Seminars in Immunopathology

, Volume 39, Issue 1, pp 55–68 | Cite as

Th9 and other IL-9-producing cells in allergic asthma

  • Sonja Koch
  • Nina Sopel
  • Susetta Finotto


Allergic asthma is a worldwide increasing chronic disease of the airways which affects more than 300 million people. It is associated with increased IgE, mast cell activation, airway hyperresponsiveness (AHR), mucus overproduction and remodeling of the airways. Previously, this pathological trait has been associated with T helper type 2 (Th2) cells. Recently, different CD4+ T cell subsets (Th17, Th9) as well as cells of innate immunity, like mast cells and innate lymphoid cells type 2 (ILC2s), which are all capable of producing the rediscovered cytokine IL-9, are known to contribute to this disease. Regarding Th9 cells, it is known that naïve T cells develop into IL-9-producing cells in the presence of interleukin-4 (IL-4) and transforming growth factor beta (TGFβ). Downstream of IL-4, several transcription factors like signal transducer and activator of transcription 6 (STAT6), interferon regulatory factor 4 (IRF4), GATA binding protein 3 (GATA3), basic leucine zipper transcription factor, ATF-like (BATF) and nuclear factor of activated T cells (NFAT) are activated. Additionally, the transcription factor PU.1, which is downstream of TGFβ signaling, also seems to be crucial in the development of Th9 cells. IL-9 is a pleiotropic cytokine that influences various distinct functions of different target cells such as T cells, B cells, mast cells and airway epithelial cells by activating STAT1, STAT3 and STAT5. Because of its pleiotropic functions, IL-9 has been demonstrated to be involved in several diseases, such as cancer, autoimmunity and other pathogen-mediated immune-regulated diseases. In this review, we focus on the role of Th9 and IL-9-producing cells in allergic asthma.


Th9 IL-9 Allergic asthma IL-9R Mast cells ILC2 



This work has been supported by the Department of Molecular Pneumology and by the Deutsche Forschungsgemeinschaft (DFG grant KO 5404/1-1).


  1. 1.
    Barnes PJ (2009) Intrinsic asthma: not so different from allergic asthma but driven by superantigens? Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 39(8):1145–1151. doi: 10.1111/j.1365-2222.2009.03298.x CrossRefGoogle Scholar
  2. 2.
    Holgate ST (2012) Innate and adaptive immune responses in asthma. Nat Med 18(5):673–683. doi: 10.1038/nm.2731 PubMedCrossRefGoogle Scholar
  3. 3.
    Lambrecht BN, Hammad H (2015) The immunology of asthma. Nat Immunol 16(1):45–56. doi: 10.1038/ni.3049 PubMedCrossRefGoogle Scholar
  4. 4.
    Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S, Kuhn R, Muller W, Palm N, Rude E (1994) IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 153(9):3989–3996PubMedGoogle Scholar
  5. 5.
    Goswami R, Jabeen R, Yagi R, Pham D, Zhu J, Goenka S, Kaplan MH (2012) STAT6-dependent regulation of Th9 development. J Immunol 188(3):968–975. doi: 10.4049/jimmunol.1102840 PubMedCrossRefGoogle Scholar
  6. 6.
    Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol 9(12):1347–1355. doi: 10.1038/ni.1677 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346. doi: 10.1038/ni.1659 PubMedCrossRefGoogle Scholar
  8. 8.
    Tamiya T, Ichiyama K, Kotani H, Fukaya T, Sekiya T, Shichita T, Honma K, Yui K, Matsuyama T, Nakao T, Fukuyama S, Inoue H, Nomura M, Yoshimura A (2013) Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. J Immunol 191(5):2360–2371. doi: 10.4049/jimmunol.1301276 PubMedCrossRefGoogle Scholar
  9. 9.
    Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, Jabeen R, McKinley C, Ahyi AN, Han L, Nguyen ET, Robertson MJ, Perumal NB, Tepper RS, Nutt SL, Kaplan MH (2010) The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11(6):527–534. doi: 10.1038/ni.1867 PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Goswami R, Kaplan MH (2012) Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol 189(6):3026–3033. doi: 10.4049/jimmunol.1201496 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Chang HC, Han L, Jabeen R, Carotta S, Nutt SL, Kaplan MH (2009) PU.1 regulates TCR expression by modulating GATA-3 activity. J Immunol 183(8):4887–4894. doi: 10.4049/jimmunol.0900363 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chang HC, Zhang S, Thieu VT, Slee RB, Bruns HA, Laribee RN, Klemsz MJ, Kaplan MH (2005) PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity 22(6):693–703. doi: 10.1016/j.immuni.2005.03.016 PubMedCrossRefGoogle Scholar
  13. 13.
    Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33(2):192–202. doi: 10.1016/j.immuni.2010.07.014 PubMedCrossRefGoogle Scholar
  14. 14.
    Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8(9):958–966. doi: 10.1038/ni1500 PubMedCrossRefGoogle Scholar
  15. 15.
    Lohoff M, Mittrucker HW, Prechtl S, Bischof S, Sommer F, Kock S, Ferrick DA, Duncan GS, Gessner A, Mak TW (2002) Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci U S A 99(18):11808–11812. doi: 10.1073/pnas.182425099 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Jabeen R, Goswami R, Awe O, Kulkarni A, Nguyen ET, Attenasio A, Walsh D, Olson MR, Kim MH, Tepper RS, Sun J, Kim CH, Taparowsky EJ, Zhou B, Kaplan MH (2013) Th9 cell development requires a BATF-regulated transcriptional network. J Clin Invest 123(11):4641–4653. doi: 10.1172/JCI69489 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Jash A, Sahoo A, Kim GC, Chae CS, Hwang JS, Kim JE, Im SH (2012) Nuclear factor of activated T cells 1 (NFAT1)-induced permissive chromatin modification facilitates nuclear factor-kappaB (NF-kappaB)-mediated interleukin-9 (IL-9) transactivation. J Biol Chem 287(19):15445–15457. doi: 10.1074/jbc.M112.340356 PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Xiao X, Balasubramanian S, Liu W, Chu X, Wang H, Taparowsky EJ, Fu YX, Choi Y, Walsh MC, Li XC (2012) OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat Immunol 13(10):981–990. doi: 10.1038/ni.2390 PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kaplan MH, Glosson NL, Stritesky GL, Yeh N, Kinzfogl J, Rohrabaugh SL, Goswami R, Pham D, Levy DE, Brutkiewicz RR, Blum JS, Cooper S, Hangoc G, Broxmeyer HE (2011) STAT3-dependent IL-21 production from T helper cells regulates hematopoietic progenitor cell homeostasis. Blood 117(23):6198–6201. doi: 10.1182/blood-2011-02-334367 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, Bettelli E, Oukka M, van Snick J, Renauld JC, Kuchroo VK, Khoury SJ (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106(31):12885–12890. doi: 10.1073/pnas.0812530106 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, Coyle AJ, Kasper LH, Noelle RJ (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206(8):1653–1660. doi: 10.1084/jem.20090246 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Wiener Z, Falus A, Toth S (2004) IL-9 increases the expression of several cytokines in activated mast cells, while the IL-9-induced IL-9 production is inhibited in mast cells of histamine-free transgenic mice. Cytokine 26(3):122–130. doi: 10.1016/j.cyto.2004.01.006 PubMedCrossRefGoogle Scholar
  23. 23.
    Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, Sparwasser T, Helmby H, Stockinger B (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol 12(11):1071–1077. doi: 10.1038/ni.2133 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Jones CP, Gregory LG, Causton B, Campbell GA, Lloyd CM (2012) Activin A and TGF-beta promote T(H)9 cell-mediated pulmonary allergic pathology. The Journal of allergy and clinical immunology 129(4):1000–1010 . doi: 10.1016/j.jaci.2011.12.965e1003PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Kara EE, Comerford I, Bastow CR, Fenix KA, Litchfield W, Handel TM, McColl SR (2013) Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites. J Immunol 191(3):1110–1117. doi: 10.4049/jimmunol.1203089 PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Kerzerho J, Maazi H, Speak AO, Szely N, Lombardi V, Khoo B, Geryak S, Lam J, Soroosh P, Van Snick J, Akbari O (2013) Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity. The Journal of allergy and clinical immunology 131(4):1048–1057 . doi: 10.1016/j.jaci.2012.09.0271057 e1041-1042PubMedCrossRefGoogle Scholar
  27. 27.
    Temann UA, Geba GP, Rankin JA, Flavell RA (1998) Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med 188(7):1307–1320PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Temann UA, Laouar Y, Eynon EE, Homer R, Flavell RA (2007) IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells. Int Immunol 19(1):1–10. doi: 10.1093/intimm/dxl117 PubMedCrossRefGoogle Scholar
  29. 29.
    Temann UA, Ray P, Flavell RA (2002) Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest 109(1):29–39. doi: 10.1172/JCI13696 PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Sehra S, Yao W, Nguyen ET, Glosson-Byers NL, Akhtar N, Zhou B, Kaplan MH (2015) TH9 cells are required for tissue mast cell accumulation during allergic inflammation. The Journal of allergy and clinical immunology 136(2):433–440 . doi: 10.1016/j.jaci.2015.01.021e431PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Ubel C, Sopel N, Graser A, Hildner K, Reinhardt C, Zimmermann T, Rieker RJ, Maier A, Neurath MF, Murphy KM, Finotto S (2014) The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma. The Journal of allergy and clinical immunology 133(1):198–206 . doi: 10.1016/j.jaci.2013.09.049e199PubMedCrossRefGoogle Scholar
  32. 32.
    Yao W, Zhang Y, Jabeen R, Nguyen ET, Wilkes DS, Tepper RS, Kaplan MH, Zhou B (2013) Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 38(2):360–372. doi: 10.1016/j.immuni.2013.01.007 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186(6):3283–3288. doi: 10.4049/jimmunol.1003049 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Yao W, Tepper RS, Kaplan MH (2011) Predisposition to the development of IL-9-secreting T cells in atopic infants. The Journal of allergy and clinical immunology 128(6):1357–1360 . doi: 10.1016/j.jaci.2011.06.019e1355PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Cheng G, Arima M, Honda K, Hirata H, Eda F, Yoshida N, Fukushima F, Ishii Y, Fukuda T (2002) Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med 166(3):409–416. doi: 10.1164/rccm.2105079 PubMedCrossRefGoogle Scholar
  36. 36.
    Oh CK, Leigh R, McLaurin KK, Kim K, Hultquist M, Molfino NA (2013) A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir Res 14:93. doi: 10.1186/1465-9921-14-93 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Holgate ST, Polosa R (2008) Treatment strategies for allergy and asthma. Nat Rev Immunol 8(3):218–230. doi: 10.1038/nri2262 PubMedCrossRefGoogle Scholar
  38. 38.
    Klein M, Bruhl TJ, Staudt V, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Bohn T, Ulges A, Stergiou N, de Graaf J, Lower M, Taube C, Becker M, Hain T, Dietzen S, Stassen M, Huber M, Lohoff M, Campos Chagas A, Andersen J, Kotal J, Langhansova H, Kopecky J, Schild H, Kotsyfakis M, Schmitt E, Bopp T (2015) Tick salivary sialostatin L represses the initiation of immune responses by targeting IRF4-dependent transcription in murine mast cells. J Immunol 195(2):621–631. doi: 10.4049/jimmunol.1401823 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442(7106):997–1002. doi: 10.1038/nature05010 PubMedCrossRefGoogle Scholar
  40. 40.
