The Role of Il-13 in Regulating Th17 Cytokine Production

描述（由申请人提供）：IL-13是过敏性气道炎症动物模型中气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存在。IL-13通过IL-13受体α 1（IL-13 Ra 1）发出信号，除了可以募集到肺的炎性细胞之外，IL-13受体α 1还存在于肺中的各种结构细胞上。自从发现这种受体以来，流行的概念是IL-13 Ra 1不在CD 4 + T淋巴细胞上表达，所述T淋巴细胞是对适应性免疫功能至关重要的细胞，并且调节多效性炎症过程。然而，我们实验室的体外实验已经确定，小鼠CD 4 + T淋巴细胞的特定亚群，Th 17细胞，表达IL-13 Ra 1，并且该受体的功能在于IL-13负调节这些细胞的细胞因子产生。这一发现代表了我们对1）IL-13调节适应性免疫的能力和2）控制Th 17细胞因子产生的机制的知识的重要范式转变。然而，尚未确定IL-13信号传导对体内Th 17细胞因子表达的影响，也未确定IL-13 Ra 1是否存在于人Th 17细胞上。在这个提议中，我们假设IL-13抑制小鼠肺特异性Th 17细胞因子的产生和免疫应答，并且通过IL-13 Ra 1的信号传导抑制人CD 4+细胞产生Th 17细胞因子。拟议的研究将促进我们对IL-13在调节Th 17介导的免疫中的作用的理解，并导致未来的研究，研究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，宿主需要一个功能齐全的Th 17应答来维持健康。 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，并且长期存在的流行概念是IL-13信号传导所通过的受体的关键组分IL-13 Ra 1不在CD 4 + T淋巴细胞上表达。然而，我们的初步体外实验确定，小鼠CD 4 + T淋巴细胞的特定亚群，Th 17细胞，表达IL-13 Ra 1，并且该受体是功能性的，因为IL-13负调节这些细胞的细胞因子产生。在这个提议中，我们假设IL-13抑制小鼠肺特异性Th 17细胞因子的产生和免疫应答，并且通过IL-13 Ra 1的信号传导抑制人CD 4+细胞产生Th 17细胞因子。

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.