Mast Cell Function in Protective And Pathological Immunity: A Role for MDSC?

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DESCRIPTION (provided by applicant): Mast cells are critical activators of innate and adaptive immunity. Although best known for their role in allergic disease, mast cells rapidly recognize bacterial and parasitic pathogens. IgE-mediated signaling is the best-studied pathway for mast cell activation - a pathway we show rapidly induces Stat5 function. Loss of this transcription factor greatly disrupts mast cell functions, including migration and cytokine production. This proposal will test the hypothesis that IgE-mediated signaling activates Stat5 via a Fyn kinase-mediated pathway with feed-forward augmentation by sphingosine kinase. We also describe a novel interaction between mast cells and myeloid derived suppressor cells (MDSC) that induces MDSC to produce inflammatory cytokines, contrary to the commonly-accepted role of these cells. We postulate that Stat3 and Stat5 signaling in MDSC is required for this effect, and support the theory that mast cell-MDSC interactions are needed for expelling the parasite Nippostrongylus. Our proposal will test the hypothesis that mast cells and MDSC interactions control protective and pathological immunity, activities that are linked by Stat5 signaling. We will test this hypothesis with mechanistic experiments in vitro and functional assays in vivo. Our Specific Aims are: I. To test the hypothesis that IgE activates Stat5A and Stat5B through a Fyn-mediated pathway augmented by sphingosine kinase. II. To test the hypothesis that mast cells regulate MDSC function. !