IL-9-producing T cells: potential players in allergy and cancer

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.

Introduction

During an adaptive immune response, CD4+ T cells can differentiate into diverse cytokine-secreting T helper cell (TH cell) types in response to environmental stimuli. In 2008, it was shown that IL-9-producing T cells — which were referred to as ‘TH9 cells’ — could be generated in vitro in the presence of transforming growth factor-β (TGFβ) and IL-4 (refs1,2). These cells differed from traditional TH2 cells in that they did not highly express the cytokines IL-4, IL-5 and IL-13. Subsequently, PU.1 and interferon regulatory factor 4 (IRF4) were described as obligatory transcription factors for TH9 cell development3,4. Recent studies have shown how multiple transcription factors, co-stimulatory molecules and chromatin remodelling across the Il9 locus coordinate and regulate the induction and function of TH9 cells3,4,5,6,7,8,9,10. Other cellular sources of IL-9 have also been identified, particularly innate immune cells, such as mucosal mast cells11 and group 2 innate lymphoid cells (ILC2s)12. In addition, production of IL-9 by TH2 cells13, regulatory T cells (Treg cells)14, T follicular helper cells15 and a fraction of memory B cells has been reported16.

IL-9 was originally found to be produced during gastrointestinal nematode infection and in allergic asthma17,18,19,20,21,22, supporting a functional role for this cytokine in type 2 immunity and type 2-associated inflammatory diseases. IL-9 has pleiotropic activities in enhancing mast cell and eosinophil recruitment and function, as well as in stimulating epithelial cell mucus production. Studies involving antibody-mediated neutralization of IL-9 or Il9-deficient mice led to controversial results in models of allergic disease23,24,25. However, later work found that deleting a regulatory region in the Il9 locus that is necessary for driving IL-9 expression and TH9 cell differentiation suppressed allergic lung inflammation26,27,28. In cancer, IL-9 was initially reported to regulate tumour cell proliferation in Hodgkin disease and in anaplastic large cell lymphoma, but increasing evidence indicates a role for TH9 cells in promoting antitumour responses in melanoma8,29,30,31.

In this Review, we highlight our current knowledge of IL-9-producing T cells. To begin with, we provide a general overview of the various cellular sources and targets of IL-9, before focusing on the development and regulation of TH9 cells and discussing whether they truly represent a distinct TH cell subset in vivo. We address the functional roles of TH9 cells in allergy and cancer and describe their regulation, considering why these cells can exert both deleterious and protective roles in these diseases. Finally, we discuss the unresolved issues in this field.

IL-9 biology: sources and targets

IL-9 belongs to the common γ-chain receptor family of cytokines that use the common IL-2 receptor γ-chain for signal transduction. In 1988, it was initially termed ‘P40’ and reported as a T cell growth factor because of its autocrine expression and ability to promote the growth of a TH cell line32. Subsequently, the biological activity of IL-9 in enhancing mast cell growth was described33. IL-9 was originally defined as a TH2-type cytokine as its expression correlated with the expansion of antigen-specific TH2 cell populations34,35. Much attention in recent years has been focused on a major population of TH cells — generated in vitro in the presence of TGFβ and IL-4 — that produces IL-9 (refs1,2), namely TH9 cells. In the following subsections, we provide an overview of the various sources and targets of IL-9.

Cellular sources of IL-9

TH cells are one of the main cellular sources of IL-9. Initial studies showed that IL-9 can be secreted by certain TH cell lines and by activated naive CD4+ T cells32,34,36. In the era of the TH1 cell and TH2 cell dichotomy, IL-9 was linked to TH2 cells, as its expression was accompanied by that of TH2-type cytokines and increased levels of IL-9 were found in a cutaneous leishmaniasis model in TH2 type cytokine-prone mice35. However, TH9 cells capable of producing IL-9 —but not IL-4, IL-5 and IL-13 — were later generated in vitro and suggested to be a distinct TH cell subset1,2. Neutralizing IL-9 attenuated TH9 cell-driven, but not TH2 cell-induced, allergic inflammation4, suggesting that TH9 cells may function independently of TH2 cells in allergy. To delineate the cellular sources of IL-9, Il9-knock-in reporter mice were constructed, which confirmed that T cells activated in vitro under TH9 cell-priming conditions — but not under TH2 cell- or TH17 cell-priming conditions — predominantly expressed IL-9 (refs37,38). Furthermore, TH9 cells were also detected in vivo, although only transient expression of IL-9 by T cells was observed during infection with the gastrointestinal nematode Nippostrongylus brasiliensis38. Because the characteristics of these TH9 cells during infection were not defined, whether they are the bona fide TH9 cells that are independent of TH2 cells in vivo remains uncertain. Following adoptive transfer, mouse TH9 cells, unlike TH2 cells, showed short-term retention at tissue sites39. The transient expression of IL-9 preceded that of IL-4, IL-5 and IL-13 in helminth infection and in house dust mite-induced allergic inflammation models38,40. In humans, a distinct population of TH9-like cells that express cutaneous homing receptors has been detected in skin. These skin-tropic memory TH9 cells that are specific for Candida albicans transiently produced IL-9, co-express tumour necrosis factor (TNF) and granzyme B, and have been suggested to mediate immunity against C. albicans41. These T cells appeared during the transient downregulation of TH2-type signature cytokines in IL-9+ TH2 cells13. They were not very stable and shared characteristics of memory TH2 cells in their expression of CC-chemokine receptor 4 (CCR4) and CCR8. In this study, IL-9-producing T cells were thus described as a subpopulation of TH2 cells that exhibited a TH9 cell-like phenotype rather than as a distinct TH9 cell lineage13. Supporting this idea, the increased expression of IL-9 seen in type 1 hypersensitivity diseases in humans was found to be derived from a pathogenic TH2 cell subset that co-expressed CRTH2, CD49d and CD161 (ref.42). These studies suggest that IL-9 expression may arise from a heterogeneous population of TH2 cells.

