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• W1992802551 abstract "Interleukin (IL)-9 was first described as a TH2-associated cytokine and, although it is clear that it is involved in ‘TH2-like’ inflammation and pathology, it has recently become apparent that its regulation and biology are unlike that of the other type 2 cytokines, IL-4, IL-5 and IL-13. In vitro, IL-9-producing T cells appear to be a subset distinct from those that produce the other type 2 cytokines.1 These IL-9-secreting T cells are dependent upon transforming growth factor (TGF-β) signalling and have been recognized as an independent T helper subset, termed TH9 (Figure 1). A new report from the lab of Chen Dong has identified a role for the IL-17 cytokine family member IL-25 in the regulation of TH9 cells and has highlighted how IL-25 signalling might affect IL-9-mediated inflammatory responses in a mouse model of allergic airways disease.2 IL-9 was originally identified as a factor promoting T-cell growth, but it also has effects in vitro on mast cells, erythroid progenitors and B cells. Transgenic mice overexpressing IL-9 eradicate infections with helminth parasites more rapidly than wild-type animals.3 As TH2 responses underpin immunity to such parasites, these results were interpreted as implicating IL-9 in regulation of TH2 responses. However, il9−/− mice show no defect in T-cell development, antibody responses or expulsion of the helminth Nippostrongylus brasiliensis,4 highlighting the redundancy of the functions of IL-9. The recent discovery of a subset of differentiated T cells that express IL-9 and IL-10 but little of the other type 2 cytokines has led to a re-evaluation of IL-9's classification as a type 2 cytokine. This CD4+ T-cell subset is induced to differentiate and produce IL-9 by a combination of TGF-β and IL-4.1 Analysis of these cells suggested that they were not Th1, Th17 or inducible regulatory T-cell populations, and so it was concluded that they represented a new subset of T helper cells, since termed TH9. TGF-β re-programmes Th2 cells to lose their ability to produce Th2 cytokines and switch to IL-9 and IL-10 production, suggesting a previously unappreciated flexibility in the TH2 lineage. Whether TH9 cells indeed represent a separate lineage of committed T cell, or whether they are simply one end of a spectrum of TH2 phenotypes, is open to debate. The identification of a TH9-specific transcription factor, analogous to T-bet for TH1 cells or GATA-3 for TH2, may settle this argument. IL-25 (IL-17E) is a member of the IL-17 family of structurally similar but functionally diverse cytokines. The family consists of six proteins (IL-17A–F), of which IL-25 is both structurally and functionally the most distantly related. IL-25 expression is associated with TH2-like inflammation and pathology, and transgenic overexpression of the cytokine or administration of recombinant protein to mice induces the hallmark features of type 2 inflammation, including eosinophilia, goblet cell hyperplasia, mucus production, elevated IL-4, IL-5 and IL-13 levels, and increased serum immunoglobulins G1 and E.5,6 IL-25 signalling requires both IL-17RA and IL-17RB as both il17ra−/− and il17rb−/− mice are non-responsive to IL-25 administration.7 Downstream of this receptor pair, little is known about IL-25 signalling pathways, although roles for the adaptor protein Act1 (CIKS),8,9 Mitogen-activated protein kinase pathways and nuclear factor κB10 have been identified. A number of cell types have been identified as being IL-25 responsive, including natural killer T cells,11 TH2 cells,12 and one or more populations of non-B, non-T cells.6,13 Many of these cells produce the type 2 cytokines IL-4, IL-5 and IL-13 in response to IL-25 stimulation. Previous findings from the lab of Chen Dong have identified a role for IL-25 in the differentiation and function of TH2 cells.12 Of the T helper subsets studied, TH2 cells were found to contain the highest levels of il17rb message, and IL-25 was demonstrated as capable of promoting TH2 cell differentiation in an IL-4- and STAT6 (signal transducer and activator of transcription 6)-dependent manner. Now, the same lab has identified a role for IL-25 in the regulation of TH9 cells. Levels of il17rb in TH9 cells were found to be comparable to those of TH2 cells and to increase following IL-4 or TGF-β treatment. However, IL-25 stimulation with or without TGF-β did not induce IL-9 production