The Role of Il-13 in Regulating Th17 Cytokine Production

描述(申请人提供)：IL-13是过敏性呼吸道炎症动物模型中呼吸道反应性和粘液表达的中心介质，在哮喘患者的支气管肺泡灌洗液中大量发现。IL-13通过IL-13受体α1(IL-13Ra1)传递信号，IL-13Ra1存在于肺中的各种结构细胞上，此外还有可被招募到肺中的炎性细胞。自从发现这种受体以来，流行的观点认为IL-13Ra1不在CD4+T淋巴细胞上表达，CD4+T淋巴细胞是适应性免疫功能的关键细胞，调节多效性炎症过程。然而，我们实验室的体外实验已经证实，小鼠CD4+T淋巴细胞的一个特殊亚群--Th17细胞表达IL-13Ra1，该受体的功能是IL-13负向调节这些细胞产生的细胞因子。这一发现代表了我们对1)IL-13调节适应性免疫的能力，以及2)控制Th17细胞因子产生的机制的认识的重要范式转变。然而，无论是IL-13信号对体内Th17细胞因子表达的影响，还是人Th17细胞上是否存在IL-13Ra1，都尚未确定。在这个方案中，我们假设IL-13抑制小鼠肺特异性Th17细胞因子的产生和免疫反应，并且通过IL-13Ra1信号抑制人CD4+细胞Th17细胞因子的产生。拟议的研究将促进我们对IL-13在调节Th17介导的免疫中的作用的理解，并导致未来的研究，探讨哮喘发病机制中不可或缺的细胞因子如何改变对病原体的防御，宿主需要完全功能的Th17反应来维持健康。 公共卫生相关性：IL-13是参与哮喘发病机制的关键细胞因子，长期以来流行的概念是IL-13信号的受体的关键组成部分IL-13Ra1在CD4+T淋巴细胞上不表达。然而，我们的初步体外实验发现，小鼠CD4+T淋巴细胞的一个特殊亚群，即Th17细胞，表达IL-13Ra1，该受体具有功能，因为IL-13负向调节这些细胞产生的细胞因子。在这个方案中，我们假设IL-13抑制小鼠肺特异性Th17细胞因子的产生和免疫反应，并且通过IL-13Ra1信号抑制人CD4+细胞Th17细胞因子的产生。

DESCRIPTION (provided by applicant): IL-13 is a central mediator of airway responsiveness and mucus expression in animal models of allergic airway inflammation, and is found in abundance in the bronchoalveolar lavage of patients with asthma. IL-13 signals through the IL-13 receptor alpha 1 (IL-13Ra1) that is present on a variety of structural cells in the lung, in addition to inflammatory cells which can be recruited to the lung. Since the discovery of this receptor, the prevailing concept has been that IL-13Ra1 is not expressed on CD4+ T lymphocytes, cells that are critical to adaptive immune function and which regulate pleiotropic inflammatory processes. However, in vitro experiments in our lab have identified that a specific subset of mouse CD4+ T lymphocytes, Th17 cells, express IL- 13Ra1 and that this receptor is functional in that IL-13 negatively regulates cytokine production from these cells. This finding represents an important paradigm shift in our knowledge of 1) the ability of IL-13 to regulate adaptive immunity, and 2) the mechanisms controlling the production of Th17 cytokines. However, neither the effect of IL-13 signaling on Th17 cytokine expression in vivo has not been determined, nor whether IL-13Ra1 is present on human Th17 cells. In this proposal, we hypothesize that IL-13 inhibits lung-specific Th17 cytokine production and immune responses in mice, and that signaling through IL-13Ra1 inhibits Th17 cytokine production by human CD4+ cells. The proposed studies will advance our understanding of the role of IL-13 in regulating Th17 mediated immunity and lead to future studies examining how a cytokine integral to asthma pathogenesis alters defense against pathogens for which the host requires a fully functional Th17 response for maintenance of health. PUBLIC HEALTH RELEVANCE: IL-13 is a critical cytokine involved in asthma pathogenesis and the long standing prevailing concept is that a key component of the receptor through which IL-13 signals, IL-13Ra1, is not expressed on CD4+ T lymphocytes. However, our preliminary in vitro experiments identified that a specific subset of mouse CD4+ T lymphocytes, Th17 cells, express IL-13Ra1 and that this receptor is functional in that IL-13 negatively regulates cytokine production from these cells. In this proposal, we hypothesize that IL-13 inhibits lung-specific Th17 cytokine production and immune responses in mice, and that signaling through IL-13Ra1 inhibits Th17 cytokine production by human CD4+ cells.