Several reports also suggested that TH17 cells can produce IL-9 in both mice and humans43,44,45,46, although the functional significance of this is unclear. IL-9 expression by Treg cells was also reported14,47,48. However, a study using forkhead box protein P3 (FOXP3)–green fluorescent protein (GFP) reporter mice showed that IL-9 was not detected in thymically derived or in peripherally induced Treg cells43. T follicular helper cells, which are specialized in supporting germinal centre reactions, were also reported to produce IL-9 in a manner that promoted the development of memory B cells15.

Because several TH cell subsets have been shown to secrete IL-9, it remains a matter of debate whether IL-9-producing T cells represent a distinct TH cell lineage or subset. A recent finding from single-cell gene expression analysis of mouse in vitro differentiated TH9 cells revealed their heterogeneous phenotypes and functions49. Two main subpopulations expressing different levels of CD96 were shown to have differential function in promoting inflammation and inducing colitis. Considering the TH cell heterogeneity and plasticity as well as the unstable TH9 cell phenotype, it is possible that IL-9-producing T cells may represent an adaptation of TH cells to certain inflammatory conditions. Further characterization of epigenetic profiles of TH9 cells and single-cell transcriptomic analysis of human TH9 cells may provide more information on whether these cells should be described as having TH9 cell phenotype or TH9 cell lineage. Fate mapping of IL-9-producing T cells would provide valuable dissection of IL-9 regulatory programmes and their stability and plasticity.

Following the discovery of ILC2s50,51,52, two studies using Il9 reporter mice showed that they represent another major cell population producing IL-9 in vivo under physiological conditions37,38. With use of an IL-9 fate-reporting bacterial artificial chromosome-transgenic mouse that expresses Cre recombinase under the control of the Il9 locus (Il9Cre mouse), ILC2s but not CD4+ T cells were shown to be the major producers of IL-9 in a model of papain-induced allergic inflammation37. However, incomplete IL-9 reporting activity was noted in this model. Another IL-9 reporter model that allows reporter expression induced by the endogenous IL-9 promoter showed that the two major cellular sources of IL-9 expression during N. brasiliensis infection are TH9 cells and ILC2s38. In humans, ILC2s isolated from blood and nasal polyps of patients with chronic rhinosinusitis produced not only IL-5 and IL-13 but also IL-9 (ref.53). The expression of IL-9 by ILC2s was suggested to amplify TH9 cell response38.

IL-9 was also found to be expressed in cell types other than TH9 cells and ILC2s. Bone marrow-derived mast cells were shown to produce IL-9 (ref.54), and a new population of IL-9-producing mucosal mast cells was recently identified in the lamina propria of small intestine tissue and shown to promote susceptibility to food allergy11. Natural killer (NK) cell/T cell lymphoma cell lines derived from patients with nasal NK cell/T cell lymphoma, but not non-nasal NK cell lymphoma, produced IL-9 as an autocrine growth factor, which may be caused by the presence of Epstein–Barr virus in this lymphoma55. Moreover, IL-9 can also be produced by CD8+ T cells56,57. These IL-9-producing CD8+ T cells had diminished cytotoxicity compared with conventional cytotoxic T cells in vitro, but adoptive transfer of ‘TC9’ cells enhanced antitumour immunity in vivo, which contributed to long-term survival and conversion of transferred cells into less exhausted effector cells57. By use of neutralizing IL-9 antibody, the mechanism of tumour cell killing was suggested to be dependent on IL-9 function to promote TC9 cell migration into tumour sites to exert cytolytic effector function. In addition, although a functional role in vivo has not been determined, human peripheral blood Vδ2+ γδ T cells that were stimulated in the presence of TGFβ and IL-15 in vitro were considered to be a potential source of IL-9 (ref.58). In a mouse immunization model, production of IL-9 by memory B cells was also reported to promote memory B cell proliferation and differentiation during secondary immune responses16.

From the findings taken together, the wide distribution of cellular sources of IL-9 points to a complex regulatory network of IL-9 expression and suggests that this cytokine has diverse functions in both physiological immune responses and disease (Fig. 1; Table 1).

Fig. 1: Expanding views of IL-9-producing cells.
figure1

a | IL-9-producing cells in allergic diseases. On allergen exposure, IL-9 can be produced by T helper 2 cells (TH2 cells) and TH9 cells. Moreover, group 2 innate lymphoid cells (ILC2s) and mast cells, including mucosal mast cells, can secrete IL-9 and coordinate with adaptive TH2 cells and TH9 cells to exacerbate allergic inflammation. b | IL-9-producing cells in cancer. The majority of IL-9-producing cells in cancer are TH9 cells; however IL-9 can be secreted by some cytotoxic T cells (which have been referred to as ‘TC9 cells’) and Vδ2+ γδ T cells. These IL-9-producing T cells play roles in promoting cancer progression or in antitumour immunity. c | Following helminth infection, IL-9 can be secreted by TH9 and TH2 cells, and these populations cooperate with IL-9-producing ILC2s to promote protective helminth immunity. d | In autoimmune diseases, IL-9 is derived mainly from TH9 cells and TH17 cells and functions to promote tissue inflammation. However, ILC2s and regulatory T (Treg) cells can secrete IL-9 to induce tissue resolution during chronic inflammation.