    Gessner A, Blum H, Rollinghoff M (1993) Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology 189(5):419–435. doi: 10.1016/S0171-2985(11)80414-6 PubMedCrossRefGoogle Scholar
  41. 41.
    He R, Oyoshi MK, Jin H, Geha RS (2007) Epicutaneous antigen exposure induces a Th17 response that drives airway inflammation after inhalation challenge. Proc Natl Acad Sci U S A 104(40):15817–15822. doi: 10.1073/pnas.0706942104 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK (2008) TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol 181(6):4089–4097PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN (2009) Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am J Respir Crit Care Med 180(8):720–730. doi: 10.1164/rccm.200904-0573OC PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Al-Ramli W, Prefontaine D, Chouiali F, Martin JG, Olivenstein R, Lemiere C, Hamid Q (2009) T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. The Journal of allergy and clinical immunology 123(5):1185–1187. doi: 10.1016/j.jaci.2009.02.024 PubMedCrossRefGoogle Scholar
  45. 45.
    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. The Journal of allergy and clinical immunology 108(3):430–438. doi: 10.1067/mai.2001.117929 PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao Y, Yang J, Gao YD, Guo W (2010) Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol 151(4):297–307. doi: 10.1159/000250438 PubMedCrossRefGoogle Scholar
  47. 47.
    Wakashin H, Hirose K, Maezawa Y, Kagami S, Suto A, Watanabe N, Saito Y, Hatano M, Tokuhisa T, Iwakura Y, Puccetti P, Iwamoto I, Nakajima H (2008) IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am J Respir Crit Care Med 178(10):1023–1032. doi: 10.1164/rccm.200801-086OC PubMedCrossRefGoogle Scholar
  48. 48.
    Chung Y, Dong C (2009) Don’t leave home without it: the IL-23 visa to T(H)-17 cells. Nat Immunol 10(3):236–238. doi: 10.1038/ni0309-236 PubMedCrossRefGoogle Scholar
  49. 49.
    McGeachy MJ, Chen Y, Tato CM, Laurence A, Joyce-Shaikh B, Blumenschein WM, McClanahan TK, O'Shea JJ, Cua DJ (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10(3):314–324. doi: 10.1038/ni.1698 PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Kearley J, Barker JE, Robinson DS, Lloyd CM (2005) Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J Exp Med 202(11):1539–1547. doi: 10.1084/jem.20051166 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kearley J, Robinson DS, Lloyd CM (2008) CD4+CD25+ regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. The Journal of allergy and clinical immunology 122(3):617–624 . doi: 10.1016/j.jaci.2008.05.048e616PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lewkowich IP, Herman NS, Schleifer KW, Dance MP, Chen BL, Dienger KM, Sproles AA, Shah JS, Kohl J, Belkaid Y, Wills-Karp M (2005) CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J Exp Med 202(11):1549–1561. doi: 10.1084/jem.20051506 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, Griese M, Krauss-Etschmann S (2007) Quantitative and functional impairment of pulmonary CD4+CD25hi regulatory T cells in pediatric asthma. The Journal of allergy and clinical immunology 119(5):1258–1266. doi: 10.1016/j.jaci.2007.02.023 PubMedCrossRefGoogle Scholar
  54. 54.
    Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY, Ziegler SF, Littman DR (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240. doi: 10.1038/nature06878 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Liu Y, Teige I, Birnir B, Issazadeh-Navikas S (2006) Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat Med 12(5):518–525. doi: 10.1038/nm1402 PubMedCrossRefGoogle Scholar
  56. 56.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490. doi: 10.1016/j.immuni.2005.09.015 PubMedCrossRefGoogle Scholar
  57. 57.
    Barlow JL, Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, McKenzie AN (2012) Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. The Journal of allergy and clinical immunology 129(1):191–198 . doi: 10.1016/j.jaci.2011.09.041e191-194PubMedCrossRefGoogle Scholar
  58. 58.
