Abstract
IL-9-producing CD4+ T cells have been considered to represent a distinct T helper cell (TH cell) subset owing to their unique developmental programme in vitro, their expression of distinct transcription factors (including PU.1) and their copious production of IL-9. It remains debatable whether these cells represent a truly unique TH cell subset in vivo, but they are closely related to the T helper 2 (TH2) cells that are detected in allergic diseases. In recent years, increasing evidence has also indicated that IL-9-producing T cells may have potent abilities in eradicating advanced tumours, particularly melanomas. Here, we review the latest literature on the development of IL-9-producing T cells and their functions in disease settings, with a particular focus on allergy and cancer. We also discuss recent ideas concerning the therapeutic targeting of these cells in patients with chronic allergic diseases and their potential use in cancer immunotherapy.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Veldhoen, M. et al. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008). Along with Dardalhon et al. (2008), this article first describes a distinct population of TH9 cells generated in vitro in the presence of TGFβ and IL-4.
Dardalhon, V. 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. 9, 1347–1355 (2008).
Chang, H. C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11, 527–534 (2010).
Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).
Goswami, R. et al. STAT6-dependent regulation of Th9 development. J. Immunol. 188, 968–975 (2012).
Xiao, X. et al. OX40 signaling favors the induction of TH9 cells and airway inflammation. Nat. Immunol. 13, 981–990 (2012).
Jabeen, R. et al. Th9 cell development requires a BATF-regulated transcriptional network. J. Clin. Invest. 123, 4641–4653 (2013).
Kim, I. K. et al. Glucocorticoid-induced tumor necrosis factor receptor-related protein co-stimulation facilitates tumor regression by inducing IL-9-producing helper T cells. Nat. Med. 21, 1010–1017 (2015).
Humblin, E. et al. IRF8-dependent molecular complexes control the Th9 transcriptional program. Nat. Commun. 8, 2085 (2017).
Benevides, L. et al. B lymphocyte-induced maturation protein 1 controls TH9 cell development, IL-9 production, and allergic inflammation. J. Allergy Clin. Immunol. 143, 1119–1130 (2019).
Chen, C. Y. et al. Induction of interleukin-9-producing mucosal mast cells promotes susceptibility to IgE-mediated experimental food allergy. Immunity 43, 788–802 (2015).
Turner, J. E. et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013). Along with Wilhelm et al. (2011), this study demonstrates that IL-9 is produced by innate lymphoid cells and acts as an autocrine factor to promote their function and survival.
Micosse, C. et al. Human “TH9” cells are a subpopulation of PPAR-γ+ TH2 cells. Sci. Immunol. 4, eaat5943 (2019). This recent report shows that human TH9 cells are a phenotypically and functionally distinct subpopulation of TH2 cells.
Eller, K. et al. IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression. J. Immunol. 186, 83–91 (2011).
Wang, Y. et al. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat. Immunol. 18, 921–930 (2017).
Takatsuka, S. et al. IL-9 receptor signaling in memory B cells regulates humoral recall responses. Nat. Immunol. 19, 1025–1034 (2018).
Grencis, R. K., Hultner, L. & Else, K. J. Host protective immunity to Trichinella spiralis in mice: activation of Th cell subsets and lymphokine secretion in mice expressing different response phenotypes. Immunology 74, 329–332 (1991).
Behnke, J. M. et al. Immunological relationships during primary infection with Heligmosomoides polygyrus (Nematospiroides dubius): downregulation of specific cytokine secretion (IL-9 and IL-10) correlates with poor mastocytosis and chronic survival of adult worms. Parasite Immunol. 15, 415–421 (1993).
Faulkner, H., Humphreys, N., Renauld, J. C., Van Snick, J. & Grencis, R. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur. J. Immunol. 27, 2536–2540 (1997).
Nicolaides, N. C. et al. Interleukin 9: a candidate gene for asthma. Proc. Natl Acad. Sci. USA 94, 13175–13180 (1997).
Temann, U. A., Geba, G. P., Rankin, J. A. & Flavell, R. A. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188, 1307–1320 (1998).
Shimbara, A. et al. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J. Allergy Clin. Immunol. 105, 108–115 (2000).
Kung, T. T. et al. Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice. Am. J. Respir. Cell Mol. Biol. 25, 600–605 (2001).
Cheng, G. et al. Anti-interleukin-9 antibody treatment inhibits airway inflammation and hyperreactivity in mouse asthma model. Am. J. Respir. Crit. Care Med. 166, 409–416 (2002).
