A Brief History of IL-9 Ritobrata Goswami and Mark H. Kaplan J Immunol 2011; 186:3283-3288; ; This information is current as doi: 10.4049/jimmunol.1003049 of October 4, 2021. http://www.jimmunol.org/content/186/6/3283

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. A Brief History of IL-9 Ritobrata Goswami and Mark H. Kaplan IL-9 was first described in the late 1980s as a member of IL-9 in T cells isolated from Leishmania major-infected of a growing number of that had pleiotropic BALB/c mice, which generate a Th2-biased immune re- functions in the immune system. Although many bio- sponse, provided the initial basis for defining IL-9 as a Th2 logical functions have been attributed to IL-9, it re- (7). However, other Th subsets also appear to have mains an understudied cytokine. A resurgence of in- the potential for IL-9 production. Th17 cells, which are de- terest in IL-9 has been spurred by recent work demon- fined by secretion of IL-17A and IL-17F, may also secrete IL- strating a role for IL-9 in regulating inflammatory 9 in vitro and ex vivo (8, 9). Human Th17 cells can secrete immunity and defining the transcription factors that ac- IL-9, and long-term Th17 cultures have the ability to coex- tivate the Il9 in cells that most efficiently produce press IL-17A and IL-9 (10). In contrast, IL-23, a cytokine IL-9. In this review, we summarize the characterization required for maintenance of the IL-17–secreting phenotype, Downloaded from of IL-9 biological activities, highlight roles for the cy- has inhibitory effects on IL-9 production (8, 11). Regulatory tokine that are clearly defined, and outline questions T cells (Tregs) may also produce IL-9. A study linking mast regarding IL-9 functions that still require further ex- cells to peripheral tolerance demonstrated that natural Tregs + ploration. The Journal of Immunology, 2011, 186: and inducible Tregs, both Foxp3 populations, secrete IL-9 3283–3288. (12). There is conflicting evidence regarding production of IL-9 from human Tregs (10, 13). http://www.jimmunol.org/ Mounting evidence suggests that there may be a specialized Discovery and of IL-9 subset of T cells dedicated to producing IL-9, in which Il9 is regulated by a number of cytokines and transcription factors IL-9 was first purified and characterized as a and (Fig. 1). More than 15 y ago, TGF-b and IL-4 were shown to respectively termed P40, based on m.w., or mast enhance IL-9 production from activated T cells (14). Naive -enhancing activity (1, 2). The cloning and com- CD4+ T cells primed in the combination of TGF-b and IL-4 plete sequencing of P40 revealed that it is struc- or Th2 cells additionally cultured in TGF-b produced high turally distinct from other T cell growth factors (3, 4) and was levels of IL-9 and showed diminished expression of other by guest on October 4, 2021 renamed IL-9 based on biological effects on both myeloid and lymphoid cells. A 14-kDa was predicted from the lineage-specific cytokines and transcription factors (15, 16). cloned sequence encoding a 144-aa , including leader The ability of IL-4 to inhibit expression of Foxp3 in cultures b sequence. The mouse Il9 gene is located on 13, containing TGF- that induce inducible Treg generation and whereas the human IL9 gene is located in a syntenic region on to promote an IL-9–secreting phenotype was dependent on (5). IL9 is 3.2 megabases telomeric from the STAT6 (15, 16). Similarly, GATA3 was required for the IL5/IL13/IL4 loci. generation of IL-9–secreting cells (15), suggesting that Th2 cells, and the IL-9–secreting population termed Th9 cells, IL-9–secreting cells have shared factors in their development. Human T cells also The major source of IL-9 is T . Initially described acquire IL-9–secreting potential when cultured with TGF-b as T cell growth factor III, IL-9 is produced by long-term T cell and IL-4 (10, 13, 17–19). The stability of the IL-9–secreting lines, Ag-specific T cell lines, and naive murine T cells (6). phenotype is still not well described, although studies suggest However, it was unclear if there were specialized cells pro- that Th9 cells can be maintained, but retain plasticity to ac- grammed for IL-9 production as was being established at the quire additional cytokine-secreting potential (20). time for other cytokines such as IL-4 and IFN-g in Th2 and Recently, two transcription factors were reported to bind Th1 cells, respectively. directly to the Il9 gene and were required for the development IL-9 production was first associated with the Th2 pheno- of IL-9–secreting cells. PU.1 is an ETS family transcription type, and many of the preliminary functions of IL-9 were factor known to have a repressive effect on the production of tested in models of Th2-associated immunity. The expression Th2 cytokines (21, 22). Ectopic expression of PU.1 not only

Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana Medicine, 1044 West Walnut Street, Indianapolis, IN 46202. E-mail address: mkaplan2@ University School of Medicine, Indianapolis, IN 46202; and Department of Microbi- iupui.edu ology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202 Abbreviations used in this article: EAE, experimental autoimmune encephalomyelitis; Received for publication November 16, 2010. Accepted for publication December 21, IRF4, IFN regulatory factor 4; Treg, . 2010. Ó This work was supported in part by Public Health Service Award AI057459. Copyright 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of www.jimmunol.org/cgi/doi/10.4049/jimmunol.1003049 3284 BRIEF REVIEWS: IMMUNOBIOLOGY OF IL-9

IL-4 TGF- IL-1 13). In addition, other cytokines and signaling pathways are IL-25 able to modulate IL-9 production. IL-2 promotes, whereas IFN-g inhibits IL-9 production (14, 30). IL-25 can enhance IL-9 production by Th9 cells and promote IL-9 production IRF4 in vivo (31). These observations are consistent with the ability k PU.1 Other STAT6 of NF- B signaling to promote transcription from the IL- Factors ? 9 promoter (28). Addition of other proinflammatory cyto- kines to human Th9 cultures, such as type I IFNs, IL-1b, IL- ? GATA-3 6, IL-10, IL-12, and IL-21, may also enhance IL-9 production (10, 13, 19, 32). The ability of type I IFNs to promote IL-9

Il9 production is dependent upon IFN-induced IL-21 expression PU.1 IRF4 PU.1 AP1 NF- B (19). Whether the effects of these accessory cytokines are

-500 -309-194 -146 to -59 to TSS dependent upon other STAT or other transcription -140 -50 factors that activate IL9 transcription such as NF-kB or AP-1 FIGURE 1. Transcription factor activation of the gene encoding IL-9. In (33) has not yet been determined. TCR signaling also induces T cells, the most efficient priming of IL-9 production occurs in response to IL-9, and though cyclosporine A inhibits IL-9 production, a combination of TGF-b and IL-4. PU.1 may be downstream of the TGF-b suggesting a role for NFAT proteins (7), the TCR-induced signal, and STAT6 and GATA3, both required for the development of IL-9– signals that lead to expression of Il9 are not characterized.

