Immunological and Microbial Mechanisms in Food Allergy

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ABSTRACT The worsening epidemic of food allergy has been attributed to a confluence of environmental factors reflective of a modern life style, including altered gut microbiota, acting upon genetically susceptible individuals. Central to the development of food allergy is the breakdown of oral tolerance, normally enforced by food allergen- specific T regulatory (TR) cells. However, the mechanisms involved in the breakdown of oral tolerance are obscure. By employing an innovative murine model of human food allergy involving a gain of function mutation in the IL-4 receptor alpha chain immunotyrosine inhibitory motif (Il4raF709), we have demonstrated that food allergy is associated with reduced formation of allergen-specific induced TR (iTR) cells. Those iTR cells that are generated are dysfunctional and fail to prevent sensitization or to suppress active disease. This failure is related to their reprogramming into Th2-cell like TR cells that express IL-4, elevated levels of GATA3 and decreased Tgfb1 transcripts. We have also observed Th2 cell-like reprogramming in allergen-specific TR cells of human food allergic subjects. Food allergic Il4raF709 mice manifest dysregulation of innate lymphoid cells type 2 (ILC2s), which play a requisite role in disease pathogenesis by secreting IL-4. They also exhibit dysbiotic commensal flora that are pathogenic, as evidenced by their promotion of food allergy when transferred into germ-free (GF) mice. Reciprocally, flora of food tolerant mice prevented disease induction when transplanted into GF Il4raF709 mice. Therapy with minimal Clostridia or Bacteroidetes consortia protect against food allergy. Accordingly, in Aim 1, we propose that Th2 cell-like TR cells play a critical role in disease pathogenesis and persistence by directing IgE production and mast cell expansion, and that suppression of the Th2 cell-like TR cell program by TR cell-specific Il4/Il13 deletion rescues established disease. We will also examine the contribution of altered Tgfb1 expression in TR cells to disease pathogenesis in mice with TR cell- specific Tgfb1 deletion or transgene expression. In Aim 2, We will test the hypothesis that IL-4 production by ILC2 plays a crucial role in disease pathogenesis by suppressing iTR cell formation and inducing Th2 cell-like reprogramming of TR cells, and that TR cells in turn regulate ILC by IL-33-dependent mechanisms. Finally, in Aim 3, we hypothesize that a minimal set of Clostridia and Bacteroidetes consortia rescues active disease, suppresses dysbiosis and restores commensalism in part by signaling via MyD88 in TR cells, which would promote iTR cell formation and redirect intestinal immunoglobulin production away from IgE and towards IgA. Our proposed studies will identify fundamental immunological and microbial mechanisms by which oral tolerance is subverted in food allergy, and will enable the development of curative therapies.