McMillan, S. J., Bishop, B., Townsend, M. J., McKenzie, A. N. & Lloyd, C. M. The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J. Exp. Med. 195, 51–57 (2002).
Xiao, X. et al. Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation. J. Exp. Med. 215, 559–574 (2018). Along with Schwartz et al. (2019), this study demonstrates that the repression of the Il9 locus in TH9 cells may control the pathology in TH9-associated allergic lung disease.
Lloyd, C. M. & Harker, J. A. Epigenetic control of interleukin-9 in asthma. N. Engl. J. Med. 379, 87–89 (2018).
Schwartz, D. M. et al. Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program to reduce allergic pathology. Immunity 50, 106–120 (2019).
Purwar, R. et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat. Med. 18, 1248–1253 (2012). This is the first study showing an antitumour effect of TH9 cells on a solid tumour.
Vegran, F. et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat. Immunol. 15, 758–766 (2014).
Lu, Y. et al. Th9 cells represent a unique subset of CD4+ T cells endowed with the ability to eradicate advanced tumors. Cancer Cell 33, 1048–1060 (2018).
Uyttenhove, C., Simpson, R. J. & Van Snick, J. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc. Natl Acad. Sci. USA 85, 6934–6938 (1988).
Hultner, L. et al. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur. J. Immunol. 20, 1413–1416 (1990).
Schmitt, E., Van Brandwijk, R., Van Snick, J., Siebold, B. & Rude, E. TCGF III/P40 is produced by naive murine CD4+ T cells but is not a general T cell growth factor. Eur. J. Immunol. 19, 2167–2170 (1989).
Gessner, A., Blum, H. & Rollinghoff, M. Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology 189, 419–435 (1993).
Van Snick, J. et al. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J. Exp. Med. 169, 363–368 (1989).
Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011). This study reports induction of IL-9 from innate lymphoid cells and a potential involvement of IL-9 in allergic lung diseases via the promotion of IL-5 and IL-13 production in innate lymphoid cells.
Licona-Limon, P. et al. Th9 cells drive host immunity against gastrointestinal worm infection. Immunity 39, 744–757 (2013).
Tan, C. et al. Antigen-specific Th9 cells exhibit uniqueness in their kinetics of cytokine production and short retention at the inflammatory site. J. Immunol. 185, 6795–6801 (2010).
Jones, C. P. et al. Activin A and TGF-β promote TH9 cell-mediated pulmonary allergic pathology. J. Allergy Clin. Immunol. 129, 1000–1010 (2012).
Schlapbach, C. et al. Human TH9 cells are skin-tropic and have autocrine and paracrine proinflammatory capacity. Sci. Transl Med. 6, 219ra8 (2014). This study reports the existence of human TH9 cells as a discrete T cell subset independent of TGFβ and IL-2 and tropic for the skin.
Wambre, E. et al. A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci. Transl Med. 9, eaam9171 (2017).
Elyaman, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl Acad. Sci. USA 106, 12885–12890 (2009).
Nowak, E. C. et al. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 206, 1653–1660 (2009).
Beriou, G. et al. TGF-beta induces IL-9 production from human Th17 cells. J. Immunol. 185, 46–54 (2010).
Wong, M. T. et al. Regulation of human Th9 differentiation by type I interferons and IL-21. Immunol. Cell Biol. 88, 624–631 (2010).
Lu, L. F. et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442, 997–1002 (2006).
Malik, S. et al. Transcription factor Foxo1 is essential for IL-9 induction in T helper cells. Nat. Commun. 8, 815 (2017).
Stanko, K. et al. CD96 expression determines the inflammatory potential of IL-9-producing Th9 cells. Proc. Natl Acad. Sci. USA 115, E2940–E2949 (2018).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Price, A. E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl Acad. Sci. USA 107, 11489–11494 (2010).
Mjosberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).
Stassen, M. et al. 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, 5549–5555 (2000).
Nagato, T. et al. Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients. Clin. Cancer Res. 11, 8250–8257 (2005).
Visekruna, A. et al. Tc9 cells, a new subset of CD8+ T cells, support Th2-mediated airway inflammation. Eur. J. Immunol. 43, 606–618 (2013).
Lu, Y. et al. 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. USA 111, 2265–2270 (2014).
Peters, C., Hasler, R., Wesch, D. & Kabelitz, D. Human Vdelta2 T cells are a major source of interleukin-9. Proc. Natl Acad. Sci. USA 113, 12520–12525 (2016).
Russell, S. M. et al. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266, 1042–1045 (1994).
