We therefore investigated the impact of peanut gavage on ILC2 homeostasis in mice, rendered inherently atopic by knock-in of an unconstrained form (lacking the ITIM motif) of the IL-4R chain. reconstituting these animals using cultured bone marrow mast cells. Mast cells activated ILC2 for IL-13 production in an IL-4R-dependent manner. Activated ILC2 amplified systemic anaphylaxis by increasing target tissue sensitivity to mast cell mediators. Conclusions & clinical relevance These findings support an important role for IgE-activated mast cells in driving intestinal ILC2 expansion in food allergy and reveal that Linderane ILC2, in turn, can enhance responsiveness to the mediators of anaphylaxis produced by mast cells. Strategies designed to inhibit IgE signaling or mast cell activation are likely to inhibit both Type 2 immunity and immediate hypersensitivity in food allergy. calculated the economic burden of food allergy at around $25 billion a year, Linderane most of which is due to indirect costs and changes in lifestyle rather than direct medical care [6]. The need for constant vigilance against allergen exposure in the course of everyday life along with the ever present fear of reaction are sources of significant anxiety [7]. The factors predisposing some individuals to the development of anaphylactic sensitivity to food allergens have not been fully elucidated. It is known that mast cells and basophils promote the induction of pro-allergic adaptive immune responses by providing cytokines, including IL-4 and IL-9, that drive Th2 expansion and inhibit the generation of regulatory T (Treg) cells in the intestinal mucosa [8C11]. This immunological environment is conducive to the production of food-specific IgE antibodies that then bind to tissue mast cells via the high-affinity IgE receptor, FcRI, and lead to activation following re-exposure to allergens. Activated mast cells release preformed and newly synthesized vasoactive amines and lipid mediators that act on vascular endothelium and a number of other target tissues to cause anaphylaxis [12]. Although the presence of food-specific IgE antibodies is required to trigger this reaction, there is a poor correlation between IgE levels and severity of anaphylaxis. For instance, some individuals testing positive for IgE will pass oral food challenges while others with similar Linderane IgE levels will develop severe reactions [5]. A number of other factors affecting mast cell homeostasis and triggering threshold or the sensitivity of target tissues to the mediators of anaphylaxis are likely to regulate the severity of reactions. The contributions of other intestinal innate immune cells to allergic reactions to foods have not been fully explored. The presence of type 2 innate lymphoid cells (ILC2) at intestinal mucosal surfaces as well as their capacity to produce significant amounts of IL-4 and IL-13 implicates them as potential collaborators of mast cells in the sensitization and effector phases of allergic responses. ILC2 are rare lymphocytes that develop from common lymphoid progenitors in an and mice, peanut ingestion resulted in over-representation of ILC2, which was reduced in mast cell-deficient mice. In a cell culture system, IgE-activated mast cells induced the secretion of Linderane IL-13 by ILC2. Adoptive transfer experiments demonstrated Rabbit Polyclonal to OR2T11 that ILC2-derived IL-13 enhanced sensitivity to mast cell mediators, thereby complementing the effects of activated mast cells in IgE-mediated anaphylactic shock. Results ILC2 exacerbate allergic sensitization to foods in murine models, but the mechanisms driving their expansion remain unclear. Recent reports have demonstrated the importance of IL-25 and IL-33 [24, 29, 31, 32]. While these are both generally considered to be epithelial-derived cytokines [30], several groups have shown that they can be produced at high levels by hematopoietic cells, including mast cells [33, 34]. Furthermore, additional cytokines including IL-2,.