (2012) Helminth protection against autoimmune diabetes in nonobese diabetic mice is independent of a type 2 immune shift and requires TGF-beta. J Immunol 188:559–568PubMedCrossRefGoogle Scholar
  123. 123.
    La Flamme AC, Ruddenklau K, Backstrom BT (2003) Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect Immun 71:4996–5004PubMedCrossRefGoogle Scholar
  124. 124.
    Khan WI, Blennerhasset PA, Varghese AK, Chowdhury SK, Omsted P, Deng Y, Collins SM (2002) Intestinal nematode infection ameliorates experimental colitis in mice. Infect Immun 70:5931–5937PubMedCrossRefGoogle Scholar
  125. 125.
    Elliott DE, Metwali A, Leung J, Setiawan T, Blum AM, Ince MN, Bazzone LE, Stadecker MJ, Urban JF Jr, Weinstock JV (2008) Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production. J Immunol 181:2414–2419Google Scholar
  126. 126.
    Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ, Finney CA, Greenwood EJ, Knox DP, Wilson MS, Belkaid Y, Rudensky AY, Maizels RM (2010) Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J Exp Med 207:2331–2341PubMedCrossRefGoogle Scholar
  127. 127.
    Walk ST, Blum AM, Ewing SA, Weinstock JV, Young VB (2010) Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflamm Bowel Dis 16:1841–1849PubMedCrossRefGoogle Scholar
  128. 128.
    Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G, Eberl G, Snel J, Kelly D, Cerf-Bensussan N (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31:677–689PubMedCrossRefGoogle Scholar
  129. 129.
    Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR (2008) Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4:337–349PubMedCrossRefGoogle Scholar
  130. 130.
    Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV, Tanoue T, Imaoka A, Itoh K, Takeda K, Umesaki Y, Honda K, Littman DR (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498PubMedCrossRefGoogle Scholar
  131. 131.
    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Foureau DM, Haque-Begum S, Kasper LH (2009) Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol 183:6041–6050PubMedCrossRefGoogle Scholar
  132. 132.
    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):4615–4622PubMedCrossRefGoogle Scholar
  133. 133.
    Perona-Wright G, Lundie RJ, Jenkins SJ, Webb LM, Grencis RK, MacDonald AS (2012) Concurrent bacterial stimulation alters the function of helminth-activated dendritic cells, resulting in IL-17 induction. J Immunol 188:2350–2358PubMedCrossRefGoogle Scholar
  134. 134.
    Dessein AJ, Hillaire D, Elwali NE, Marquet S, Mohamed-Ali Q, Mirghani A, Henri S, Abdelhameed AA, Saeed OK, Magzoub MM, Abel L (1999) Severe hepatic fibrosis in Schistosoma mansoni infection is controlled by a major locus that is closely linked to the interferon-gamma receptor gene. Am J Hum Genet 65:709–721PubMedCrossRefGoogle Scholar
  135. 135.
    Dessein AJ, Marquet S, Henri S, El Wali NE, Hillaire D, Rodrigues V, Prata A, Ali QM, Gharib B, de Reggi M, Magzoub MM, Saeed OK, Abdelhameed AA, Abel L (1999) Infection and disease in human schistosomiasis mansoni are under distinct major gene control. Microbes Infect 1:561–567PubMedCrossRefGoogle Scholar
  136. 136.
    Rutitzky LI, Hernandez HJ, Yim YS, Ricklan DE, Finger E, Mohan C, Peter I, Wakeland EK, Stadecker MJ (2005) Enhanced egg-induced immunopathology correlates with high IFN-gamma in murine schistosomiasis: identification of two epistatic genetic intervals. J Immunol 174:435–440PubMedGoogle Scholar
  137. 137.
    Smith PM, Shainheit MG, Bazzone LE, Rutitzky LI, Poltorak A, Stadecker MJ (2009) Genetic control of severe egg-induced immunopathology and IL-17 production in murine schistosomiasis. J Immunol 183:3317–3323PubMedCrossRefGoogle Scholar
  138. 138.
    Teuscher C, Doerge RW, Fillmore PD, Blankenhorn EP (2006) eae36, a locus on mouse chromosome 4, controls susceptibility to experimental allergic encephalomyelitis in older mice and mice immunized in the winter. Genetics 172:1147–1153PubMedCrossRefGoogle Scholar
  139. 139.
    Morel L, Tian XH, Croker BP, Wakeland EK (1999) Epistatic modifiers of autoimmunity in a murine model of lupus nephritis. Immunity 11:131–139PubMedCrossRefGoogle Scholar
  140. 140.
    Roberts LJ, Baldwin TM, Curtis JM, Handman E, Foote SJ (1997) Resistance to Leishmania major is linked to the H2 region on chromosome 17 and to chromosome 9. J Exp Med 185:1705–1710Google Scholar
  141. 141.
    Fortin A, Stevenson MM, Gros P (2002) Complex genetic control of susceptibility to malaria in mice. Genes Immun 3:177–186PubMedCrossRefGoogle Scholar
  142. 142.
    Jurynczyk M, Jurewicz A, Raine CS, Selmaj K (2008) Notch3 inhibition in myelin-reactive T cells down-regulates protein kinase C theta and attenuates experimental autoimmune encephalomyelitis. J Immunol 180:2634–2640PubMedGoogle Scholar
  143. 143.
    Frazer KA, Eskin E, Kang HM, Bogue MA, Hinds DA, Beilharz EJ, Gupta RV, Montgomery J, Morenzoni MM, Nilsen GB, Pethiyagoda CL, Stuve LL, Johnson FM, Daly MJ, Wade CM, Cox DR (2007) A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Nature 448:1050–1053PubMedCrossRefGoogle Scholar
  144. 144.
    Yang H, Bell TA, Churchill GA, Pardo-Manuel de Villena F (2007) On the subspecific origin of the laboratory mouse. Nat Genet 39:1100–1107PubMedCrossRefGoogle Scholar
  145. 145.
    Guenet JL, Bonhomme F (2003) Wild mice: an ever-increasing contribution to a popular mammalian model. Trends Genet 19:24–31PubMedCrossRefGoogle Scholar
  146. 146.
    Smith PM, Jacque B, Conner JR, Poltorak A, Stadecker MJ (2011) IRAK-2 regulates IL-1-mediated pathogenic Th17 cell development in helminthic infection. PLoS Pathog 7:e1002272PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Bridget M. Larkin
    • 1
  • Patrick M. Smith
    • 1
  • Holly E. Ponichtera
    • 1
  • Mara G. Shainheit
    • 1
  • Laura I. Rutitzky
    • 1
  • Miguel J. Stadecker
    • 1
  1. 1.Department of PathologyTufts University School of MedicineBostonUSA

Personalised recommendations