Kimura, Y. et al. Sharing of the IL-2 receptor gamma chain with the functional IL-9 receptor complex. Int. Immunol. 7, 115–120 (1995).
Renauld, J. C. et al. Expression cloning of the murine and human interleukin 9 receptor cDNAs. Proc. Natl Acad. Sci. USA 89, 5690–5694 (1992).
Townsend, J. M. et al. 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 (2000).
Kearley, J. et al. IL-9 governs allergen-induced mast cell numbers in the lung and chronic remodeling of the airways. Am. J. Respir. Crit. Care Med. 183, 865–875 (2011).
Sehra, S. et al. TH9 cells are required for tissue mast cell accumulation during allergic inflammation. J. Allergy Clin. Immunol. 136, 433–440 (2015).
Forbes, E. E. et al. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J. Exp. Med. 205, 897–913 (2008).
Vink, A., Warnier, G., Brombacher, F. & Renauld, J. C. Interleukin 9-induced in vivo expansion of the B-1 lymphocyte population. J. Exp. Med. 189, 1413–1423 (1999).
Temann, U. A., Ray, P. & Flavell, R. A. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J. Clin. Invest. 109, 29–39 (2002).
Longphre, M. et al. Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J. Clin. Invest. 104, 1375–1382 (1999).
Louahed, J. et al. Interleukin-9 upregulates mucus expression in the airways. Am. J. Respir. Cell Mol. Biol. 22, 649–656 (2000).
Gounni, A. S. et al. IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells. J. Immunol. 173, 2771–2779 (2004).
Gerlach, K. et al. 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, 676–686 (2014).
Schmitt, E. et al. 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, 3989–3996 (1994). This early report is the first to demonstrate the effect of TGFβ and IL-4 in enhancing IL-9 production from activated T cells.
Chang, H. C. et al. PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity 22, 693–703 (2005).
Kara, E. E. et al. Distinct chemokine receptor axes regulate Th9 cell trafficking to allergic and autoimmune inflammatory sites. J. Immunol. 191, 1110–1117 (2013).
Wang, A. et al. Cutting edge: Smad2 and Smad4 regulate TGF-β-mediated Il9 gene expression via EZH2 displacement. J. Immunol. 191, 4908–4912 (2013).
Yang, X. O. et al. The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat. Immunol. 14, 732–740 (2013).
Olson, M. R., Verdan, F. F., Hufford, M. M., Dent, A. L. & Kaplan, M. H. STAT3 impairs STAT5 activation in the development of IL-9-secreting T cells. J. Immunol. 196, 3297–3304 (2016).
Ulrich, B. J., Verdan, F. F., McKenzie, A. N., Kaplan, M. H. & Olson, M. R. STAT3 activation impairs the stability of Th9 cells. J. Immunol. 198, 2302–2309 (2017).
Becker, K. L. et al. Th2 and Th9 responses in patients with chronic mucocutaneous candidiasis and hyper-IgE syndrome. Clin. Exp. Allergy 46, 1564–1574 (2016).
Zhang, Y. et al. Human TH9 differentiation is dependent on signal transducer and activator of transcription (STAT) 3 to restrain STAT1-mediated inhibition. J. Allergy Clin. Immunol. 143, 1108–1118 (2019).
Liao, W. et al. Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc. Natl Acad. Sci. USA 111, 3508–3513 (2014).
Gomez-Rodriguez, J. et al. Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat. Commun. 7, 10857 (2016).
Angkasekwinai, P., Chang, S. H., Thapa, M., Watarai, H. & Dong, C. Regulation of IL-9 expression by IL-25 signaling. Nat. Immunol. 11, 250–256 (2010).
Ramadan, A. et al. Specifically differentiated T cell subset promotes tumor immunity over fatal immunity. J. Exp. Med. 214, 3577–3596 (2017).
Yao, W. et al. Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP. Immunity 38, 360–372 (2013).
Angkasekwinai, P. et al. Interleukin-25 (IL-25) promotes efficient protective immunity against Trichinella spiralis infection by enhancing the antigen-specific IL-9 response. Infect. Immun. 81, 3731–3741 (2013).
Schmitt, E. et al. IL-1 serves as a secondary signal for IL-9 expression. J. Immunol. 147, 3848–3854 (1991).
Xue, G., Jin, G., Fang, J. & Lu, Y. IL-4 together with IL-1beta induces antitumor Th9 cell differentiation in the absence of TGF-beta signaling. Nat. Commun. 10, 1376 (2019).
Jash, A. et al. 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, 15445–15457 (2012).
