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IL-9 and Th9 Cells in Tumor Immunity

  • Ying He
  • Lin Dong
  • Yejin Cao
  • Yujing Bi
  • Guangwei LiuEmail author
Chapter
  • 78 Downloads
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1240)

Abstract

T cells can be categorized into functionally diverse subpopulations, which include Th1, Th2, Th9, Th17, Th22, and Tfh cells and Foxp3+ Tregs, based on their role in maintaining normal immune homeostasis and affecting pathological immune-associated diseases. Among these subpopulations, Th9 cells are relatively new, and less is known about their signaling and effects on tumor immunity. Recently, some studies have focused on regulation of the IL-9/IL-9R signaling pathway and Th9 cell differentiation and their roles in tumor environments. Herein, we summarize recent progress in understanding the regulatory signaling of IL-9 and Th9 cells and their critical roles and mechanisms in antitumor immunity.

Keywords

IL-9 Th9 cells Th9 PU.1 Antitumor Tumor immunity Cancer Tumor immunotherapy T cell function T cell differentiation CTL T cell activity Tc9 HIF1α SIRT1 

Abbreviation

AKT

Protein kinase B

ALCL

Anaplastic large cell lymphoma

Bcl6

B cell lymphoma 6

CTL

Cytotoxic lymphocyte

DCs

Dendritic cells

EAE

Experimental autoimmune encephalitis

FOXO1

Forkhead box protein O1

GATA3

GATA binding protein 3

GITR

TNF receptor-related protein

GrzB

Granzyme B

HAT

Histone acetyltransferase

HIF1α

Hypoxia-inducible factor-1α

HTLV-1

Human cell leukemia virus 1

IFNγ

Interferon-γ

IL-9

Interleukin 9

IL-9R

IL-9 receptor

MAPK

Mitogen-activated protein kinase

mTOR

Mechanistic target of rapamycin

NFAT

Nuclear factor of activated T cells

NF-kB

Nuclear factor-kappa B

NK cells

Natural killer cells

NKT cells

Natural killer T cells

PI-3K

Phosphatidylinositol 3′-kinase

rIL-9

Recombinant IL-9 protein

STAT6

Signal transducer and activator of transcription 6

TAK1

Transforming growth factor-activated kinase-1

T-bet

T-box transcription factor

Tc9

IL-9-producing CD8+ T cells

Tfh cells

T follicular helper cells

TGFβ1

Transforming growth factor-β1

Th

T helper cells

Th1

IFNγ-producing CD4+ T cells

Th9

IL-9-producing CD4+ T cells

TNFα

Tumor necrosis factor-α

Treg cells

Regulatory T cells

TSLP

Thymic stromal lymphopoietin

Notes

Acknowledgments

The authors’ research is supported by grants from the National Natural Science Foundation for Key Programs of China (31730024, G.L.) and National Natural Science Foundation for General Programs of China (31671524 and 81273201, G.L.).

Competing Financial Interests

The authors declare no competing financial interests.