from naive CD4 T cells, indicating that IL-25 does not initiate TH9 polarization, at least in vitro. By contrast, treatment of differentiated TH9 cells with IL-25 induced substantial IL-9 and IL-10 production. The requirement of TGF-β and IL-4 for IL-25-dependent IL-9 production can be bypassed by retroviral expression of IL-17RB in T cells or in transgenic mice in which IL-17RB expression is controlled by the CD4 promoter, implying that TGF-β and IL-4 render T cells IL-25-responsive by inducing IL-17RB expression. Interestingly, IL-25 signalling promotes IL-9 expression through a mechanism that is independent of endogenous IL-4 production from the treated T cells but dependent upon endogenous TGF-β. When T cells from CD4-IL-17RB transgenic mice (which can be induced to produce IL-9 in the absence of exogenous TGF-β and IL-4) were treated with IL-25 in the presence of blocking antibodies for IL-4 or TGF-β, blockade of TGF-β, but not IL-4, led to a reduction in IL-9 production. Thus, the mechanism of IL-25's action on TH9 cells differs from that on TH2 cells, wherein enhancement of TH2 differentiation seems to be achieved via a pathway depending on endogenous IL-4 production from the differentiating T cells.12 The role of IL-25 in IL-9 biology in vivo is less straightforward. Although CD4-IL-17RB transgenic mice show increased inflammatory responses following challenge with Aspergillus oryzae protease and ovalbumin allergens, it is not clear to what extent this results from TH9 activity and how much is attributable to increased TH2 and type 2 cytokine production. No ovalbumin-specific IL-9 could be detected in allergen-challenged wild-type mice, although low levels were detectable in challenged CD4-IL-17RB transgenic mice. Furthermore, IL-9 blockade partially reduced inflammatory responses in transgenic mice. It is noteworthy that the main effect of IL-9 blockade in this model was a reduction in airway eosinophilia, as eosinophilia is known to be driven by other type 2 cytokines and, in particular, IL-5. Using an alternative model of allergic lung disease, ovalbumin-specific IL-9 was detected from wild-type mice. In il25−/− mice, IL-9 levels were decreased, although there was also a significant reduction in the levels of the other type 2 cytokines, as reported previously in alternative models of allergic airways disease.14 These data highlight the unique position of IL-9 among the type 2 cytokines. It is regulated through mechanisms different from those of IL-4, IL-5 and IL-13, but there are also shared pathways. This is typified by the role of IL-25 in regulating both TH2 and TH9 populations. TGF-β seems to be the critical factor influencing the consequence that T-cell exposure to IL-25 has, but more work will be required to elucidate how these interactions are mediated in vivo. Key among the unanswered questions is what role, if any, IL-9 has in allergic inflammation? The importance of TH2 cells in such responses is established, but could the presence of TGF-β in the lung microenvironment push responses away from IL-4, IL-5 and IL-13-dominated activities and towards an IL-9-driven process? Furthermore, what would be the consequences of such a shift to the resolution or continuation of lung inflammation? It would also be of interest to assess the contribution of IL-9 to other IL-25-driven responses. Immunity to helminth infections is dominated by the type 2 cytokines and IL-25 has a well-appreciated role in murine helminth-infection models.13 It has been reported that il9−/− mice have no defect in N. brasiliensis expulsion, but assessment of the airways inflammatory response to A. oryzae protease and ovalbumin in these mice might be of interest. Despite the question mark over the role of IL-9 in immune responses, these recent findings highlight the intriguing position of the cytokine as a ‘type 2’ effector controlled by regulatory pathways distinct from those governing IL-4, IL-5 and IL-13. Schematic of the factors regulating TH9 and TH2 development and expansion." @default.
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• W1992802551 date "2010-03-23" @default.
• W1992802551 modified "2023-09-27" @default.
• W1992802551 title "T _H 9: the latest addition to the expanding repertoire of IL‐25 targets" @default.
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• W1992802551 doi "https://doi.org/10.1038/icb.2010.43" @default.
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