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