Tsuda, M. et al. A role for BATF3 in TH9 differentiation and T-cell-driven mucosal pathologies. Mucosal Immunol. 12, 644–655 (2019).
Postma, D. S. et al. Genetic susceptibility to asthma–bronchial hyperresponsiveness coinherited with a major gene for atopy. N. Engl. J. Med. 333, 894–900 (1995).
Doull, I. J. et al. Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness. Am. J. Respir. Crit. Care Med. 153, 1280–1284 (1996).
Ulbrecht, M. et al. High serum IgE concentrations: association with HLA-DR and markers on chromosome 5q31 and chromosome 11q13. J. Allergy Clin. Immunol. 99, 828–836 (1997).
Mock, B. A. et al. IL9 maps to mouse chromosome 13 and human chromosome 5. Immunogenetics 31, 265–270 (1990).
Kelleher, K. et al. 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, 1436–1441 (1991).
McLane, M. P. et al. Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. Am. J. Respir. Cell Mol. Biol. 19, 713–720 (1998).
Levitt, R. C. et al. IL-9 pathway in asthma: new therapeutic targets for allergic inflammatory disorders. J. Allergy Clin. Immunol. 103, S485–S491 (1999).
Dong, Q. et al. IL-9 induces chemokine expression in lung epithelial cells and baseline airway eosinophilia in transgenic mice. Eur. J. Immunol. 29, 2130–2139 (1999).
Angkasekwinai, P. TH9 cells in allergic disease. Curr. Allergy Asthma Rep. 19, 29 (2019).
Tsicopoulos, A. et al. Involvement of IL-9 in the bronchial phenotype of patients with nasal polyposis. J. Allergy Clin. Immunol. 113, 462–469 (2004).
Ma, L. et al. Possible pathogenic role of T helper type 9 cells and interleukin (IL)-9 in atopic dermatitis. Clin. Exp. Immunol. 175, 25–31 (2014).
Brough, H. A. et al. IL-9 is a key component of memory TH cell peanut-specific responses from children with peanut allergy. J. Allergy Clin. Immunol. 134, 1329–1338 (2014).
Osterfeld, H. et al. Differential roles for the IL-9/IL-9 receptor alpha-chain pathway in systemic and oral antigen-induced anaphylaxis. J. Allergy Clin. Immunol. 125, 469–476 (2010).
Steenwinckel, V. et al. IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J. Immunol. 178, 3244–3251 (2007).
Jones, T. G. et al. Antigen-induced increases in pulmonary mast cell progenitor numbers depend on IL-9 and CD1d-restricted NKT cells. J. Immunol. 183, 5251–5260 (2009).
Uyttenhove, C. et al. Autonomous growth and tumorigenicity induced by P40/interleukin 9 cDNA transfection of a mouse P40-dependent T cell line. J. Exp. Med. 173, 519–522 (1991).
Merz, H. et al. Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin’s disease and large cell anaplastic lymphoma. Blood 78, 1311–1317 (1991).
Gruss, H. J., Brach, M. A., Drexler, H. G., Bross, K. J. & Herrmann, F. Interleukin 9 is expressed by primary and cultured Hodgkin and Reed-Sternberg cells. Cancer Res. 52, 1026–1031 (1992).
Renauld, J. C. et al. Thymic lymphomas in interleukin 9 transgenic mice. Oncogene 9, 1327–1332 (1994).
Vink, A., Renauld, J. C., Warnier, G. & Van Snick, J. Interleukin-9 stimulates in vitro growth of mouse thymic lymphomas. Eur. J. Immunol. 23, 1134–1138 (1993).
Fischer, M. et al. Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin’s lymphoma. Leukemia 17, 2513–2516 (2003).
Qiu, L. et al. Autocrine release of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells. Blood 108, 2407–2415 (2006).
Feng, L. L., Gao, J. M., Li, P. P. & Wang, X. IL-9 contributes to immunosuppression mediated by regulatory T cells and mast cells in B-cell non-Hodgkin’s lymphoma. J. Clin. Immunol. 31, 1084–1094 (2011).
Lv, X., Feng, L., Ge, X., Lu, K. & Wang, X. Interleukin-9 promotes cell survival and drug resistance in diffuse large B-cell lymphoma. J. Exp. Clin. Cancer Res. 35, 106 (2016).
Chen, J. et al. Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism. Blood 111, 5163–5172 (2008).
Demoulin, J. B. et al. STAT5 activation is required for interleukin-9-dependent growth and transformation of lymphoid cells. Cancer Res. 60, 3971–3977 (2000).
