Impaired Development of Th2 Cells in IL-13-Deficient Mice

McKenzie, Grahame J.; Emson, Claire; Bell, Sarah E.; Anderson, Shannon M.; Fallon, Padraic G.; Zurawski, Gérard; Murray, Richard M.; Grencis, Richard K.; McKenzie, Andrew N. J.

doi:10.1016/s1074-7613(00)80625-1

Cited by 359 publications

(257 citation statements)

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“…IL-13 plays a central role in the development of AHR (4,5,29,36,47). Several cell types produce IL-13, including Th2-type cells, mast cells, airway smooth muscle cells, NK cells, and NK T cells; some have been implicated in the development of AHR (41,42,48,49).…”

Section: Discussionmentioning

confidence: 99%

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Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13

Miyahara

Takeda

Kodama

et al. 2004

The Journal of Immunology

102

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The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8+ T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8+ T cells in the development of these allergen-induced responses. CD8-deficient (CD8−/−) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type mice, CD8−/− mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8−/− mice with allergen-sensitized CD8+ T cells fully restored the development of AHR, BAL eosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8+ T cells or allergen-sensitized CD8+ T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8+ T cells were a source of IL-13. These data suggest that Ag-primed CD8+ T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells.

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Section: Discussionmentioning

confidence: 99%

“…CD4 ϩ T cells, especially Th2-type cells, which produce IL-4, IL-5, and IL-13, are considered pivotal cells in the development of AHR and eosinophilic inflammation (1)(2)(3)(4)(5). In atopic asthma, increased expression of Th2-type cytokines has been shown in lymphocytes in bronchoalveolar lavage (BAL) fluid (6).…”

mentioning

confidence: 99%

Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13

Miyahara

Takeda

Kodama

et al. 2004

The Journal of Immunology

102

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“…-1198 Immunity to infection IL-13, originally described as a T cell-derived antiinflammatory cytokine, has multiple biological activities. Like IL-4, IL-13 up-regulates CD23, CD71 and MHC class II expression on B cells and monocytes [32], elicits B cell proliferation and induces IgG4 and IgE production by human B cells [32], and promotes Th2 cell differentiation [33]. In addition, IL-13 plays a dominant role to IL-4 in mediating worm expulsion to Nippostrongylus brasiliensis [34], exerts protective functions both in the chronic stages of some Leishmaniasis major infections [35] and in Listeria monocytogenes infection in the context of a Th1 cytokine response [36], and acts as the key mediator in the pathogenesis of allergic asthma [37].…”

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confidence: 99%

IL‐18 stimulates IL‐13‐mediated IFN‐γ‐sensitive host resistance in vivo

Liu

Whitmire

et al. 2006

Eur J Immunol

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IL-4 and IL-13 are up-regulated during in vivo responses to many nematode parasites, but increasing evidence suggests that increases in IL-13 can also occur independently of the IL-4-dominant Th2 response. Blocking B7 after Trichuris muris inoculation inhibits resistance and IL-4 elevations, instead resulting in an IFN-c-dominant response associated with susceptibility. However, blocking IFN-c under these conditions restores IL-13-dependent resistance. In this study, we examined the mechanism of IL-13 upregulation and associated protection during this in vivo immune response. CD4 + T cells and DX5 + TCR -cells were identified as the major producers of IL-13, and the DX5 + TCRcells were phenotyped as NK cells, since they expressed CD11b, IL-2Rb and Ly49C but not c-kit or FceRI. NK cell-derived IL-13 elevations were T cell-dependent, as CD4 + T cell depletion blocked IL-13 production by mesenteric lymph node cells and induced susceptibility. IL-13 expression was increased independently of IL-12; however, blocking IL-18 function inhibited IL-13 production and increased susceptibility. These results indicate that CD4 + T cells and NK cells are the major sources of IL-13 during the in vivo Th1 response induced by B7 blockade and that under these conditions, IL-18 is specifically required for the in vivo up-regulation of IL-13 production and associated host protection. IntroductionThe host protective response that develops following infection varies greatly with the particular pathogen. The type 2 immune response, associated with high levels of IL-4, IL-13 and other Th2 cytokines, provides protection against intestinal nematode parasites [1-3], while type 1 immunity, associated with an IFNc-dominant response, mediates resistance against many viruses and bacteria [4,5]. The events that lead to the development of type 1 and type 2 immunity are generally thought to be distinct, and as each response matures, production of characteristic cytokines can down-regulate the reciprocal response, resulting in further polarization.Typically, type 2 responses leading to resistance require the development of IL-4-producing effector CD4 + T cells, which then utilize autocrine IL-4 for their rapid expansion [3]. These Th2 cells mediate worm expulsion through their production of Th2 cytokines, with IL-4 and IL-13 being particularly important for the expulsion of gastrointestinal nematode parasites [1,2]. The development and expansion of IL-4-producing T cells is preferentially dependent on B7 costimulatory molecules [6,7], and in a number of infectious diseases, B7 blockade can actually deviate a Th2 response to an IFN-c-dominant Th1 response [8,9]. In the Th2 cell differentiation model just described, blockade of IL-4 production with B7 antagonists would be expected to also inhibit IL-13 production. However, other studies suggest that under certain circumstances IL-4 and IL-13 are regulated independently, and certain signaling pathways involving c-maf [10] and can differentially regulate these two cytokines. Consistent with these fin...

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“…3,5 The functions of these cytokines diverge in key areas such as Th2 cell development, tissue fibrosis, and endotoxemia. 6,7 The complex roles of IL-4 and IL-13 are further compounded by their interaction with an array of cell surface receptors. IL-4 directly binds the IL-4 receptor ␣ (IL-4R␣) and IL-13 specifically binds the IL-13R␣1 chain, 8 but IL-4R␣ and IL-13R␣1 can form a functional receptor complex that binds both ligands.…”

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confidence: 99%