TH9 Cells in Immunity and Disease

Abstract

T helper (TH) cells differentiated from CD4+ T cells comprise an integral part of the adaptive immune system by providing the ‘help’ for humoral and cellular immune responses. Subsets of TH cells are defined based on the production of signature cytokines that regulate subsequent inflammatory immune responses. Among the TH subsets, TH9 cells are identified by secretion of the signature cytokine IL‐9. Although TH9 cells share some functional roles with TH2 cells, including promoting allergic inflammation and helminthic parasite immunity, TH9 cells can also promote autoimmunity in responses that are generally characterised as dependent on TH1 or TH17 cells. This article offers a concise summary of some key features of TH9 cells and describes how they contribute to immunity and disease.

Key Concepts

  • TH9 cells are differentiated under a cytokine environment containing both IL‐4 and transforming growth factor β (TGFβ), which induce the transcriptional network required for the expression of IL‐9.
  • The TH9 subset is defined by its ability to produce large amounts of the signature cytokine IL‐9.
  • Transcription factors required for the development of TH9 cells include signal transducer and activator of transcription‐6 (STAT6), interferon regulatory factor 4 (IRF4), B‐cell activating transcription factor‐like (BATF), GATA3, PU.1 and Smads.
  • TH9 cells express high levels of IL‐25 receptor (Il17rb), which is a potential surface maker to distinguish TH9 cells from other TH subsets.
  • Immune responses mediated by TH9 cells contribute to the protective immunity against intestinal parasite infection and to antitumour immunity; they are also involved in allergic, inflammatory and autoimmune diseases.

Keywords: IL‐9; TH9; cytokines; transcription factors; parasite infection; allergic reactions; inflammatory diseases; autoimmune diseases

Figure 1. The transcription factors involved in the development of TH9 subset for the production of IL‐9. TH9 cells are differentiated following stimulation with two cytokines IL‐4 and TGFβ, resulting in the activation or induction of transcription factors that promote the expression of Il9. Additional cytokines such as IL‐2, TSLP, IL‐25, IL‐1 and IFNα/β, through activation of their respective transcription factors, can further enhance the expression of Il9 by TH9 cells. Transcription factors that are able to directly bind to the Il9 locus are indicated with arrows.
close

References

Angkasekwinai P, Chang SH, Thapa M, Watarai H and Dong C (2010) Regulation of IL‐9 expression by IL‐25 signaling. Nature Immunology 11: 250–256.

Angkasekwinai P, Srimanote P, Wang YH, et al. (2013) Interleukin‐25 (IL‐25) promotes efficient protective immunity against Trichinella spiralis infection by enhancing the antigen‐specific IL‐9 response. Infection and Immunity 81: 3731–3741.

Blom L, Poulsen BC, Jensen BM, Hansen A and Poulsen LK (2011) IL‐33 induces IL‐9 production in human CD4+ T cells and basophils. PLoS One 6: e21695.

Brough HA, Cousins DJ, Munteanu A, et al. (2014) IL‐9 is a key component of memory TH cell peanut‐specific responses from children with peanut allergy. Journal of Allergy and Clinical Immunology 134: 1329–1338.e1310.

Chang H‐C, Sehra S, Goswami R, et al. (2010) The transcription factor PU. 1 is required for the development of IL‐9‐producing T cells and allergic inflammation. Nature Immunology 11: 527–534.

Chang HC, Zhang S, Thieu VT, et al. (2005) PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity 22: 693–703.

Dardalhon V, Awasthi A, Kwon H, et al. (2008) IL‐4 inhibits TGF‐beta‐induced Foxp3+ T cells and, together with TGF‐beta, generates IL‐9+ IL‐10+ Foxp3(‐) effector T cells. Nature Immunology 9: 1347–1355.

Dugas B, Renauld JC, Pene J, et al. (1993) Interleukin‐9 potentiates the interleukin‐4‐induced immunoglobulin (IgG, IgM and IgE) production by normal human B lymphocytes. European Journal of Immunology 23: 1687–1692.

Elyaman W, Bradshaw EM, Uyttenhove C, et al. (2009) IL‐9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America 106: 12885–12890.

Gerlach K, Hwang Y, Nikolaev A, 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. Nature Immunology 15: 676–686.

Goswami R, Jabeen R, Yagi R, et al. (2012) STAT6‐dependent regulation of Th9 development. Journal of Immunology 188: 968–975.

