Role of the PP2A-FoxO1 Axis in Treg Function and Allergic Airway Inflammation

University Of Virginia, Charlottesville VA

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Abstract

DESCRIPTION (provided by applicant): Role of the PP2A-FoxO1 axis in Treg function and allergic airway inflammation Allergic airway inflammation, the precursor to allergic asthma, occurs when the immune system develops an inappropriate inflammatory response to innocuous antigens. In healthy individuals, immunogenic responses to innocuous foreign antigens are dampened by peripheral tolerogenic mechanisms. Understanding why peripheral tolerance is either not elicited or overpowered in individuals with allergic asthma could elucidate new therapeutic targets. We propose that altered signaling and intrinsic dysfunction of T regulatory cells is partially responsible for the inadequate tolerogenic response in individuals with allergic airway inflammation. FoxO1 is a transcription factor critical for normal T regulatory cell function and PP2A is a serine/threonine phosphatase. Our studies focus on the role of the PP2A-FoxO1 axis in mediating T regulatory cell function and the control of allergic airway inflammation. Our preliminary data suggest that PP2A promotes FoxO1 function by mediating its dephosphorylation. Furthermore, we have observed that PP2A expression is decreased in the mediastinal lymph nodes of mice with allergic airway inflammation, recapitulating a similar finding in patients with allergic asthma. We hypothesize that PP2A-FoxO1 axis is an important component of normal T regulatory cell function and that decreased PP2A expression in the context of allergic airway inflammation could lead to T regulatory cell dysfunction, potentially exacerbating disease. In Aim1, we will investigate the PP2A-FoxO1 axis function in Treg cells using a combination of pharmacologic and genetic rescue approaches. In Aim2, we will use knockout mice and adoptive transfers in a model of allergic airway inflammation to test how the activity of the PP2A-FoxO1 axis in T regulatory cells affects allergic airway inflammation. Collectively, we expect these studies will provide new insights on Treg cell function, tolerance to common allergens, and airway inflammation