Table 1 Potential IL-9-producing cells and possible functions

Potential target cells for IL-9 and their function

The receptor for IL-9 consists of a unique α-chain (IL-9Rα) subunit and the common γ-chain59,60. Initial characterization of IL-9 pointed to TH cells as an important target because IL-9 promoted their growth in a dose-dependent manner32,61. The highest expression of the Il9r transcript was found in effector TH2 cells and in TH17 cells in a mouse study44. Consistent with this, in an experimental autoimmune encephalomyelitis model, deficiency in IL-9R reduced TH17 cell frequency and disease severity44. However, deficiency in IL-9 did not directly affect the development of TH cell populations in N. brasiliensis infection62. IL-9 also can enhance Treg cell-mediated suppression in vitro and in vivo by promoting Treg cell survival through STAT3 and STAT5 activation43. In a human study, IL-9R was shown to be highly expressed by activated TH cells that expressed the skin-homing receptor cutaneous lymphocyte antigen (CLA). IL-9 may thus be involved in the pathogenesis of allergic disease through its autocrine and paracrine effects on TH cells that express IL-9R. During in vitro culture of CLA+ TH cells, neutralization of IL-9 inhibited T cell proliferation and production of not only IL-9 but also other cytokines, including interferon-γ (IFNγ), IL-13 and IL-17 (ref.41). A subpopulation of CRTH2+ TH2 cells expressing high levels of IL-9 was recognized as a pathogenic TH2 cell population42. Whether these cells express IL-9R, which may amplify their functional response to simultaneously produce multiple TH2 cell effector cytokines to drive allergic disease remains unclear. Further investigation of IL-9 function in these pathogenic TH2 cells would provide greater insight on the role of IL-9 in human allergic diseases.

Mast cells are another important target cell for IL-9. With use of a mast cell line and primary mast cells, an effect of IL-9 on mast cell growth and function was noted33,63,64. IL-9 stimulated mast cell proliferation and induced IL-6 production by bone marrow-derived mast cells in vitro33. In vivo studies using Il9-transgenic and IL-9-deficient mice further substantiated the roles of IL-9 in regulating mast cell proliferation, accumulation and survival21,62. Adoptive transfer of TH9 cells increased the numbers of mast cells and the expression of mast cell proteases in an allergic lung inflammation model64. Neutralization of IL-9 in mice reduced mast cell numbers and their activation and also decreased the expression of the profibrotic mediators TGFβ1, vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2), and led to reduced airway remodelling63. In the lung tissues of patients with asthma, mast cells were the major IL-9R-expressing cells that were responsible for secretion of profibrotic mediators. Moreover, overexpression of IL-9 in the intestine induced the expression of several mast cell proteases, and this was associated with increased mast cell numbers and enhanced intestinal permeability in a model of hypersensitivity induced by oral antigen sensitization65.

A transcriptomic profiling analysis found high levels of IL-9R expression in ILC2s52. The expression of IL-5 and IL-13 in ILC2s can be upregulated by IL-9 stimulation37. In N. brasiliensis infection, the expression of IL-9R in ILC2s was higher than in TH cells12. The numbers of GATA3+ ILC2s, but not RORγt+ ILC3s, were significantly reduced in the lungs of IL-9R-deficient mice during infection, and IL-9 was suggested to act as an autocrine factor to promote the survival of ILC2s by inducing antiapoptotic protein expression in vivo12.

Besides these major IL-9-responsive cells, additional haematopoietic and non-haematopoietic cell types have been reported to respond to IL-9. In Il9-transgenic mice, IL-9 expression was associated with the expansion of B1 cell populations but not splenic B cell populations66. Indeed, B1 cells exhibited high expression of IL-9R but treatment with IL-9 did not induce their cellular proliferation, suggesting that IL-9 may have other effects on B1 cells, such as promoting cell differentiation and survival. A recent study indicated that IL-9R on memory B cells can be selectively induced on immunization, and IL-9–IL-9R signalling was required for the proliferation of memory B cells and plasma cell differentiation during secondary immune response16. These studies suggest a role of IL-9 in regulating B cell function.

For non-haematopoietic cell types, a study using IL-9-deficient mice demonstrated the involvement of IL-9 in goblet cell hyperplasia62. Although this effect has been suggested to be mediated mainly by IL-9-induced IL-13 production67, airway epithelial cells and smooth muscle cells can also be a direct target for IL-9, which has been shown to stimulate mucin synthesis and the production of chemokines associated with eosinophil recruitment68,69,70. In an experimental colitis model, IL-9R was found to be expressed by intestinal epithelial cells; treatment of intestinal epithelial cells with IL-9 enhanced their expression of tight junction molecules associated with impaired barrier function, therefore driving colitis pathogenesis71. Altogether, these data suggest that there are many cellular target cells of IL-9 and that IL-9 may have multiple biological activities in various inflammatory diseases.

