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 October 3, 2016; First published September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):4030-4044. https://doi.org/10.1172/JCI85129.
View: Text | PDF
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

×

Figure 2

Spontaneous sensitization to food antigens and food allergy in Was–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Spontaneous sensitization to food antigens and food allergy in Was–/– mi...
(A) Comparative analysis of total sIgE and IgG1 levels in 3-month-old WT BALB/c (open circles, n = 7) and Was–/– mice (gray circles, n = 9) of mixed genders. (B) IgE and IgG1 reactivity against the 5 main (% w/w) chow components as determined by ELISA in 1:30 (IgE) or 1:1,000 (IgG1) diluted serum samples. (C) Loading of WT bone marrow–derived mast cells with serum of food-allergic (FA sens) or non–food-allergic (FA non-sens) Was–/– mice compared with no-serum control (left panel). Appearance of surface LAMP-1 as a marker of mast cell degranulation after stimulation with antigen extracts from conventional chow (CCh), elemental chow (ECh), or PBS (–). (D) Intestinal mast cell expansion as determined by chloroacetate esterase staining of jejunal cross-sections (×20, with digital magnification to ×50 shown in window) and quantification per 4 high-power fields (4hpf) in WT (n = 7) and Was–/– mice (n = 8). (E) Serum levels of mast cell protease 1 (MCPT1) determined by ELISA. (F) Effect of 7-day treatment with elemental diet on serum MCPT1 in Was–/– mice (n = 11). Spearman’s rank correlation between cumulative anti-food IgE titers of mice and response to allergen elimination defined as ΔMCPT1. (G) Effect of oral rechallenge with 12.5 mg soy protein extract on body temperature and serum MCPT1 after 4 hours. Symbols represent individual mice and error bars depict SEM. *P < 0.05, **P < 0.01, ***P < 0.001 as determined by 2-tailed Student’s t test. NS, not significant; ND, not detectable. Results in C are representative of 2 independent experiments. Equivalent results were obtained in a cohort of WT and Was–/– mice on the 129SvEv background.