References

  1. 1.
    Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, Rubira MR et al (1989) Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med 169(1):363–368PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Mock BA, Krall M, Kozak CA, Nesbitt MN, McBride OW, Renauld JC et al (1990) IL9 maps to mouse chromosome 13 and human chromosome 5. Immunogenetics 31(4):265–270PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Kaplan MH, Hufford MM, Olson MR (2015) The development and in vivo function of T helper 9 cells. Nat Rev Immunol 15(5):295–307PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186(6):3283–3288PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Rojas-Zuleta WG, Vasquez G (2016) Th9 lymphocytes: a recent history from IL-9 to its potential role in rheumatic diseases. Autoimmun Rev 15(7):649–655PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Demoulin JB, Uyttenhove C, Van Roost E, DeLestre B, Donckers D, Van Snick J et al (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
  7. 7.
    Vermeesch JR, Petit P, Kermouni A, Renauld JC, Van Den Berghe H, Marynen P (1997) The IL-9 receptor gene, located in the Xq/Yq pseudoautosomal region, has an autosomal origin, escapes X inactivation and is expressed from the Y. Hum Mol Genet 6(1):1–8PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Knoops L, Renauld JC (2004) IL-9 and its receptor: from signal transduction to tumorigenesis. Growth Factors 22(4):207–215PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    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. J Allergy Clin Immunol 120(5):1208–1215PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Nalleweg N, Chiriac MT, Podstawa E, Lehmann C, Rau TT, Atreya R et al (2015) IL-9 and its receptor are predominantly involved in the pathogenesis of UC. Gut 64(5):743–755PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Fontaine RH, Cases O, Lelievre V, Mesples B, Renauld JC, Loron G et al (2008) IL-9/IL-9 receptor signaling selectively protects cortical neurons against developmental apoptosis. Cell Death Differ 15(10):1542–1552PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Hong CH, Chang KL, Wang HJ, Yu HS, Lee CH (2015) IL-9 induces IL-8 production via STIM1 activation and ERK phosphorylation in epidermal keratinocytes: a plausible mechanism of IL-9R in atopic dermatitis. J Dermatol Sci 78(3):206–214PubMedCrossRefGoogle Scholar
  13. 13.
    Malik S, Sadhu S, Elesela S, Pandey RP, Chawla AS, Sharma D et al (2017) Transcription factor Foxo1 is essential for IL-9 induction in T helper cells. Nat Commun 8(1):815PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Bi E, Ma X, Lu Y, Yang M, Wang Q, Xue G et al (2017) Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7. Sci Signal 10(500)PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Martelli AM, Tabellini G, Ricci F, Evangelisti C, Chiarini F, Bortul R et al (2012) PI3K/AKT/mTORC1 and MEK/ERK signaling in T-cell acute lymphoblastic leukemia: new options for targeted therapy. Adv Biol Regul 52(1):214–227PubMedCrossRefGoogle Scholar
  16. 16.
    Li Y, Yu Q, Zhang Z, Wang J, Li S, Zhang J et al (2016) TH9 cell differentiation, transcriptional control and function in inflammation, autoimmune diseases and cancer. Oncotarget 7(43):71001–71012PubMedPubMedCentralGoogle Scholar
  17. 17.
    Gorczynski R, Yu K, Chen Z (2014) Anti-CD200R2, anti-IL-9, anti-IL-35, or anti-TGF-beta abolishes increased graft survival and Treg induction induced in cromolyn-treated CD200R1KO.CD200tg mice. Transplantation 97(1):39–46PubMedCrossRefGoogle Scholar
  18. 18.
    Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S et al (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
  19. 19.
    Gerlach K, Hwang Y, Nikolaev A, Atreya R, Dornhoff H, Steiner S et al (2014) TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 15(7):676–686PubMedCrossRefGoogle Scholar
  20. 20.
    Gomez-Rodriguez J, Meylan F, Handon R, Hayes ET, Anderson SM, Kirby MR et al (2016) Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun 7:10857PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J et al (2008) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Jabeen R, Goswami R, Awe O, Kulkarni A, Nguyen ET, Attenasio A et al (2013) Th9 cell development requires a BATF-regulated transcriptional network. J Clin Invest 123(11):4641–4653PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Wang Y, Bi Y, Chen X, Li C, Li Y, Zhang Z et al (2016) Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4(+) T cells. Immunity 44(6):1337–1349PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Micosse C, von Meyenn L, Steck O, Kipfer E, Adam C, Simillion C et al (2019) Human “TH9” cells are a subpopulation of PPAR-gamma(+) TH2 cells. Sci Immunol 4(31)Google Scholar