TH9 cells

Discovery of TH9 cells and their characteristics

TH9 cells were originally generated in vitro from naive CD4+ T cells cultured in the presence of TGFβ and IL-4 (refs1,2,72). The cells generated in these cultures showed high levels of IL-9 expression without the induction of key transcription factors, such as T-bet, GATA3, FOXP3 or RORγt, that are known to regulate the differentiation of other T cell subsets1,2. Under some conditions, TH9 cells may secrete IL-10, but they do not function as Treg cells and have instead been shown to promote tissue inflammation2. Although the expression of GATA3 is not substantially induced during their development, TH9 cells do actually require both STAT6 and GATA3 for their generation1,2,5. However, the selective expression of PU.1 induced by TGFβ in TH9 cells may function to restrict the ability of STAT6 and GATA3 to induce TH2-type cytokines3. Furthermore, TH2 cells cultured with TGFβ can convert into TH9 cells1, further emphasizing the close relationship between these cells. To date, such cells generated in vitro under the influence of TGFβ and IL-4 have displayed distinct features compared with TH2 cells. However, more analyses are needed to identify such cells in animal models and human tissues. If such cells exist, whether they represent a unique lineage or a transitional state and whether they are plastic or stable need to be investigated carefully and thoroughly.

Earlier studies indicated that the ETS family transcription factor PU.1 and IRF4 are essential for TH9 cell development3,4. Deficiency of PU.1 resulted in impaired TH9 cell generation but normal TH2 cell responses, clearly indicating PU.1 is a crucial regulator of TH9 cell differentiation3. PU.1 was expressed in a subpopulation of TH2 cells that showed low levels of IL-4 production73. Ectopic expression of PU.1 in TH2 cells drove the induction of IL-9 expression with low expression of TH2-type cytokines, indicating that PU.1 may be a switch factor for IL-9 induction by TH9 cells3. However, it remains possible that IL-9-producing T cells may be a heterogeneous TH2 cell subpopulation generated under certain conditions. A more recent study in humans showed that the transcription factor peroxisome proliferator-activated receptor-γ may indirectly mediate the development of IL-9+ TH2 cell subpopulations by functioning as a positive regulator of IL-9 expression in TH2 cells polarizing under TGFβ exposure13. Whether TH9 cells represent a stand-alone TH cell lineage remains a subject of debate because the regulation of IL-9 expression in vivo remains uncertain — importantly, major transcription factors expressed by TH9 cells, such as PU.1 and IRF4, are also co-expressed by other TH cells and therefore not are strictly classed as lineage-defining master transcription factors.

Gene expression analysis revealed that TH9 cells have distinct transcriptional signatures that are more similar to those of TH2 cells than to those of Treg cells7. In helminth infections, TH9 cells developed and were found to be the major in vivo source of IL-9 (ref.38). An IL-9 promoter-driven GFP reporter was found mostly in in vitro differentiated TH9 cells and only at very low levels in TH2 cell- and TH17 cell-polarizing conditions; thus, the source of IL-9 in vitro was not TH2 cells or TH17 cells. However, the expression of TH2-type cytokines or other cytokines by IL-9+ cells in vivo was not characterized in this study. Although it remains unclear whether IL-9+ TH cells are distinct population of TH9 cells in vivo, adoptive transfer of TH9 cells, but not TH2 cells, was efficient in driving basophilia and an increase in mast cell numbers that led to worm expulsion, indicating the unique functional characteristics of TH9 cells in promoting basophil and mast cell function38. The phenotype of TH9 cells in vivo was, however, not stable because a rapid decline of IL-9 expression was seen during helminth infection.

In humans, IL-9 production was seen only in TH cells that expressed the skin-homing receptor CLA, and these cells lacked co-expression of signature cytokines associated with other TH cell lineages but instead co-expressed TNF and the cytotoxic molecule granzyme B41. Human TH9 cells showing these characteristics were found to be uniquely increased in number in the skin of patients with psoriasis and to be involved in driving skin inflammation. High numbers of circulating TH9 cells co-expressing PU.1 were also identified in patients with asthma and showed distinct kinetics with earlier induction compared with TH2 cells40. Altogether, these data suggested the unique multifunctional activities of TH9 cells in different disease settings. Recently, single-cell profiling analysis demonstrated the heterogeneity in the phenotypes and functions of TH9 cells generated in vitro49. As described previously74, it is likely that differential expression of activation markers and chemokine receptors by TH9 cells may be responsible for driving different types of immune response. Moreover, antigen-specific TH9 cells may not be a stable population as IL-9 secretion was downregulated at sites of tissue inflammation13,39. The dynamic IL-9 expression and diverse effects of TH9 cells may result from transient IL-9 expression in adaption to physiological or pathological environmental stimuli.