    Klein Wolterink RG, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M, Levani Y, Hendriks RW (2012) Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol 42(5):1106–1116. doi: 10.1002/eji.201142018 PubMedCrossRefGoogle Scholar
  59. 59.
    Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN (2010) Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464(7293):1367–1370. doi: 10.1038/nature08900 PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Turner JE, Morrison PJ, Wilhelm C, Wilson M, Ahlfors H, Renauld JC, Panzer U, Helmby H, Stockinger B (2013) IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J Exp Med 210(13):2951–2965. doi: 10.1084/jem.20130071 PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Stassen M, Arnold M, Hultner L, Muller C, Neudorfl C, Reineke T, Schmitt E (2000) Murine bone marrow-derived mast cells as potent producers of IL-9: costimulatory function of IL-10 and kit ligand in the presence of IL-1. J Immunol 164(11):5549–5555PubMedCrossRefGoogle Scholar
  62. 62.
    Kronenberg M, Gapin L (2002) The unconventional lifestyle of NKT cells. Nat Rev Immunol 2(8):557–568. doi: 10.1038/nri854 PubMedGoogle Scholar
  63. 63.
    Lisbonne M, Leite-de-Moraes MC (2003) Invariant Valpha14 NKT lymphocytes: a double-edged immuno-regulatory T cell population. Eur Cytokine Netw 14(1):4–14PubMedGoogle Scholar
  64. 64.
    DeKruyff RH, Yu S, Kim HY, Umetsu DT (2014) Innate immunity in the lung regulates the development of asthma. Immunol Rev 260(1):235–248. doi: 10.1111/imr.12187 PubMedCrossRefGoogle Scholar
  65. 65.
    Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278(5343):1626–1629PubMedCrossRefGoogle Scholar
  66. 66.
    Lisbonne M, Diem S, de Castro KA, Lefort J, Araujo LM, Hachem P, Fourneau JM, Sidobre S, Kronenberg M, Taniguchi M, Van Endert P, Dy M, Askenase P, Russo M, Vargaftig BB, Herbelin A, Leite-de-Moraes MC (2003) Cutting edge: invariant V alpha 14 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. J Immunol 171(4):1637–1641PubMedCrossRefGoogle Scholar
  67. 67.
    Lauwerys BR, Garot N, Renauld JC, Houssiau FA (2000) Cytokine production and killer activity of NK/T-NK cells derived with IL-2, IL-15, or the combination of IL-12 and IL-18. J Immunol 165(4):1847–1853PubMedCrossRefGoogle Scholar
  68. 68.
    Monteiro M, Agua-Doce A, Almeida CF, Fonseca-Pereira D, Veiga-Fernandes H, Graca L (2015) IL-9 expression by invariant NKT cells is not imprinted during thymic development. J Immunol 195(7):3463–3471. doi: 10.4049/jimmunol.1403170 PubMedCrossRefGoogle Scholar
  69. 69.
    Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, Gyarmati D, Aye T, Campbell DJ, Ziegler SF (2005) Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 6(10):1047–1053. doi: 10.1038/ni1247 PubMedCrossRefGoogle Scholar
  70. 70.
    Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, Qin FX, Yao Z, Cao W, Liu YJ (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202(9):1213–1223. doi: 10.1084/jem.20051135 PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Richard AC, Tan C, Hawley ET, Gomez-Rodriguez J, Goswami R, Yang XP, Cruz AC, Penumetcha P, Hayes ET, Pelletier M, Gabay O, Walsh M, Ferdinand JR, Keane-Myers A, Choi Y, O'Shea JJ, Al-Shamkhani A, Kaplan MH, Gery I, Siegel RM, Meylan F (2015) The TNF-family ligand TL1A and its receptor DR3 promote T cell-mediated allergic immunopathology by enhancing differentiation and pathogenicity of IL-9-producing T cells. J Immunol 194(8):3567–3582. doi: 10.4049/jimmunol.1401220 PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Gomez-Rodriguez J, Meylan F, Handon R, Hayes ET, Anderson SM, Kirby MR, Siegel RM, Schwartzberg PL (2016) Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun 7:10857. doi: 10.1038/ncomms10857 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Ubel C, Graser A, Koch S, Rieker RJ, Lehr HA, Muller M, Finotto S (2014) Role of Tyk-2 in Th9 and Th17 cells in allergic asthma. Scientific reports 4:5865. doi: 10.1038/srep05865 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Koch S, Reppert S, Finotto S (2015) NFATc1 deletion in T lymphocytes inhibits the allergic trait in a murine model of asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 45(8):1356–1366. doi: 10.1111/cea.12493 CrossRefGoogle Scholar
  75. 75.
    Koch S, Graser A, Mirzakhani H, Zimmermann T, Melichar VO, Wolfel M, Croteau-Chonka DC, Raby BA, Weiss ST, Finotto S (2016) Increased expression of nuclear factor of activated T cells 1 drives IL-9-mediated allergic asthma. The Journal of allergy and clinical immunology 137(6):1898–1902 . doi: 10.1016/j.jaci.2015.11.047e1897PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Karwot R, Maxeiner JH, Schmitt S, Scholtes P, Hausding M, Lehr HA, Glimcher LH, Finotto S (2008) Protective role of nuclear factor of activated T cells 2 in CD8+ long-lived memory T cells in an allergy model. The Journal of allergy and clinical immunology 121(4):992–999 . doi: 10.1016/j.jaci.2007.12.1172e996PubMedCrossRefGoogle Scholar
  77. 77.
    Hoppenot D, Malakauskas K, Lavinskiene S, Sakalauskas R (2015) P-STAT6, PU.1, and NF-kappaB are involved in allergen-induced late-phase airway inflammation in asthma patients. BMC pulmonary medicine 15:122. doi: 10.1186/s12890-015-0119-7 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Barnes PJ, Adcock IM (1997) NF-kappa B: a pivotal role in asthma and a new target for therapy. Trends Pharmacol Sci 18(2):46–50PubMedCrossRefGoogle Scholar
  79. 79.
    Qiao G, Ying H, Zhao Y, Liang Y, Guo H, Shen H, Li Z, Solway J, Tao E, Chiang YJ, Lipkowitz S, Penninger JM, Langdon WY, Zhang J (2014) E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation. Cell Rep 6(4):709–723. doi: 10.1016/j.celrep.2014.01.012 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Mikami N, Miyagi Y, Sueda K, Takatsuji M, Fukada S, Yamamoto H, Tsujikawa K (2013) Calcitonin gene-related peptide and cyclic adenosine 5'-monophosphate/protein kinase A pathway promote IL-9 production in Th9 differentiation process. J Immunol 190(8):4046–4055. doi: 10.4049/jimmunol.1203102 PubMedCrossRefGoogle Scholar
  81. 81.
    Li H, Edin ML, Bradbury JA, Graves JP, DeGraff LM, Gruzdev A, Cheng J, Dackor RT, Wang PM, Bortner CD, Garantziotis S, Jetten AM, Zeldin DC (2013) Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB. Am J Respir Crit Care Med 187(8):812–822. doi: 10.1164/rccm.201211-2073OC PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Reuter S, Maxeiner J, Meyer-Martin H, Michel A, Baars P, Bopp T, Waisman A, Reissig S, Wehler TC, Schild H, Taube C, Stassen M, Becker M (2016) Cylindromatosis (Cyld) gene mutation in T cells promotes the development of an IL-9-dependent allergic phenotype in experimental asthma. Cell Immunol. doi: 10.1016/j.cellimm.2016.06.003 PubMedGoogle Scholar
  83. 83.
