The Role of Il-13 in Regulating Th17 Cytokine Production

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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.