The lung is a barrier surface of the mammalian body that is continuously exposed to microbes, allergens and other irritants, and dysregulated immune responses to these stimuli underlies the pathogenesis of multiple airway diseases, including asthma, COPD, IPF, and respiratory viral infections. Basic and translational evidence suggests that populations of innate lymphoid cells (ILCs) are critical orchestrators of inflammation at mucosal barrier sites. While recent research has defined the priming and downstream effector pathways of ILCs in the lung, the cell-intrinsic mechanisms that limit ILCs or influence immune-regulatory responses remain poorly understood. Based upon on our new preliminary data, this renewal will directly test the role of two previously unknown ILC-intrinsic pathways in limiting inflammation in the lung. Group 2 ILCs (ILC2) are a recently described populations of innate immune cells that are enriched in the lung parenchyma that respond to epithelial-derived cytokines IL-25, IL-33 and TSLP, constitutively express the transcription factor GATA3, and can mediate inflammatory processes in the lung through production of effector cytokines IL-4, IL-5, IL-9 and IL-13 or promoting of a Th2 cell response. Despite their recent discovery and the upstream pathways that promote ILC2 responses, it remains unclear what negatively regulates or turns off ILC2 responses in the lung. In new preliminary data, we identify for the first time that ILC2 are enriched in receptors for the Beta-2 adrenergic receptor (?2AR) pathway, a common drug target in asthma. Our new gain- of-function and loss-of-function studies identify that the ?2AR is essential to limit pathogen- and allergen- induced ILC2 responses and inflammation at mucosal sites. Studies outlined in Aim 1 will directly test whether the ?2AR pathway is acting directly on ILC2 in a cell-intrinsic manner and mechanistically how the ?2AR pathway may regulate ILC2 responses. In contrast to type 2 cytokine-dominated inflammation in the lung, recent translational studies suggest that a mixed Th2 and Th17 cell response in airway inflammation results in more severe disease and often patients are refractory to most conventional therapies. Previously we defined that group 3 ILCs (ILC3) directly limit dysregulated Th17 cell responses in the intestine of mice and humans through MHCII-dependent interactions. In new studies, we now demonstrate that while the lung parenchyma is dominantly populated with ILC2, ROR?t+ group 3 ILCs (ILC3) are the dominant ILC group in the lung-draining lymph node of healthy humans and mice. Further, in a model of chronic house dust mite (HDM)-induced lung inflammation, mice with a genetic deletion of ILC3-intrinsic MHCII exhibited increased Th2 and Th17 cell responses, granulocyte recruitment and airway inflammation. Collectively, these data provoke the central hypothesis of Aim 2 that ILC3-intrinsic MHCII critically limits pathologic CD4+ T cells in the context of airway inflammation.
The lung is a barrier surface of the mammalian body that is continuously exposed to microbes, allergens and other irritants, and dysregulated immune responses to these stimuli underlies the pathogenesis of multiple airway diseases, including asthma, COPD, IPF, and respiratory viral infections. The focus of this proposal is define two novel pathways that limit dysregulated responses and chronic inflammation in the airway, and determine whether this knowledge could prove useful in the design of novel preventative and therapeutic strategies to limit disease at mucosal sites.
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