RELMb Sets the Threshold for Microbiome-Dependent Oral Tolerance

Tolerance to dietary antigens is critical to avoid deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens is poorly understood. Here we demonstrate that the goblet cell-derived resistin-like molecule beta (RELM-beta) is a critical regulator of oral tolerance. We find that RELM-beta is abundant in sera of both food allergic patients and mouse models of FA. Deletion of RELM-beta protects mice from FA, development of food antigen specific IgE and anaphylaxis. RELM-beta disrupts food tolerance through modulation of the gut microbiome and depletion of indole metabolite producing Lactobacilli and Alistipes. Tolerance is maintained via local production of indole derivatives driving FA protective RORyt+ regulatory T (T reg) cells via activation of the aryl hydrocarbon receptor (AhR). RELM-beta antagonism in the peri-weaning period restored oral tolerance and protected genetically prone offspring from developing FA later in life. Together, our data identify RELM-beta as mediating both a novel gut immune-epithelial circuit regulating tolerance to food antigens, a new mode of innate control of adaptive immunity via microbiome editing and targetable candidates in this circuit for prevention and treatment of FA.