  25. 25.
    Goswami R, Jabeen R, Yagi R, Pham D, Zhu J, Goenka S et al (2012) STAT6-dependent regulation of Th9 development. J Immunol 188(3):968–975PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, et al. 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 2008, 9(12): 1347–1355PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R et al (2002) IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity 17(1):7–17PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Xue G, Jin G, Fang J, Lu Y (2019) IL-4 together with IL-1beta induces antitumor Th9 cell differentiation in the absence of TGF-beta signaling. Nat Commun 10(1):1376PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Wu B, Huang C, Kato-Maeda M, Hopewell PC, Daley CL, Krensky AM et al (2008) IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol 126(2):202–210PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Matsuki A, Takatori H, Makita S, Yokota M, Tamachi T, Suto A et al (2017) T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production. J Allergy Clin Immunol 139(4):1355–1367. e1356PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Smith SE, Hoelzinger DB, Dominguez AL, Van Snick J, Lustgarten J (2011) Signals through 4-1BB inhibit T regulatory cells by blocking IL-9 production enhancing antitumor responses. Cancer Immunol Immunother 60(12):1775–1787PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252(1):104–115PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183(11):7169–7177PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Lu Y, Lin H, Zhai K, Wang X, Zhou Q, Shi H (2016) Interleukin-17 inhibits development of malignant pleural effusion via interleukin-9-dependent mechanism. Sci China Life Sci 59(12):1297–1304PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Schutze N, Trojandt S, Kuhn S, Tomm JM, von Bergen M, Simon JC et al (2016) Allergen-induced IL-6 regulates IL-9/IL-17A balance in CD4+ T cells in allergic airway inflammation. J Immunol 197(7):2653–2664PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Anuradha R, George PJ, Hanna LE, Chandrasekaran V, Kumaran P, Nutman TB et al (2013) IL-4-, TGF-beta-, and IL-1-dependent expansion of parasite antigen-specific Th9 cells is associated with clinical pathology in human lymphatic filariasis. J Immunol 191(5):2466–2473PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Liao W, Spolski R, Li P, Du N, West EE, Ren M et al (2014) Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc Natl Acad Sci U S A 111(9):3508–3513PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T et al (2010) TGF-beta induces IL-9 production from human Th17 cells. J Immunol 185(1):46–54PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Angkasekwinai P, Sodthawon W, Jeerawattanawart S, Hansakon A, Pattanapanyasat K, Wang YH (2017) ILC2s activated by IL-25 promote antigen-specific Th2 and Th9 functions that contribute to the control of Trichinella spiralis infection. PLoS One 12(9):e0184684PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Verma M, Liu S, Michalec L, Sripada A, Gorska MM, Alam R (2018) Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin-driven IL-9(+) and IL-13(+) type 2 innate lymphoid cell subpopulations. J Allergy Clin Immunol 142(3):793–803. e798PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Pritchard AL, Carroll ML, Burel JG, White OJ, Phipps S, Upham JW (2012) Innate IFNs and plasmacytoid dendritic cells constrain Th2 cytokine responses to rhinovirus: a regulatory mechanism with relevance to asthma. J Immunol 188(12):5898–5905PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA et al (2011) TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477(7363):229–233PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Murugaiyan G, Beynon V, Pires Da Cunha A, Joller N, Weiner HL (2012) IFN-gamma limits Th9-mediated autoimmune inflammation through dendritic cell modulation of IL-27. J Immunol 189(11):5277–5283PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Rivera Vargas T, Cai Z, Shen Y, Dosset M, Benoit-Lizon I, Martin T et al (2017) Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of TH9 cells. Nat Commun 8(1):559PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Vegran F, Berger H, Boidot R, Mignot G, Bruchard M, Dosset M et al (2014) The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat Immunol 15(8):758–766PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Maier E, Werner D, Duschl A, Bohle B, Horejs-Hoeck J (2014) Human Th2 but not Th9 cells release IL-31 in a STAT6/NF-kappaB-dependent way. J Immunol 193(2):645–654PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Bassil R, Orent W, Olah M, Kurdi AT, Frangieh M, Buttrick T et al (2014) BCL6 controls Th9 cell development