Goswami R and Kaplan MH (2012) Gcn5 is required for PU.1‐dependent IL‐9 induction in Th9 cells. Journal of Immunology 189: 3026–3033.

Horka H, Staudt V, Klein M, et al. (2012) The tick salivary protein sialostatin L inhibits the Th9‐derived production of the asthma‐promoting cytokine IL‐9 and is effective in the prevention of experimental asthma. Journal of Immunology 188: 2669–2676.

Jabeen R, Goswami R, Awe O, et al. (2013) Th9 cell development requires a BATF‐regulated transcriptional network. The Journal of Clinical Investigation 123: 4641–4653.

Jager A, Dardalhon V, Sobel RA, Bettelli E and Kuchroo VK (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. Journal of Immunology 183: 7169–7177.

Kara EE, Comerford I, Bastow CR, et al. (2013) Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites. Journal of Immunology 191: 1110–1117.

Kearley J, Erjefalt JS, Andersson C, et al. (2011) IL‐9 governs allergen‐induced mast cell numbers in the lung and chronic remodeling of the airways. American Journal of Respiratory and Critical Care Medicine 183: 865–875.

Khan WI, Richard M, Akiho H, et al. (2003) Modulation of intestinal muscle contraction by interleukin‐9 (IL‐9) or IL‐9 neutralization: correlation with worm expulsion in murine nematode infections. Infection and Immunity 71: 2430–2438.

Liao W, Spolski R, Li P, et al. (2014) Opposing actions of IL‐2 and IL‐21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proceedings of the National Academy of Sciences of the United States of America 111: 3508–3513.

Licona‐Limon P, Henao‐Mejia J, Temann AU, et al. (2013) Th9 cells drive host immunity against gastrointestinal worm infection. Immunity 39: 744–757.

Lu Y, Hong S, Li H, et al. (2012) Th9 cells promote antitumor immune responses in vivo. The Journal of Clinical Investigation 122: 4160–4171.

Luger D, Silver PB, Tang J, et al. (2008) Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. The Journal of Experimental Medicine 205: 799–810.

Melen E, Gullsten H, Zucchelli M, et al. (2004) Sex specific protective effects of interleukin‐9 receptor haplotypes on childhood wheezing and sensitisation. Journal of Medical Genetics 41: e123.

Nicolaides NC, Holroyd KJ, Ewart SL, et al. (1997) Interleukin 9: a candidate gene for asthma. Proceedings of the National Academy of Sciences of the United States of America 94: 13175–13180.

Niedbala W, Besnard AG, Nascimento DC, et al. (2014) Nitric oxide enhances Th9 cell differentiation and airway inflammation. Nature Communications 5: 4575.

O'Connor RA, Prendergast CT, Sabatos CA, et al. (2008) Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. Journal of Immunology 181: 3750–3754.

Pai SY, Truitt ML and Ho IC (2004) GATA‐3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proceedings of the National Academy of Sciences of the United States of America 101: 1993–1998.

Park J, Li H, Zhang M, et al. (2014) Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy. Cancer Immunology, Immunotherapy 63: 835–845.

Purwar R, Schlapbach C, Xiao S, et al. (2012) Robust tumor immunity to melanoma mediated by interleukin‐9‐producing T cells. Nature Medicine 18: 1248–1253.

Richard M, Grencis RK, Humphreys NE, Renauld JC and Van Snick J (2000) Anti‐IL‐9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris‐infected mice. Proceedings of the National Academy of Sciences of the United States of America 97: 767–772.

Sakaguchi M, Sugita S, Sagawa K, Itoh K and Mochizuki M (1998) Cytokine production by T cells infiltrating in the eye of uveitis patients. Japanese Journal of Ophthalmology 42: 262–268.

Schmitt E, Germann T, Goedert 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. Journal of Immunology 153: 3989–3996.

Sehra S, Yao W, Nguyen ET, et al. (2015) Th9 cells are required for tissue mast cell accumulation during allergic inflammation. Journal of Allergy and Clinical Immunology 136 (2): 433–440.e1.

Stassen M, Muller C, Arnold M, et al. (2001) IL‐9 and IL‐13 production by activated mast cells is strongly enhanced in the presence of lipopolysaccharide: NF‐kappa B is decisively involved in the expression of IL‐9. Journal of Immunology 166: 4391–4398.

