Mast cell-intrinsic TGFβ signaling modulates mast cell effector function and allergic responses

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B850
Abstract ID: 4788

Presenting Author:
Tamara Haque , Postdoctoral fellow at NIAID, NIH

Abstract:

Mast cell (MC) activation via the high affinity IgE receptor, FcεRI, causes the release of mediators that are directly involved in the allergy diathesis. TGFβ has been shown to regulate MC development and function in vitro however it’s role in allergic diseases is unclear. Patients with Loeys Dietz Syndrome (LDS), a disorder caused by loss-of-function variants in genes encoding the TGFβ receptors are highly predisposed to develop atopy, thus provide an opportunity to study the role of MC TGFβ signaling in allergic diseases. Unexpectedly, IgE mediated degranulation of LDS MC were reduced compared to healthy controls in vitro. We examined active and passive IgE responses in a mouse model of LDS and mice with conditional deletion of Tgfbr1 in MCs. Both models exhibited less IgE mediated anaphylaxis and degranulation. This could not be attributed to alterations in IgE or stem cell factor receptor expression on MCs, or to the distribution of MCs in tissues. In contrast, LDS MCs exhibited enhanced responses to the type 2 alarmin, IL-33, in vitro and in vivo. Mechanistically, altered responses to IgE, IL-33, and TGFβ were linked, as the reduction of anaphylaxis in LDS mice was partially restored in IL-33RKO LDS mice. Moreover, this was tied to both transcriptional and proximal signaling mechanisms. Taken together, TGFβ signaling upregulates MC function by disrupting an IL-33/ST2 mediated regulatory pathway, which likely plays a major role in controlling IgE mediated MC functions.