    Wang Y, Bi Y, Chen X, Li C, Li Y, Zhang Z, Wang J, Lu Y, Yu Q, Su H, Yang H, Liu G (2016) Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4(+) T cells. Immunity 44(6):1337–1349. doi: 10.1016/j.immuni.2016.05.009 PubMedCrossRefGoogle Scholar
  84. 84.
    Keating P, Munim A, Hartmann JX (2014) Effect of vitamin D on T-helper type 9 polarized human memory cells in chronic persistent asthma. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 112(2):154–162. doi: 10.1016/j.anai.2013.11.015 CrossRefGoogle Scholar
  85. 85.
    Li P, Spolski R, Liao W, Wang L, Murphy TL, Murphy KM, Leonard WJ (2012) BATF-JUN is critical for IRF4-mediated transcription in T cells. Nature. doi: 10.1038/nature11530 Google Scholar
  86. 86.
    Froidure A, Shen C, Gras D, Van Snick J, Chanez P, Pilette C (2014) Myeloid dendritic cells are primed in allergic asthma for thymic stromal lymphopoietin-mediated induction of Th2 and Th9 responses. Allergy 69(8):1068–1076. doi: 10.1111/all.12435 PubMedCrossRefGoogle Scholar
  87. 87.
    Bauer JH, Liu KD, You Y, Lai SY, Goldsmith MA (1998) Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis. J Biol Chem 273(15):9255–9260PubMedCrossRefGoogle Scholar
  88. 88.
    Demoulin JB, Uyttenhove C, Van Roost E, DeLestre B, Donckers D, Van Snick J, Renauld JC (1996) A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Mol Cell Biol 16(9):4710–4716PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Renauld JC, Druez C, Kermouni A, Houssiau F, Uyttenhove C, Van Roost E, Van Snick J (1992) Expression cloning of the murine and human interleukin 9 receptor cDNAs. Proc Natl Acad Sci U S A 89(12):5690–5694PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Pilette C, Ouadrhiri Y, Van Snick J, Renauld JC, Staquet P, Vaerman JP, Sibille Y (2002) IL-9 inhibits oxidative burst and TNF-alpha release in lipopolysaccharide-stimulated human monocytes through TGF-beta. J Immunol 168(8):4103–4111PubMedCrossRefGoogle Scholar
  91. 91.
    Wu B, Huang C, Kato-Maeda M, Hopewell PC, Daley CL, Krensky AM, Clayberger C (2008) IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol 126(2):202–210. doi: 10.1016/j.clim.2007.09.009 PubMedCrossRefGoogle Scholar
  92. 92.
    Eklund KK, Ghildyal N, Austen KF, Stevens RL (1993) Induction by IL-9 and suppression by IL-3 and IL-4 of the levels of chromosome 14-derived transcripts that encode late-expressed mouse mast cell proteases. J Immunol 151(8):4266–4273PubMedGoogle Scholar
  93. 93.
    Hultner L, Moeller J (1990) Mast cell growth-enhancing activity (MEA) stimulates interleukin 6 production in a mouse bone marrow-derived mast cell line and a malignant subline. Exp Hematol 18(8):873–877PubMedGoogle Scholar
  94. 94.
    Lora JM, Al-Garawi A, Pickard MD, Price KS, Bagga S, Sicoli J, Hodge MR, Gutierrez-Ramos JC, Briskin MJ, Boyce JA (2003) FcepsilonRI-dependent gene expression in human mast cells is differentially controlled by T helper type 2 cytokines. The Journal of allergy and clinical immunology 112(6):1119–1126. doi: 10.1016/j.jaci.2003.08.042 PubMedCrossRefGoogle Scholar
  95. 95.
    Matsuzawa S, Sakashita K, Kinoshita T, Ito S, Yamashita T, Koike K (2003) IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J Immunol 170(7):3461–3467PubMedCrossRefGoogle Scholar
  96. 96.
