FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy
Willem S. Lexmond, … , Scott B. Snapper, Edda Fiebiger
Willem S. Lexmond, … , Scott B. Snapper, Edda Fiebiger
Published September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):4030-4044. https://doi.org/10.1172/JCI85129.
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Research Article Gastroenterology Immunology

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

Abstract

In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen–free as well as germ-free housing conditions. Conditional deletion of Was in FOXP3+ Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory FOXP3+ Tregs, but not in naive-like FOXP3+ Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg-specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens.

Authors

Willem S. Lexmond, Jeremy A. Goettel, Jonathan J. Lyons, Justin Jacobse, Marion M. Deken, Monica G. Lawrence, Thomas H. DiMaggio, Daniel Kotlarz, Elizabeth Garabedian, Paul Sackstein, Celeste C. Nelson, Nina Jones, Kelly D. Stone, Fabio Candotti, Edmond H.H.M. Rings, Adrian J. Thrasher, Joshua D. Milner, Scott B. Snapper, Edda Fiebiger

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Figure 1

Increased sensitization and prevalence of food allergy among patients with WAS mutations.

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Increased sensitization and prevalence of food allergy among patients wi...
(A) Schematic of WAS gene with mutations identified among cohort (n = 25). Bold indicates WAS diagnosis; unbolded indicates XLT; italicized indicates mutations associated with food allergy in childhood. (B) Total serum IgE (sIgE) levels and food allergen–specific sIgE levels among cohort; limit of detection for sIgE was 0.1 IU/ml. Light gray fill indicates the normal range; boxes indicate median and interquartile ranges for 4 foods reported in NHANES (ref. 23). White circles indicate food-allergic individuals. (C) Among patients with sera obtained prior to transplantation (n = 22), percent of WAS (n = 12) or XLT (n = 10) patients positive for sIgE against foods (minimum cutoff 0.35 IU/ml) compared with the general population as reported in NHANES analysis (left panel). Prevalence of food allergy during childhood among all WAS (n = 15) and XLT (n = 10) patients compared with those reported in the general population (NHANES) and in patients with moderate to severe atopic dermatitis (AD) (right panel) (refs. 24 and 25). (D) Concordance between sIgE measurement and SPT for foods in individuals who underwent both modalities (n = 14) (left panel). Results of SPT and sIgE testing among patients with persistent clinical food allergy (n = 4); 2 individuals with food allergy in childhood without current evidence of sensitization were excluded (right panel). (E) Percentage of positive wheal responses to SPT with morphine titration among patients with WAS mutations (n = 13) compared with sex-matched controls (n = 15), *P = 0.03 by Fisher’s exact test. UD, undefined; ND, none detected; WH1, WASP Homology domain 1; GBD, GTPase binding domain; PPP, polyproline domain; VCA, verprolin homology, cofilin homology, and acidic region domain.