Regulation of TH9 cell development

As already mentioned, the induction of TH9 cells requires the combination of TGFβ and IL-4 (refs1,2). SMAD2 and SMAD4 activation by TGFβ is required for IL-9 expression but suppresses the expression of TH2-type cytokines75. The TGFβ–SMAD signalling axis regulated IL-9 expression, not through the induction of IRF4 and PU.1 but through the displacement of EZH and removal of repressive chromatin modifications at the Il9 locus75. On the other hand, IL-4 can mediate STAT6, IRF4 and GATA3 activation. Both STAT5 and STAT6 can transactivate Il9 transcription5,76. It has also been suggested that the suppressor of cytokine signalling (SOCS) family member cytokine-inducible SH2-containing protein (CISH; also known as CIS), negatively regulates TH9 cell responses76. The induction of CISH by IL-2 and IL-4 reduced the binding of STAT5 and STAT6 to TH2 cell- and TH9 cell-associated signature genes and inhibited the development of allergic airway inflammation76. In addition, STAT3 was found to be another negative regulator of mouse TH9 cell differentiation, partly through STAT5 inhibition, and STAT3 may be responsible for TH9 cell instability77,78. However, unlike in mouse studies, patients with STAT3 loss-of-function mutations exhibited impaired TH9 cell differentiation and IL-21 production79,80. STAT3-activating cytokines such as IL-21 and IL-6 can enhance human TH9 cell differentiation46. These data suggest a discrepancy in the regulation of human versus mouse TH9 cells, which requires further investigation.

Several additional cytokines amplify IL-9 production. IL-2 can augment IL-9 expression by activating STAT5 binding to the IL9 gene72,81. Moreover, IL-2 can potentiate the induction of STAT5, which binds to the IRF4 promotor through the regulation of ITK, a member of the TEC family of cytosolic tyrosine kinases, an important component of T cell receptor-mediated signalling82. Unlike in mouse TH9 cells, TGFβ and IL-2 were not required for IL-9 production by human TH9 cells in the skin41. IL-25, IL-33 and TSLP, which are known regulators of type 2 immune responses, were shown to enhance the production of IL-9 by TH9 cells in vitro and to promote TH9 cell function during allergic inflammation and helminth infection in vivo83,84,85,86. Activin A, another TGFβ superfamily member, together with IL-4, can promote TH9 cell generation and act together with IL-25 to enhance IL-9 expression40.

Moreover, various pro-inflammatory cytokines can influence the expression of IL-9 by TH9 cells. IL-1β can activate the expression of IL-9 during TH cell activation87, possibly through the activation of phosphorylated STAT1 and subsequent expression of IRF1 (ref.30). Recently, the combination of IL-1β and IL-4 was shown to enhance the induction of TH9 cells through activation of the nuclear factor-κB (NF-κB) pathway, even in the absence of TGFβ signalling30,88. Classical TH9 cells differentiated with TGFβ and IL-4 had increased expression of genes associated with T cell exhaustion, such as Ctla4, Pdcd1 and Lag3, while TH9 cells induced by IL-1β and IL-4 showed increased expression of genes associated with cytolytic T cell responses (such as Eomes, Tbx21 and granzyme genes) that may lead to greater antitumour immune activity88. Indeed, NF-κB can potentiate the expression of IL-9 by cooperating with the activation of NFAT1, which regulates accessibility at the Il9 locus89. Moreover, OX40-activated TRAF6, without affecting PU.1 expression, triggered the non-canonical NF-κB pathway to potentiate the induction of TH9 cells6. Further study indicated that OX40 mediated the assembly of IL-9 superenhancer through the activation of RELB, which drives chromatin modifications in TH9 cells26. In addition, the TNF family cytokine TL1A (also known as TNFSF15) can be a potent IL-9 inducer in TH9 cell differentiation through the induction of BATF and BATF3, which bind to the IL-9 promoter90.

TH9 cells and IL-9-producing cells in allergy

Numerous studies have indicated the involvement of TH9 cells and IL-9-producing cells in the pathogenesis of allergic diseases. Implication of a role for IL-9 in allergy first came from a linkage analysis that showed an association between the Il9 gene locus and atopy as well as serum IgE levels91,92,93. The human IL9 gene resides within the TH2-type cytokine gene cluster on chromosome 5, which contains the IL3, IL4, IL5, IL13 and CSF2 genes94,95. Moreover, increased expression of IL-9 was associated with asthma22. Transgenic mice overexpressing IL-9 or administration of IL-9 enhanced eosinophilic airway inflammation, IgE production, mast cell hyperplasia, subepithelial collagen deposition and airway hyperresponsiveness21,67,96,97,98. Although there was no defect in allergen-induced pulmonary inflammation and airway hyperreactivity in mice deficient in IL-9 (refs25,62), neutralization of IL-9 in a mouse model of allergic airway sensitization led to reduced eosinophilia, reduced serum IgE levels, goblet cell hyperplasia and lower levels of airway hyperreactivity23,24. These studies thus indicated the importance of IL-9 in allergic disease.

IL-9 acts on various cell types, such as TH cells, ILC2s, mast cells, B cells, eosinophils and epithelial cells, to exacerbate allergic responses. A wealth of evidence indicates the major function of IL-9 and TH9 cells is related to the induction of IgE production, allergic inflammation, mucous cell metaplasia and mast cell activation, without directly influencing the development of TH2 cells4,23,24,40,62,64 (Fig. 2). An elevation of IL-9 production in plasma or allergen-restimulated peripheral blood mononuclear cells was reported in patients with respiratory and food allergy as well as in patients with skin allergies such as atopic dermatitis99. IL-9 has been suggested to be involved in the bronchial hyperresponsiveness, although eosinophil and TH2-type cytokines may be responsible for asthma phenotypes100. The numbers of circulating TH9 cells were correlated with IgE levels in children with asthma and with the clinical severity in atopic dermatitis40,101. Analyses of gene expression profiles of memory TH cells from patients with peanut allergies and patients with peanut sensitization showed that IL-9 was expressed at higher levels in the cells from patients with peanut allergy, thereby implicating TH9 cells as a key component in peanut allergy102.

