DOCK8 in T cells promotes Th17 and Treg cell functionality to restrain mucosal mast cells and limit susceptibility to oral anaphylaxis

Immunoglobulin E (IgE)-mediated release of mediators from mast cells (MCs) drives food allergy, and intestinal MC load is an important determinant of disease severity. Dedicator of cytokinesis 8 (DOCK8)-deficient patients are highly susceptible to food allergy. We found that they exhibited elevated serum MC tryptase levels, suggesting increased MC load. Dock8^−/− mice also had exaggerated IgE-mediated oral anaphylaxis, expansion of jejunal mucosal MCs (MMCs), and elevated serum levels of MMC-derived tryptase. This resulted in increased intestinal permeability, which promoted antigen absorption and thereby oral anaphylaxis. Mechanistically, these events were driven by an intestinal cascade in which reduced interleukin (IL)-17 cytokines led to dysbiosis, which drove IL-25 production. Increased IL-25 enhanced T helper (Th)2 production of IL-4 that expanded MMCs and exaggerated oral anaphylaxis. Furthermore, the failure of DOCK8-deficient T regulatory (Treg) cells to suppress intestinal IL-4 production and MC expansion left the exaggerated anaphylaxis unrestrained. These results suggest multi-faceted coordination between the microbiome, mucosal T cells, and MCs to restrict oral anaphylaxis.