    Ingram JL, Kraft M (2012) IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. The Journal of allergy and clinical immunology 130(4):829–842 . doi: 10.1016/j.jaci.2012.06.034quiz 843-824PubMedCrossRefGoogle Scholar
  97. 97.
    Gounni AS, Gregory B, Nutku E, Aris F, Latifa K, Minshall E, North J, Tavernier J, Levit R, Nicolaides N, Robinson D, Hamid Q (2000) Interleukin-9 enhances interleukin-5 receptor expression, differentiation, and survival of human eosinophils. Blood 96(6):2163–2171PubMedGoogle Scholar
  98. 98.
    Mohapatra A, Van Dyken SJ, Schneider C, Nussbaum JC, Liang HE, Locksley RM (2016) Group 2 innate lymphoid cells utilize the IRF4-IL-9 module to coordinate epithelial cell maintenance of lung homeostasis. Mucosal immunology 9(1):275–286. doi: 10.1038/mi.2015.59 PubMedCrossRefGoogle Scholar
  99. 99.
    Dugas B, Renauld JC, Pene J, Bonnefoy JY, Peti-Frere C, Braquet P, Bousquet J, Van Snick J, Mencia-Huerta JM (1993) Interleukin-9 potentiates the interleukin-4-induced immunoglobulin (IgG, IgM and IgE) production by normal human B lymphocytes. Eur J Immunol 23(7):1687–1692. doi: 10.1002/eji.1830230743 PubMedCrossRefGoogle Scholar
  100. 100.
    Petit-Frere C, Dugas B, Braquet P, Mencia-Huerta JM (1993) Interleukin-9 potentiates the interleukin-4-induced IgE and IgG1 release from murine B lymphocytes. Immunology 79(1):146–151PubMedPubMedCentralGoogle Scholar
  101. 101.
    Fawaz LM, Sharif-Askari E, Hajoui O, Soussi-Gounni A, Hamid Q, Mazer BD (2007) Expression of IL-9 receptor alpha chain on human germinal center B cells modulates IgE secretion. The Journal of allergy and clinical immunology 120(5):1208–1215. doi: 10.1016/j.jaci.2007.08.022 PubMedCrossRefGoogle Scholar
  102. 102.
    Baraldo S, Faffe DS, Moore PE, Whitehead T, McKenna M, Silverman ES, Panettieri RA Jr, Shore SA (2003) Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. American journal of physiology Lung cellular and molecular physiology 284(6):L1093–L1102. doi: 10.1152/ajplung.00300.2002 PubMedCrossRefGoogle Scholar
  103. 103.
    Gounni AS, Hamid Q, Rahman SM, Hoeck J, Yang J, Shan L (2004) IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells. J Immunol 173(4):2771–2779PubMedCrossRefGoogle Scholar
  104. 104.
    Yamasaki A, Saleh A, Koussih L, Muro S, Halayko AJ, Gounni AS (2010) IL-9 induces CCL11 expression via STAT3 signalling in human airway smooth muscle cells. PLoS One 5(2):e9178. doi: 10.1371/journal.pone.0009178 PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Little FF, Cruikshank WW, Center DM (2001) Il-9 stimulates release of chemotactic factors from human bronchial epithelial cells. Am J Respir Cell Mol Biol 25(3):347–352. doi: 10.1165/ajrcmb.25.3.4349 PubMedCrossRefGoogle Scholar
  106. 106.
    Dong Q, Louahed J, Vink A, Sullivan CD, Messler CJ, Zhou Y, Haczku A, Huaux F, Arras M, Holroyd KJ, Renauld JC, Levitt RC, Nicolaides NC (1999) IL-9 induces chemokine expression in lung epithelial cells and baseline airway eosinophilia in transgenic mice. Eur J Immunol 29(7):2130–2139. doi: 10.1002/(SICI)1521-4141(199907)29:07<2130::AID-IMMU2130>3.0.CO;2-S PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Molecular PneumologyFriedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum ErlangenErlangenGermany

Personalised recommendations