Fig. 2: Regulation and function of IL-9-producing cells in allergic diseases.
figure2

During allergic responses, T helper 9 cells (TH9 cells), TH2 cells, group 2 innate lymphoid cells (ILC2s) and mucosal mast cells are the predominant IL-9-producing cells. Proallergic cytokines, namely IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), act on these cells to promote the amplification of IL-9 production and the co-expression of other cytokines. IL-9 derived from these cells has multiple effects on other cell types: it promotes the survival and expansion of mast cell populations and their production of immune mediators such as mast cell proteases and cytokines; it promotes B cell memory responses and IgE production; it can act on non-haematopoietic cells (such as epithelial cells and smooth muscle cells) to induce mucus production and chemokine expression; it can act on eosinophils to promote their tissue infiltration, survival and mediator secretion. The effector functions induced by IL-9-producing cells occur in both IL-9-dependent and IL-9-independent pathways, leading to the amplification of allergic reactions that can exacerbate allergic symptoms in chronic allergic airway diseases such as asthma, IgE-mediated food allergy and skin inflammation. TGFβ, transforming growth factor-β.

Other studies have shown important roles for TH9 cells in allergic disease. In a mouse model of allergic airway inflammation, failure to induce TH9 cells in mice with PU.1- or IRF4-deficient T cells attenuated allergic pulmonary inflammation, eosinophilia and airway hyperresponsiveness without affecting IgE or IgG1 production3,4. Adoptive transfer of TH2 cells or TH9 cells into lymphopenic mice led to identical asthma symptoms in an allergic airway disease model4,40. Although the phenotype of transferred cells in recipient mice was not analysed in these studies, neutralization of IL-9 in mice that received TH9 cells but not TH2 cells resulted in reduced allergic inflammation, indicating the stability of TH9 cells in this model and further supporting an independent role of TH9 cells in promoting allergic responses. Further analysis of transferred cell phenotype in TH9 cell- and TH2 cell-induced allergic inflammation may substantiate these findings. Histological analyses of lung tissues indicated that TH9 cells were more potent than TH2 cells in promoting mast cell accumulation, whereas comparable mucous cell metaplasia was observed in mice receiving TH2 cells or TH9 cells64. In food allergy, IL-9 plays a non-redundant role in the development of intestinal anaphylaxis by inducing an increase in intestinal mast cell numbers and mast cell degranulation65,103. These data suggest that the roles of TH9 cells and TH2 cells in the pathogenesis of allergic diseases are not entirely identical. It has been shown that the effect of IL-9 on promoting mucus secretion by lung epithelial cells was dependent on IL-13 but IL-9-induced mastocytosis was IL-13 independent104. In chronic asthma and food allergy, the pathology was associated with the cross-regulation between mast cells and IL-9 (refs11,63,105).

More recently, a study in humans identified a subpopulation of IL-9+ TH2 cells in allergic skin diseases, particularly in acute inflammatory diseases13. Further emphasizing its significance in allergy, the amount of IL-9 in chronic atopic dermatitis and acute contact dermatitis reactions to nickel in the skin was positively associated with disease severity13. IL-9 expression was transiently activated on allergen stimulation. High levels of expression of IL-9 and IL-5 were also found in a new subset of pathogenic TH2 cells (‘TH2A cells’) in patients with type 1 allergic diseases42. The depletion of these cells was linked to allergen desensitization immunotherapy42. Therefore, the induction IL-9-producing T cells may contribute to the pathogenesis of allergic diseases, differently from conventional TH2 cells. Such a population might be clinically important in allergic diseases and requires further investigation.

TH9 cells and IL-9-producing cells in cancer

In keeping with the role of IL-9 as a growth factor for T cells, IL-9-transfected T cell lines proliferated autonomously and became tumorigenic106. Moreover, there was a strong association of IL-9 expression with Hodgkin lymphomas and large cell anaplastic lymphoma107. Administration of anti-IL-9 inhibited the growth of Hodgkin and Reed–Sternberg cells in vitro108, whereas overexpression of IL-9 or IL-9 treatment induced the proliferation and development of thymic lymphoma109,110. TH9 cells were also found to be present in tumour-infiltrating lymphocytes isolated from melanoma lesions from patients with stage IV metastatic melanoma and were shown to inhibit melanoma growth in melanoma-bearing mice29.