Demoulin, J. B., Van Snick, J. & Renauld, J. C. Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor. Cell Growth Differ. 12, 169–174 (2001).
Carlsson, A. et al. Molecular serum portraits in patients with primary breast cancer predict the development of distant metastases. Proc. Natl Acad. Sci. USA 108, 14252–14257 (2011).
Ye, Z. J. et al. Differentiation and immune regulation of IL-9-producing CD4+ T cells in malignant pleural effusion. Am. J. Respir. Crit. Care Med. 186, 1168–1179 (2012).
Hoelzinger, D. B., Dominguez, A. L., Cohen, P. A. & Gendler, S. J. Inhibition of adaptive immunity by IL9 can be disrupted to achieve rapid T-cell sensitization and rejection of progressive tumor challenges. Cancer Res. 74, 6845–6855 (2014).
Tan, H., Wang, S. & Zhao, L. A tumour-promoting role of Th9 cells in hepatocellular carcinoma through CCL20 and STAT3 pathways. Clin. Exp. Pharmacol. Physiol. 44, 213–221 (2017).
Lu, Y. et al. Th9 cells promote antitumor immune responses in vivo. J. Clin. Invest. 122, 4160–4171 (2012).
Abdul-Wahid, A. et al. Induction of antigen-specific TH 9 immunity accompanied by mast cell activation blocks tumor cell engraftment. Int. J. Cancer 139, 841–853 (2016).
Zhao, Y. et al. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat. Commun. 7, 12368 (2016).
Bu, X. N. et al. Recruitment and phenotypic characteristics of interleukin 9-producing CD4+ T cells in malignant pleural effusion. Lung 191, 385–389 (2013).
Parrot, T. et al. IL-9 promotes the survival and function of human melanoma-infiltrating CD4+ CD8+ double-positive T cells. Eur. J. Immunol. 46, 1770–1782 (2016).
Kim, M. S., Cho, K. A., Cho, Y. J. & Woo, S. Y. Effects of interleukin-9 blockade on chronic airway inflammation in murine asthma models. Allergy Asthma Immunol. Res. 5, 197–206 (2013).
White, B., Leon, F., White, W. & Robbie, G. Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. Clin. Ther. 31, 728–740 (2009).
Parker, J. M. et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm. Med. 11, 14 (2011).
Oh, C. K. et al. A randomized, controlled trial to evaluate the effect of an anti-interleukin-9 monoclonal antibody in adults with uncontrolled asthma. Respir. Res. 14, 93 (2013).
Nonomura, Y. et al. Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients. Oncoimmunology 5, e1248327 (2016).
Anuradha, R. et al. IL-10- and TGFβ-mediated Th9 responses in a human helminth infection. PLoS Negl. Trop. Dis. 10, e0004317 (2016).
Moretti, S. et al. A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. Nat. Commun. 8, 14017 (2017).
Acknowledgements
The authors thank their colleagues for scientific insights. C.D.’s research is supported, in part, by grants from the National Key Research and Development Program of China (2016YFC0906200), the National Natural Science Foundation of China (31630022, 31991173, 31821003 and 91642201) and Beijing Municipal Science and Technology (Z181100001318007, Z181100006318015 and Z171100000417005). P.A.’s research is supported by a grant from the Thai Government Research Fund (630000050161). The authors acknowledge and apologize to those whose important contributions could not be cited owing to space limitations.
Author information
Authors and Affiliations
Contributions
P.A. and C.D. developed the article together. P.A. drafted the article and C.D. revised it.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Immunology thanks C. Schlapbach, S. Tangye and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Papain
-
A cysteine protease allergen that has been commonly used as a model of exposure to natural allergen sources to induce allergic airway inflammation in mice. On airway papain challenge, it can trigger type 2 T helper cell-type cytokine production, induce eosinophilia and enhance IgE production.
Rights and permissions
About this article
Cite this article
Angkasekwinai, P., Dong, C. IL-9-producing T cells: potential players in allergy and cancer. Nat Rev Immunol 21, 37–48 (2021). https://doi.org/10.1038/s41577-020-0396-0
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41577-020-0396-0
This article is cited by
-
Smith-specific regulatory T cells halt the progression of lupus nephritis
Nature Communications (2024)
-
Pathogenesis of allergic diseases and implications for therapeutic interventions
Signal Transduction and Targeted Therapy (2023)
-
T cells in health and disease
Signal Transduction and Targeted Therapy (2023)
-
Deep computational image analysis of immune cell niches reveals treatment-specific outcome associations in lung cancer
npj Precision Oncology (2023)
-
PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis
Nature Communications (2023)
