DOCK8 and STAT3 cooperate to restrain IgE-inducing T follicular helper cells 3840

Abstract Description Allergy is the result of immune responses directed against innocuous substances and can precipitate life-threatening anaphylaxis, through cross-linking of allergen-specific immunoglobulin E (IgE) on mast cells.Interestingly, several monogenic diseases lead to dysregulated hyper-IgE responses and allergy in humans, providing possible insights into allergen-specific IgE induction.One such disease is deficiency in Dedicator of Cytokinesis 8 (DOCK8), which previously led us to discover that T cell intrinsic DOCK8 restrains the development of IL-13 expressing T follicular helper (Tfh13) cells, which are required for the induction of anaphylactic IgE.Here we report that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells.Curiously, STAT3 dominant negative (DN) mutations in humans are also associated with dysregulated IgE production but are not consistently associated with elevated food-specific IgE and food allergy.Indeed, we found that, unlike patients with DOCK8 deficiency, donors with STAT3 DN mutations did not have elevated levels of circulating Tfh13 cells.Furthermore, when fed peanut without an adjuvant only T-Dock8-/- mice, but not Stat3-/- animals, had elevated Tfh13 cells, peanut-specific IgE and reduced Foxp3+CD4 T cells.Thus, DOCK8 and STAT3 cooperate in CD4+ T cells to prevent aberrant Tfh13 differentiation, but an additional impairment of regulatory T cells in DOCK8 deficiency allows for Tfh13-driven production of food-specific IgE. Funding Sources T32AI083216 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)