secreting T cells, are downstream of IL-4. IRF4 expression may be regulated Downloaded from by both signals. It is not known if STAT6 or GATA3 binds the Il9 gene The IL-9R: signaling and expression directly. PU.1 and IRF4 bind the Il9 promoter directly in Th9 cells. AP-1 and NF-kB bind the promoter in response to TLR stimulation in mast cells and The IL-9R has two subunits: the a-chain (IL-9Ra) and the are likely downstream of IL-1 and IL-25 signaling in T cells. common g-chain receptor shared by other cytokines in- cluding IL-2, IL-4, and IL-7 (34, 35). The human IL-9R gene represses Th2 cytokines, but also induces IL-9 production contains 11 exons and encodes a 522-aa protein, whereas the (17). PU.1-deficient T cells have greatly diminished IL-9 mouse receptor contains 468 aa. The IL-9Ra is a member of http://www.jimmunol.org/ production compared with wild-type cells when cultured in the hematopoietin superfamily based on the presence of the presence of TGF-b and IL-4. PU.1 binds directly to the WSXWS motif in the extracellular domain and the Box1 and Il9 gene, and histone modifications associated with the Th9 Box2 motifs in the intracellular domain. IL-9–mediated signal phenotype are dependent upon PU.1. PU.1 is also important transduction results in the activation of STAT1, STAT3, and for IL-9 production in human T cells as PU.1-specific small STAT5 (36). A single tyrosine residue (Tyr407) in the IL-9Ra interfering RNA results in impaired IL-9 production by is phosphorylated after ligand binding to the receptor and human T cells. Importantly, PU.1 is expressed in greater activation of associated Jak1, and mutation of this residue amounts in cells cultured under Th9 conditions compared demonstrates that it is required for IL-9–dependent responses by guest on October 4, 2021 with Th2 cells, suggesting that PU.1 is a critical factor in (37). The Box1 intracellular domain between aa 338 and 422, diverting Th2 cells into an IL-9–secreting lineage (17). IFN including a YLPQ motif, is critical for IL-9–induced cell regulatory factor 4 (IRF4) was also shown to be required for growth, activation of STAT3, and induced Th9 generation (18). Like PU.1, and possibly in concert with (38). IL-9R signaling also activates MAPK and insulin re- PU.1 because IRF4 was originally identified as a PU.1- ceptor substrate–PI3K pathway (37, 39, 40), though the physio- interacting protein, IRF4 bound the Il9 gene directly (18). logical requirement for these pathways in primary cells has Moreover, IRF4 expression is correlated with both human not been well documented. and mouse Th9 differentiation and is induced by cytokines As expected from its initial identification as a T cell growth that promote IL-9 production including IL-4, IL-2, and factor, IL-9R is expressed on T cell lines and on effector T cells TGF-b (18). As IRF4 is also required for Th2 and Th17 but not naive T cells (41, 42). Among the Th cell subsets, IL-9R development (23–25), this transcription factor plays an im- has highest expression in Th2 and Th17 cells (9). In portant role in the cytokine-secreting potential of several Th patients, IL-9R is found on mast cells and polymorphonuclear subsets. cells in the lung (43, 44). Based on the responsiveness of airway Mast cells also produce IL-9 in response to LPS and IL-1, epithelial cells and smooth muscle cells, IL-9R is expressed on correlating with the presence of NF-kB binding sites in the Il9 nonhematopoietic cells as well. Because gc is unlikely to be promoter that mediate gene activation (26–28). GATA1 in expressed in these cells, the exact composition of the receptor mast cells promotes IL-9 production and Il9 promoter acti- on nonhematopoietic cells is not clearly defined. vation in a manner that is dependent upon p38 MAPK (29). The relative amounts of IL-9 produced by mast cells and Cell type-specific functions of IL-9 T cells, as well as the scenarios in which each cell may con- As suggested by the patterns of receptor expression, IL-9 has tribute to IL-9 production in vivo, have not been determined. biological effects on a number of distinct cell types (Fig. 2). Beyond the first description as T cell or mast cell growth factor, Amplifiers of IL-9 production IL-9 may affect other immune cells, as well as resident tissue TGF-b and IL-4 are potent cytokines in promoting the cells that contribute to the development of inflammation. generation of IL-9–secreting cells. Indeed, the ability of TGF- T cells. Although IL-9 was originally cloned as a T cell growth b to promote IL-9 expression is likely responsible for the factor, its function was more restricted than cytokines with ability of Treg and Th17 cultures to secrete IL-9 (8, 9) and similar functions, like IL-2 and IL-4. IL-9 could promote may have similar effects on both naive and memory cells (10, T cell growth, but it functioned preferentially on CD4+ The Journal of Immunology 3285