As IL-9 has pleiotropic functions in multiple cell types, dual roles of IL-9 in cancer development have been reported (Fig. 3). Overexpression of IL-9 and IL-9R was detected in multiple haematological malignancies, including Hodgkin lymphoma111, nasal NK cell/T cell lymphoma55, anaplastic large cell lymphoma112 and B and T cell lymphomas113,114,115. Most of these studies indicated the mechanisms by which IL-9 promotes tumorigenesis through the autocrine growth-promoting effect and antiapoptotic activities. The function of IL-9 in promoting lymphoid cell transformation was mediated directly through the activation of Janus kinase and the phosphorylation of STAT3 and STAT5 pathways116,117. Particularly, STAT5 activation was recognized as a key mediator of IL-9-driven proliferation and tumorigenesis116. Moreover, blockade of IL-9 in a murine lymphoma model inhibited tumour growth through the indirect function of IL-9 in mediating mast cell and Treg cell immunosuppression113. IL-9 is also involved in establishing a permissive tumour growth environment in non-haematological malignancies118,119,120. Serum levels of IL-9 correlated with breast cancer progression118, and an increase in the number of pleural cavity TH9 cells was associated with an increased risk of death in patients, as TH9 cells promoted the proliferation and migratory capacity of lung cancer cells through STAT3 activation119. Because IL-9-deficient mice showed enhanced levels of activated T cells with IFNγ production, IL-9 secreted in the tumour microenvironment was suggested to function as a tolerogenic factor that can inhibit adaptive antitumour immunity120. A more recent study suggested that TH9 cells can promote the proliferation of hepatocellular carcinoma cells by inducing STAT3 activation and tumour cell production of CCL20, which promotes tumour cell migration and tumour progression121.

Fig. 3: Dual function of TH9 cells in cancer.
figure3

T helper 9 cells (TH9 cells) play dual roles in promoting or inhibiting cancer development. IL-9 derived from TH9 cells acts as a growth factor to promote the survival and proliferation of haematopoietic tumour cells (such as Hodgkin lymphoma) or non-haematopoietic tumour cells (for example, breast cancer and hepatocellular carcinoma) that are characterized by the overexpression of IL-9 receptor. Moreover, IL-9 derived from TH9 cells contributes to cancer development by promoting the recruitment and suppressive properties of regulatory T cells (Treg cells) and mast cells that inhibit adaptive antitumour immunity. In different types of cancer, particularly melanoma, TH9 cells participate in promoting antitumour immunity through the production of IL-9, IL-21 and granzyme. The mechanisms underlying TH9 cell function in enhancing antitumour immunity include supporting mast cell activation and cytotoxic function, promoting the activation and recruitment of CC-chemokine receptor 6-positive (CCR6+) dendritic cells, promoting antitumour cytotoxic T lymphocyte (CTL) responses, enhancing natural killer (NK) cell function and directly killing tumour cells. IFNγ, interferon-γ.

There have been increasing reports of antitumour roles for TH9 cells in several non-haematopoietic tumours using mouse tumour models. Several studies have consistently shown that IL-9 and TH9 cells inhibit tumour growth in melanoma29,30,122. Adoptive transfer of TH9 cells into mice into which melanoma cells had been injected resulted in strong inhibition of melanoma growth, even in immunocompromised mice that lacked T cells29, indicating T cell-independent effects of TH9 cells in antitumour immunity. Compared with TH1 cells, TH9 cells were more potent in inducing antitumour immunity in mice with established tumour metastasis29,31,122. The antitumour effects of IL-9 could not be detected in mast cell-deficient mice29, suggesting the indirect effect of IL-9 on mast cells in mediating melanoma cell inhibition. Further study using vaccination against carcinoembryonic antigen indicated the function of TH9 cells in preventing the engraftment of cancer cells through the activation of mast cells123. There are also other mechanisms involved in TH9 cell-mediated tumour rejection. It was demonstrated that dendritic cells activated by dectin 1 agonists induced the production of cytokines and co-stimulatory molecules such as TNFSF15 and OX40L through NF-κB signalling, which facilitated the induction of IL-9 production by TH9 cells124. The immunization with dectin 1-activated dendritic cells induced potent antitumour responses that relied on TH9 cells and IL-9-dependent induction of anticancer cytotoxic T lymphocyte responses. Antibody-mediated neutralization of IL-9 in mice with melanoma resulted in larger tumours with decreased leukocyte infiltration and reduced tumour-specific CD8+ cytotoxic T lymphocyte responses122. The protective mechanisms of IL-9 were shown to involve CCL20-mediated leukocyte recruitment into the tumour microenviroment and the regulation of dendritic cell function in a CCR6-dependent manner122. IL-9 may indirectly enhance CD8+ T cell function by promoting the cross-presentation of tumour antigens and the upregulation of co-stimulatory and MHC class II molecules on tumour-infiltrating dendritic cells8. IL-1β-induced TH9 cells can synergize with chemotherapy to promote complete tumour regression through the activation of IFNγ production by resident CD8+ T cells and NK cells in an IL-21-dependent manner30. Some studies suggested that TH9 cells with high expression of EOMES and granzymes exhibited cytotoxic activity directly on melanoma cells and thereby eradicated advanced late-stage tumours29,31. These studies thus indicated multiple pathways used by TH9 cells in antitumour immunity.

Despite convincing evidence for a role for IL-9 and IL-9-producing T cells in the development of murine tumour models, the significance of human TH9 cells in cancer remains elusive. In patients with lung cancer, the numbers of TH9 cells in malignant pleural effusion serve as a significant predictor of increased risk of death in patients119,125. Although there have been human studies associating the frequencies of TH9 cells and IL-9 levels with melanoma29,126, the contribution of TH9 cells in patient survival has not yet been determined. Extensive study in patients with cancer is essential to understand human TH9 cell function and its possible clinical relevance for cancer immunotherapy.

