Cell-Intrinsic Effects of TGF-b Signaling in Mast Cell Effector Function that Modulate Allergic Inflammation

Abstract IgE mediated mast cell activation is a key feature of allergic disease, although the mechanisms that govern homeostasis are not fully understood. The TGFb signaling pathway has been shown to regulate effector function. Furthermore, variants in associated with diseases; regulation likely involved allergy diathesis. Patients Loeys Dietz Syndrome (LDS), disorder caused by loss function TGFBR1and TGFBR2, predisposed develop diseases, thus provide an opportunity study role diseases. Mast cells activated through high affinity receptor FcERI causing release granules containing mediators directly anaphylaxis and other symptoms. can be modulated co-stimulatory signals such as type 2 alarmin IL-33. We examined murine carrying LDS mutation, or conditional deletion Tgfbr1, found they degranulated less response IgE/antigen, vivo vitro. This phenotype was tied changes SCF expression tissue distribution mice recapitulated human cells, Additionally, responded more IL-33 stimulation. Mechanistically, linked IL-33, reduction partially restored IL-33RKO mice. Thus, TGFb-IL-33R axis plays major controlling functions. Taken together, upregulates disrupting IL-33/ST2 regulatory pathway. Intramural NIAID Support