Staudt V, Bothur E, Klein M, et al. (2010) Interferon‐regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33: 192–202.

Tamiya T, Ichiyama K, Kotani H, et al. (2013) Smad2/3 and IRF4 play a cooperative role in IL‐9‐producing T cell induction. Journal of Immunology 191: 2360–2371.

Tan C, Aziz MK, Lovaas JD, et al. (2010) Antigen‐specific Th9 cells exhibit uniqueness in their kinetics of cytokine production and short retention at the inflammatory site. Journal of Immunology 185: 6795–6801.

Townsend JM, Fallon GP, Matthews JD, et al. (2000) IL‐9‐deficient mice establish fundamental roles for IL‐9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13: 573–583.

Vegran F, Berger H, Boidot R, et al. (2014) The transcription factor IRF1 dictates the IL‐21‐dependent anticancer functions of TH9 cells. Nature Immunology 15: 758–766.

Veldhoen M, Uyttenhove C, van Snick J, et al. (2008) Transforming growth factor‐beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9‐producing subset. Nature Immunology 9: 1341–1346.

Wang A, Pan D, Lee YH, et al. (2013) Cutting edge: Smad2 and Smad4 regulate TGF‐beta‐mediated Il9 gene expression via EZH2 displacement. Journal of Immunology 191: 4908–4912.

Wong MT, Ye JJ, Alonso MN, et al. (2010) Regulation of human Th9 differentiation by type I interferons and IL‐21. Immunology and Cell Biology 88: 624–631.

Xavier RJ and Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448: 427–434.

Xie J, Lotoski LC, Chooniedass R, et al. (2012) Elevated antigen‐driven IL‐9 responses are prominent in peanut allergic humans. PLoS One 7: e45377.

Yang Y, Du L, Sun M, Kijlstra A and Yang P (2012) IFN‐beta inhibits the increased expression of IL‐9 during experimental autoimmune uveoretinitis. PLoS One 7: e48566.

Yao W, Tepper RS and Kaplan MH (2011) Predisposition to the development of IL‐9‐secreting T cells in atopic infants. Journal of Allergy and Clinical Immunology 128: 1357–1360.e1355.

Yao W, Zhang Y, Jabeen R, et al. (2013) Interleukin‐9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 38: 360–372.

Zhou Y, Sonobe Y, Akahori T, et al. (2011) IL‐9 promotes Th17 cell migration into the central nervous system via CC chemokine ligand‐20 produced by astrocytes. Journal of Immunology 186: 4415–4421.

Zhu J, Min B, Hu‐Li J, et al. (2004) Conditional deletion of Gata3 shows its essential function in T(H)1‐T(H)2 responses. Nature Immunology 5: 1157–1165.

Further Reading

Glosson NL, Bruns HA and Kaplan MH (2012) Wheezing and itching: The requirement for STAT proteins in allergic inflammation. JAK‐STAT 1: 3–12.

Goswami R and Kaplan MH (2011) A brief history of IL‐9. Journal of Immunology 186: 3283–3288.

Jabeen R and Kaplan MH (2012) The symphony of the ninth: the development and function of Th9 cells. Current Opinion in Immunology 24: 303–307.

Jager A and Kuchroo VK (2010) Effector and regulatory T‐cell subsets in autoimmunity and tissue inflammation. Scandinavian Journal of Immunology 72: 173–184.

Kaplan MH, Hufford MM and Olson MR (2015) The development and in vivo function of T helper 9 cells. Nature Reviews Immunology 15 (5): 295–307.

Pan HF, Leng RX, Li XP, Zheng SG and Ye DQ (2013) Targeting T‐helper 9 cells and interleukin‐9 in autoimmune diseases. Cytokine and Growth Factor Reviews 24: 515–522.

Petermann F and Korn T (2011) Cytokines and effector T cell subsets causing autoimmune CNS disease. FEBS Letters 585: 3747–3757.

Schmitt E, Klein M and Bopp T (2014) Th9 cells, new players in adaptive immunity. Trends in Immunology 35: 61–68.

Soroosh P and Doherty TA (2009) Th9 and allergic disease. Immunology 127: 450–458.

Wilhelm C, Turner JE, Van Snick J and Stockinger B (2012) The many lives of IL‐9: a question of survival? Nature Immunology 13: 637–641.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Chang, Hua‐Chen, and Kaplan, Mark H(Oct 2015) TH9 Cells in Immunity and Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026234]