Immunological and Microbial Mechanisms in Food Allergy

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ABSTRACT The high prevalence of food allergy (FA) places many at risk of severe reactions to foods including anaphylaxis (1). Our studies on human subjects with FA and in relevant mouse models have identified changes in regulatory T (Treg) cell populations as playing a pivotal role in disease pathogenesis. Specifically, we have identified a critical role of RORgt+ Treg cells, induced by the gut commensal bacteria, in mediating oral tolerance to food allergens (2, 3). In contrast, FA is associated with defective microbiota-dependent differentiation of RORgt+ Treg cells due to dysbiosis. We identified Resistin like molecule beta (RELMβ), a gut goblet cell cytokine previously linked to the innate immune response to parasitic infections (4-6), as pivotal to FA pathogenesis by promoting dysbiosis and disrupting RORgt+ Treg cell differentiation. Reciprocally, there emerges in FA food allergen-specific Treg cells with a T helper cell type (Th2) cell like phenotype, with high expression of the transcription factor GATA3 and the Th2 cytokines IL-4 (7, 8). These reprogrammed Treg cells play an essential role in amplifying disease pathology, and they decline in patients receiving oral immunotherapy (7, 8). Our recent analysis of circulating Treg cells of human subjects with FA identified Thymic stromal lymphopoietin receptor (TSLPR) as a marker of their Th2 cell-like reprogramming. Accordingly, the focus of this proposal is to identify immune regulatory checkpoints that govern FA and means of resetting them to promote oral tolerance. Our overall hypothesis is that the evolution of FA entails two critical checkpoints each involving a distinct Treg cell population under control of dedicated innate cell and cytokine circuits. The first involves microbiota-dependent Helios– RORgt+ Treg cells generated at the peri-weaning period and thereafter which enforced oral tolerance. This circuit is negatively controlled by RELMb, itself induced by an upstream Tuft cell (IL-25)-ILC2(IL-13) axis (9-11), which predisposes to FA by promoting dysbiosis. The second involves Helios+TSLPR+ Th2 cell-like Treg cells that are positively regulated by IgE/Mast cells and which augment the FA responses. To explore this hypothesis, we will under Aim 1 examine the evolution of the pro-tolerogenic immune response in FA Il4raF709 mice following therapy with anti-RELMb mAb or the acute deletion of the RELMb gene Retnlb. We will also elucidate the mechanisms by which RELMb antagonism resets the gut microbiota to enforce oral tolerance, including the expansion of Lactobacilli species rich in indole metabolites that act via the aryl hydrocarbon receptor (AhR) to suppress FA by inducing RORgt+ Treg cells. Under Aim 2, we will dissect the role of TSLPR on Th2 cell-like reprogrammed Treg cell in disease pathogenesis. These findings will then be extending to studies under Aim 3 on FA subjects to relate changes in serum RELMb and Treg cell populations to dysbiosis and disease severity. The proposed studies will provide fundamental new insights relevant to disease pathogenesis and novel therapeutic approaches to re-establish oral tolerance in FA.