Therapeutic manipulation of TH9 cells in disease

Considerable evidence from animal studies indicates that IL-9 may be a promising therapeutic target for allergic diseases23,24,63,127. A humanized monoclonal antibody to IL-9, MEDI-528, was developed, and when administered to patients it showed a favourable safety profile and led to a potential reduction in asthma exacerbation rates in patients with mild asthma128,129. However, the results from a larger phase II study involving patients with persistent moderate-to-severe asthma demonstrated that MEDI-528 did not improve clinical activities and health-related quality of life130. The heterogeneous phenotypes of asthma perhaps account for the ineffectiveness of IL-9 blockade in this study130. Targeting IL-9 in a selected subgroup of patients with asthma, or combining IL-9 blockade with other anticytokine regimens, may provide better outcomes.

Recently, the epigenetic landscape surrounding the IL9 gene has been described and the therapeutic potential of targeting its regulatory elements was proposed for asthma26,27. The superenhancer elements were found downstream of IL-9 after co-stimulation with OX40 and showed high levels of chromatin acetylation at the Il9 locus. Disruption of superenhancer elements using the specific BET protein inhibitor JQ1 showed strong inhibitory effects on IL-9 expression and allergic airway inflammation26, although an IL-9 independent effect of this treatment could not be excluded. A more recent study targeting the TH9 cell epigenome used retinoic acid to antagonize IL-9-regulating transcription factors, and this repression of IL-9 accessibility was markedly effective in the control of allergic lung diseases28. Such epigenome-targeting strategies may be a new therapeutic direction for allergic diseases, particularly asthma (Fig. 4).

Fig. 4: Therapeutic strategies for targeting TH9 cells in allergy and cancer.
figure4

Considering the multiple biological activities of T helper 9 cells (TH9 cells), potential therapeutic strategies targeting these cells in allergic diseases and cancer have been proposed. Potential strategies include targeting the pathway for TH9 cell generation, promoting epigenetic modifications at the Il9 locus, and neutralization of IL-9 receptor and of IL-9 production. Such therapies may alleviate symptoms of certain disease phenotypes in patients with chronic asthma. Similarly, these strategies may be used to reduce the growth of specific tumour cells that express IL-9 or IL-9 receptor. The most promising strategy could be to use TH9 cells as a cellular therapy for tumour treatment, particularly for melanoma.

Although IL-9 and TH9 cells represent a potential target for cancer immunotherapy, a pleiotropic effect of IL-9 should be taken into consideration when one is modulating IL-9 and TH9 cells (Fig. 4). Several reports have shown the potent effect of anti-IL-9 on inhibiting the development of multiple types of haematopoietic cancer. In vitro inhibition of autocrine IL-9 in a nasal NK cell/T cell lymphoma cell line caused a dose-dependent reduction in tumour cell growth55. The spontaneous proliferation of adult T leukaemia cells from several patients was inhibited by treatment with a neutralizing monoclonal antibody to IL-9Rα, which acts by targeting monocyte–T cell interactions115. In vitro treatment with IL-9-neutralizing antibody also decreased proliferation and colony formation of Hodgkin lymphoma cells112. The presence of IL-9R in haematopoietic cells may be responsible for its therapeutic effect. Therapeutic approaches using TH9 cell adoptive T cell therapy showed promise consistently in a particular type of solid tumour, especially melanoma29,31,88,122. Even in an established tumour metastasis, adoptive TH9 cell therapy was found to be effective in the induction of tumour immunity in a murine melanoma model31. Thus, it is likely that TH9 cells can be a potential target for clinical application of tumour-specific T cell-based immunotherapy in patients with cancer, particularly melanoma.

Perspective

Although considerable insights have been gained over the past few years on the pleiotropic roles of IL-9 and TH9 cells in health and disease, much remains to be learned regarding the phenotypes, regulation, function and clinical relevance of TH9 cells. Particularly, it remains unclear whether TH9 cells are genuinely a distinct subset from TH2 cells or if they are, in fact, a subgroup of TH2 cells that have become adapted in response to certain environmental stimuli to become specialized in secreting IL-9. To date, there are no data showing stable IL-9 production in TH cells in vivo in both human and mouse studies.

Moreover, the functions of TH9 cells in human allergy and cancer remain to be further elucidated. In a clinical trial involving patients with asthma, there was no substantial beneficial effect of treatment with the humanized anti-IL-9 agent MEDI-528, despite IL-9 blockade showing beneficial effects in mouse models of allergic lung disease. A combination approach to block cytokines derived from both TH2 cells and TH9 cells may likely be more effective as both TH2 cells and TH9 cells have redundant and non-redundant roles in asthma pathogenesis. It also remains inconclusive whether TH9 cell function in human melanoma parallels that observed in murine models. A recent study that discovered an increase in TH9 cell numbers in patients with melanoma who were successfully treated with the anti-PD1 agent nivolumab131 strongly supported the potential benefits of using TH9 cell-based immunotherapies in patients with this disease.

Future studies on TH9 cell biology and its clinical relevance may improve our understanding of the roles of TH9 cell immune regulation and eventually lead to effective treatments for human diseases involving these cells.

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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.

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P.A. and C.D. developed the article together. P.A. drafted the article and C.D. revised it.

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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.

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Angkasekwinai, P., Dong, C. IL-9-producing T cells: potential players in allergy and cancer. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-0396-0

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