Experimental Food Allergy with defective formation of induced Regulatory T (iTreg) Cells: Phenotype Rescue With Allergen-Specific Treg cell therapy

Abstract

RATIONALE: Mechanisms underlying the breakdown of oral tolerance in food allergic subjects are poorly understood. We hypothesized that a Th2-biased gut cytokine milieu subverts the tolerogenic iTreg cell response to food antigens into a pathogenic one. EXPERIMENTAL DESIGN: Mice with a gain of function mutation in the IL-4Ra immunotyrosine inhibitory motif (Il4raF709) and wild-type (WT) control mice were orally sensitized and challenged with Ovalbumin (OVA). Naïve T cells were converted into iTreg cells using TGF-beta in the absence or presence of graded concentrations of IL-4. iTreg cells bearing the OVA323-339 peptide-specific D011.10 T cell receptor were administered at the onset of the sensitization protocol in phenotype rescue experiments. RESULTS: . Il4raF709 but not WT mice were readily sensitized to orally administered OVA even in the absence of an adjuvant, and responded to subsequent oral challenge with OVA with IgE mediated anaphylaxis. OVA-stimulated mesenteric lymph node cultures exhibited decreased expansion of Foxp3+ T cells in OVA-sensitized Il4raF709 relative to WT mice. Purified naïve T cells of WT and Il4raF709 mice were equally converted into induced iTreg cells using TGF-beta. However, IL-4 disproportionately inhibited iTreg formation in Il4raF709 as compared to WT controls, resulting instead in heightened production by the TGF-beta treated cells of Th2 cytokines. In vivo, administration of OVA-specific iTreg cells at the onset of the sensitization protocol abrogated the induction of anaphylaxis in Il4raF709 mutant mice. CONCLUSION: Heightened IL-4R signaling may precipitate food allergy by antagonizing the formation of oral allergen-specific iTreg cells, promoting instead pathogenic Th2 cells.