Novel IL-9-Secreting innate helper cells promote oral antigen-induced anaphylaxis (P6249)

Abstract

IgE-mediated food allergy is manifested by an overactive T-helper 2 immune response to dietary antigens in the gastrointestinal (GI) tract. Interleukin (IL)-9 promote intestinal mastocytosis which allow the development of oral antigen-induced anaphylaxis. However, little is known about the primary cellular sources of IL-9 or the mechanisms that promote intestinal mastocytosis. Here, we report the identification of multifunctional IL-9-producing innate helper cells (IHC9) 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 intestinal IHC9 and CD4+TH2 cells, which correlate positively with symptoms and susceptibility to oral antigen-induced anaphylaxis. IHC9 development requires T cells and IL-4R, not IL-9R, signaling. The failure of irradiated mice reconstituted with STAT6-deficient bone marrow to generate IHC9 was accompanied by reduced serum MCPt-1, intestinal TH2 inflammation, mastocytosis, and goblet cell hyperplasia and loss of allergic diarrhea. Furthermore, inhibition of food allergy symptoms in mice ablated of IHC9 by anti-FcϵRIα antibody treatment could be reversed by adoptive transfer of IHC9. Thus, IHC9 represent a new type of innate helper cell lineage and function in promoting intestinal TH2 inflammation and mastocytosis that drive IgE-mediated anaphylaxis.