Novel Intestinal IL-9-Producing Mast Cell Precursors Promotes IgE-Mediated Food Allergy

Accumulating evidence have documented a pivotal role of mast cells (MCs), IgE, and T_H2 cytokines in mediating food hypersensitivity. Currently, our knowledge of why only some, rather than all, individuals who have high levels of dietary allergen–specific serum IgE develop life-threatening anaphylaxis remains limited. This enigma results from the lack of detailed information about the cellular and molecular immune response that underlies the gastrointestinal (GI) allergic reaction to dietary antigens. Interleukin (IL)-9 promotes intestinal mastocytosis that drives the development of experimental food allergy; however, little is known about the primary cellular sources of IL-9 or the mechanisms that promote intestinal anaphylaxis. Here, we report the identification of multifunctional IL-9-producing mast cell precursors (IMCP9) that secrete prodigious amounts of TH2 cytokines and mast cell protease-1 (MCPt-1) in response to IL-33 and antigen/IgE complex crosslinking, respectively. Repeated intragastric antigen challenge induces significant accumulations of both IMCP9 and CD4⁺TH2 cell accumulation, which correlate positively with symptoms and susceptibility to experimental food allergy. Unlike the conventional mast cell lineage, IMCP9 development requires T cells and IL-4/STAT6, not IL-9/IL-9R signals. Mice ablated of IMCP9 induction fail to develop intestinal mastocytosis, which result in decreased food allergy symptoms that can be restored by adoptively transferred IMCP9. Notably, expression levels of the T_H2 cytokine Il9 and Il13, and MC-associated Cpa3, tryptase, and chymase transcripts are significantly increased in the duodenum of atopic patients with a history of food allergy. Thus, the induction of novel IMCP9 is a pivotal step to acquire susceptibility to IgE-mediated food allergy.