by repressing Il9 transcription. J Immunol 193(1):198–207PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Elyaman W, Bassil R, Bradshaw EM, Orent W, Lahoud Y, Zhu B et al (2012) Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells. Immunity 36(4):623–634PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Nakatsukasa H, Zhang D, Maruyama T, Chen H, Cui K, Ishikawa M et al (2015) The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells. Nat Immunol 16(10):1077–1084PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ye ZJ, Zhou Q, Yin W, Yuan ML, Yang WB, Xiong XZ et al (2012) Differentiation and immune regulation of IL-9-producing CD4+ T cells in malignant pleural effusion. Am J Respir Crit Care Med 186(11):1168–1179PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Kelleher K, Bean K, Clark SC, Leung WY, Yang-Feng TL, Chen JW et al (1991) Human interleukin-9: genomic sequence, chromosomal location, and sequences essential for its expression in human T-cell leukemia virus (HTLV)-I-transformed human T cells. Blood 77(7):1436–1441PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Lavorgna A, Matsuoka M, Harhaj EW (2014) A critical role for IL-17RB signaling in HTLV-1 tax-induced NF-kappaB activation and T-cell transformation. PLoS Pathog 10(10):e1004418PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Hsieh TH, Hsu CY, Tsai CF, Chiu CC, Liang SS, Wang TN et al (2016) A novel cell-penetrating peptide suppresses breast tumorigenesis by inhibiting beta-catenin/LEF-1 signaling. Sci Rep 6:19156PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Zivancevic-Simonovic S, Mihaljevic O, Majstorovic I, Popovic S, Markovic S, Milosevic-Djordjevic O et al (2015) Cytokine production in patients with papillary thyroid cancer and associated autoimmune Hashimoto thyroiditis. Cancer Immunol Immunother 64(8):1011–1019PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Hoelzinger DB, Dominguez AL, Cohen PA, Gendler SJ (2014) Inhibition of adaptive immunity by IL9 can be disrupted to achieve rapid T-cell sensitization and rejection of progressive tumor challenges. Cancer Res 74(23):6845–6855PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Qiu L, Lai R, Lin Q, Lau E, Thomazy DM, Calame D et al (2006) Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells. Blood 108(7):2407–2415PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Koo GC, Tan SY, Tang T, Poon SL, Allen GE, Tan L et al (2012) Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma. Cancer Discov 2(7):591–597PubMedCrossRefGoogle Scholar
  58. 58.
    Lv X, Wang X (2013) The role of interleukin-9 in lymphoma. Leuk Lymphoma 54(7):1367–1372PubMedCrossRefGoogle Scholar
  59. 59.
    Kim IK, Kim BS, Koh CH, Seok JW, Park JS, Shin KS et al (2015) Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells. Nat Med 21(9):1010–1017PubMedCrossRefGoogle Scholar
  60. 60.
    Lu Y, Hong S, Li H, Park J, Hong B, Wang L et al (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122(11):4160–4171PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    You FP, Zhang J, Cui T, Zhu R, Lv CQ, Tang HT et al (2017) Th9 cells promote antitumor immunity via IL-9 and IL-21 and demonstrate atypical cytokine expression in breast cancer. Int Immunopharmacol 52:163–167PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Lu Y, Wang Q, Yi Q (2014) Anticancer Tc9 cells: long-lived tumor-killing T cells for adoptive therapy. Oncoimmunology 3:e28542PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Lu Y, Hong B, Li H, Zheng Y, Zhang M, Wang S et al (2014) Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci U S A 111(6):2265–2270PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Quezada SA, Peggs KS (2014) An antitumor boost to TH9 cells. Nat Immunol 15(8):703–705PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X et al (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18(8):1248–1253PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Shang Y, Kakinuma S, Nishimura M, Kobayashi Y, Nagata K, Shimada Y (2012) Interleukin-9 receptor gene is transcriptionally regulated by nucleolin in T-cell lymphoma cells. Mol Carcinog 51(8):619–627PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Li HJ, Sun QM, Liu LZ, Zhang J, Huang J, Wang CH et al (2015) High expression of IL-9R promotes the progression of human hepatocellular carcinoma and indicates a poor clinical outcome. Oncol Rep 34(2):795–802PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie AN et al (2011) IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. J Immunol 186(1):83–91PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J et al (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):12885–12890PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Hoyle GW, Brody AR (2001) IL-9 and lung fibrosis: a Th2 good guy? Am J Respir Cell Mol Biol 24(4):365–367PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Liu J, Harberts E, Tammaro A, Girardi N, Filler RB, Fishelevich R et al (2014) IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis. J Invest Dermatol 134(7):1903–1911PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Fang Y, Chen X, Bai Q, Qin C, Mohamud AO, Zhu Z et al (2015) IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL. J Surg Oncol 111(8):969–974PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Lendeckel U, Arndt M, Frank K, Spiess A, Reinhold D, Ansorge S (2000) Modulation of WNT-5A expression by actinonin: linkage of APN to the WNT-pathway? Adv Exp Med Biol 477:35–41PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Clark RA, Schlapbach C (2017) TH9 cells in skin disorders. Semin Immunopathol 39(1):47–54PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Schlapbach C, Gehad A, Yang C, Watanabe R, Guenova E, Teague JE et al (2014) Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci Transl Med 6(219):219ra218CrossRefGoogle Scholar
  76. 76.
    Kim IK, Chung Y, Kang CY (2016) GITR drives TH9-mediated antitumor immunity. Oncoimmunology 5(5):e1122862PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Xiao X, Shi X, Fan Y, Zhang X, Wu M, Lan P et al (2015) GITR subverts Foxp3(+) Tregs to boost Th9 immunity through regulation of histone acetylation. Nat Commun 6:8266PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Abdul-Wahid A, Cydzik M, Prodeus A, Alwash M, Stanojcic M, Thompson M et al (2016) Induction of antigen-specific TH 9 immunity accompanied by mast cell activation blocks tumor cell engraftment. Int J Cancer 139(4):841–853PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Vegran F, Apetoh L, Ghiringhelli F (2015) Th9 cells: a novel CD4 T-cell subset in the immune war against cancer. Cancer Res 75(3):475–479PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442(7106):997–1002PubMedCrossRefGoogle Scholar
  81. 81.
    Park J, Li H, Zhang M, Lu Y, Hong B, Zheng Y et al (2014) Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy. Cancer Immunol Immunother 63(8):835–845PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Jiang Y, Chen J, Bi E, Zhao Y, Qin T, Wang Y et al (2019) TNF-alpha enhances Th9 cell differentiation and antitumor immunity via TNFR2-dependent pathways. J Immunother Cancer 7(1):28PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Ma X, Bi E, Huang C, Lu Y, Xue G, Guo X et al (2018) Cholesterol negatively regulates IL-9-producing CD8(+) T cell differentiation and antitumor activity. J Exp Med 215(6):1555–1569PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Petrella TM, Tozer R, Belanger K, Savage KJ, Wong R, Smylie M et al (2012) Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J Clin Oncol Off J Am Soc Clin Oncol 30(27):3396–3401CrossRefGoogle Scholar
  85. 85.
    Zeng R, Spolski R, Finkelstein SE, Oh S, Kovanen PE, Hinrichs CS et al (2005) Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201(1):139–148PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    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):5464–5469PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Kasaian MT, Whitters MJ, Carter LL, Lowe LD, Jussif JM, Deng B et al (2002) IL-21 limits NK cell responses and promotes antigen-specific T cell activation: a mediator of the transition from innate to adaptive immunity. Immunity 16(4):559–569PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Chen N, Lv X, Li P, Lu K, Wang X (2014) Role of high expression of IL-9 in prognosis of CLL. Int J Clin Exp Pathol 7(2):716–721PubMedPubMedCentralGoogle Scholar
  89. 89.
    Yang Z, Zhang B, Li D, Lv M, Huang C, Shen GX et al (2010) Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One 5(1):e8922PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Rawstron AC, Bottcher S, Letestu R, Villamor N, Fazi C, Kartsios H et al (2013) Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia 27(1):142–149PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Nagato T, Kobayashi H, Kishibe K, Takahara M, Ogino T, Ishii H et al (2005) Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients. Clin Cancer Res 11(23):8250–8257PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Ying He
    • 1
  • Lin Dong
    • 1
  • Yejin Cao
    • 1
  • Yujing Bi
    • 2
  • Guangwei Liu
    • 1
    Email author
  1. 1.Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of EducationInstitute of Cell Biology, College of Life Sciences, Beijing Normal UniversityBeijingChina
  2. 2.State Key Laboratory of Pathogen and BiosecurityBeijing Institute of Microbiology and EpidemiologyBeijingChina

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