Growth factor (T cells) direct induction of mucus (67–70). Thus, IL-9 may IgE production (B cells) have both direct and indirect effects in the airway. Enhances Treg function Promotes Th17 differentiation Airway smooth muscle cells. In the lung environment, IL-9 also acts on airway smooth muscle cells. Human airway smooth Activates production of Lymphocytes IL-8, IL-13, eotaxin Mast cell growth and muscle cells express both IL-9R (71), and IL-9 can Smooth muscle cells survival Induces expression of potentiate the ERK-dependent release of CCL11 and IL-8 IL-9 Fc RI from these cells (71, 72). IL-9–mediated CCL11 expression Increases expression Mast cells of IL-6, mast cell in primary smooth muscle cells is dependent upon STAT3 proteases Supports erythroid colony but not STAT6 (73). IL-9–activated STAT3 binds directly formation Induces to the Ccl11 promoter (73). Promotes maturation of metaplasia Hematopoietic stem/ hematopoietic progenitors Enhances progenitor cells production IL-9–dependent regulation of inflammation Epithelial cells FIGURE 2. IL-9 demonstrates proinflammatory activity in several mouse IL-9 is a pleiotropic cytokine. IL-9 has direct and indirect effects on models of inflammation. Transgenic expression of IL-9 in the multiple cell types that affect the development of immunity and inflammation. lung results in allergic inflammation that is at least partially dependent on the presence of Th2 cytokines (46, 62). IL- 25 also promotes allergic inflammation through an IL-9– T cell, not on CD8+ T cells, and was unable to support long- dependent mechanism (31). Although allergic inflammation term Ag-independent growth of Th lines (2, 6). Crossing of 2 2 Downloaded from can develop in Il9 / mice using a standard sensitization- IL-9 transgenic mice to Th2 cytokine-deficient mice suggests challenge model (74), four reports have demonstrated that that some effects of IL-9 in vivo may be due to promoting blockade of IL-9 in a similar model results in decreased al- Th2 cytokine production, though whether these are direct or lergic inflammation (17, 31, 75, 76). Similarly, blocking IL-9 indirect effects is unclear (45, 46). More recently, IL-9 was in a chronic model of lung inflammation inhibits mastocy- shown to promote Th17 development but has variable effects tosis and airway remodeling (44). Moreover, Th9-polarized on Treg development (8, 9). http://www.jimmunol.org/ allergen-specific T cells can promote allergic inflammation B cells. IL-9 has effects on both development and that is blocked by anti–IL-9 (18). The reason for the dis- function. Transgenic expression of IL-9 results in an + crepancy between germline disruption of Il9 and acute increase of peritoneal CD11b B1 B cells and can recover blockade by anti–IL-9 is not entirely clear, but the immune the B1 cell numbers, but not natural IgM production, in system may be able to compensate for the germline loss of xid mice (47, 48). IL-9 enhances IL-4–mediated IgE and cytokine. A role for IL-9 in the development of allergic pul- IgG production from human B cells without having any monary inflammation is further supported by the requirement effect on IgM production (49, 50). IL-9 has similar for the T cell expression of IL-9–promoting transcription

a by guest on October 4, 2021 functions on germinal center B cells, and IL-9R expression factors PU.1 and IRF4 in this process (17, 18). In mice with is greater on germinal center B cells than on other B cells (51). PU.1-deficient T cells, Th2 development is normal, stressing Mast cells. One of the main functions of IL-9 is to promote the importance of IL-9–secreting cells for the development of mast cell growth and function, though the primary effects inflammation even in the presence of allergen-specific Th2 are observed in response to pathogens, because basal mast responses (17). cell numbers are normal in the absence of IL-9 (52). IL-9 IL-9 mediates allergic inflammation in tissues other than the can promote the growth of mast cells from bone marrow lung. IL-9 provided either by transgene or injection increases and mast cell progenitors in concert with susceptibility to passive or active systemic anaphylaxis (77). 2 2 2 2 (53). IL-9, alone or in combination with stem cell factor or However, systemic anaphylaxis occurred in Il9 / and Il9r / Fc«RI, promotes the expression of mast cell proteases and mice, suggesting that IL-9 is not absolutely required for proallergic cytokines in cultured mast cells (1, 54–56). anaphylaxis (77, 78). In contrast, deficiency in IL-9 or IL-9R Hematopoietic progenitor cells. IL-9 has been extensively attenuates intestinal anaphylaxis, and transgenic expression of characterized as a factor that regulates hematopoiesis. IL-9 IL-9 in the intestine results in local mastocytosis and increased synergizes with IL-3 in promoting the growth of IL-3– susceptibility to intestinal anaphylaxis (78, 79). Thus, IL-9 dependent cell lines and can enhance burst-forming unit may be required for anaphylaxis caused by allergen challenge erythroid, CFU erythroid, and multilineage colony formation at mucosal surfaces but not parenterally administered allergen. in combination with other factors including stem cell factor IL-9 provides a protective role in immunity to intestinal from cord blood and bone marrow precursors (57–60). Hu- parasites. In mice with transgenic expression of IL-9, there is man IL-9 also acts as an activator of megakaryocyte progenitor increased clearance of worms following infection with Tri- cells (61). churis muris and Trichinella spiralis (80, 81). Similarly, Airway epithelial cells. Transgenic expression of IL-9 in the lung adoptive transfer of IL-9 transgenic bone marrow-derived results in changes in gene expression in airway epithelial cells dendritic cells increases immunity to T. spiralis, whereas anti– including goblet cell metaplasia (62). Many of the effects of IL-9 blocks T. muris immunity (82, 83). Blocking TGF-b IL-9 in the lung are thought to occur due to indirect effects of signaling, which inhibits the development of Th9 cells, also IL-13 (46, 63–66). In this scenario, IL-9 promotes allergic results in diminished immunity to T. muris (16). In contrast, inflammation through effects on hematopoietic cells that then IL-9–deficient mice were able to control Giardia lamblia and produce IL-13 to have direct effects on airway epithelium Nippostrongylus brasiliensis infection, and neutralization of (64). However, IL-9 can have direct effects on human IL-9 resulted in enhanced immunity to L. major, owing to primary airway epithelial cells and cells lines including the blockade of Th2 immunity (52, 84, 85). IL-9 was also not 3286 BRIEF REVIEWS: IMMUNOBIOLOGY OF IL-9 required for granuloma formation following injection with Treg responses. The factors required for IL-9 production in Schistosoma mansoni eggs, though it was important for mas- T cells are only beginning to be elucidated and require the tocytosis and goblet cell metaplasia in this model (52). Yet, integration of signals from multiple cytokines (Fig. 1). The IL-4 is able to promote intestinal parasite immunity in the next challenges will be to develop a more detailed under- absence of IL-9 and other Th2 cytokines (86). standing of Il9 regulation and define the relevant IL-9 target There is also evidence that IL-9 plays a role in regulating cells in various inflammatory diseases. Although IL-9 has immunity to infectious disease. IL-9 negatively impacts clear- been understudied, recent advances in defining IL-9 biology ance of respiratory syncytial virus and neutralization of IL-9 will likely promote greater attention. may be therapeutic (87). Symptoms of may also be attenuated by IL-9, which may be through several mech- Disclosures anisms, including suppression of inflammatory cytokines and The authors have no financial conflicts of interest. the respiratory burst in (88, 89). Although IL-9 is involved in what are classically thought to References be Th2 responses, there are conflicting data on how it may be 1. Hu¨ltner, L., C. Druez, J. Moeller, C. Uyttenhove, E. Schmitt, E. Ru¨de, involved in autoimmune inflammation. Adoptive transfer of P. Do¨rmer, and J. Van Snick. 1990. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth Th9-polarized cells can promote the development of experi- factor P40/TCGFIII ( 9). Eur. J. Immunol. 20: 1413–1416. mental autoimmune encephalomyelitis (EAE) and experi- 2. Uyttenhove, C., R. J. Simpson, and J. Van Snick. 1988. Functional and structural mental autoimmune uveitis, though the inflammation that characterization of P40, a mouse glycoprotein with T-cell growth factor activity.

Proc. Natl. Acad. Sci. USA 85: 6934–6938. Downloaded from develops is distinct from Th1- or Th17-mediated immunity 3. Van Snick, J., A. Goethals, J. C. Renauld, E. Van Roost, C. Uyttenhove, (11, 20). In two reports, IL-9Ra deficiency or treatment with M. R. Rubira, R. L. Moritz, and R. J. Simpson. 1989. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J. Exp. Med. 169: 363–368. anti–IL-9 were either partially protective or resulted in 4. Yang, Y. C., S. Ricciardi, A. Ciarletta, J. Calvetti, K. Kelleher, and S. C. Clark. 1989. delayed development of EAE (9, 90). Results from another Expression cloning of cDNA encoding a novel human hematopoietic growth factor: 2/2 human homologue of murine T-cell growth factor P40. Blood 74: 1880–1884. report demonstrated increased severity of EAE in Il9r 5. Mock, B. A., M. Krall, C. A. Kozak, M. N. Nesbitt, O. W. McBride, mice that was correlated with an effect of IL-9 on Treg J. C. Renauld, and J. Van Snick. 1990. 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