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 4

WASP deficiency in Tregs is sufficient for the development of spontaneous food allergy and results in more severe disease.

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WASP deficiency in Tregs is sufficient for the development of spontaneou...
(A) Comparison of MCPT1 levels in mice with cell type–specific WASP deletions. Mice with conditional deletion of Wasfl/fl alleles in B cells (Wasfl/fl Mb1-Cre), CD11c+ dendritic cells (Wasfl/fl Itgax-Cre) or Tregs (Wasfl/fl Foxp3-Cre) of ≥ 2 months of age, n ≥ 5 per group. (B) Representative H&E (×10 magnification) and chloroacetate esterase (CAE) staining (×20 magnification) of intestinal cross-sections in Wasfl/fl Foxp3-Cre or WasWT Foxp3-Cre littermates on the C57BL/6 background. (C) Comparison of total and soy-specific IgE and IgG1 at 2 months in cohoused WT (open circles, n = 9), Was–/– (gray circles, n = 12), and Wasfl/fl Foxp3-Cre (black circles, n = 9) mice of mixed genders on the C57BL/6 background. (D) Comparison of serum protein and jejunal mRNA expression levels of mucosal mast cell marker MCPT1. Symbols represent individual mice and error bars depict SEM. *P < 0.05, **P < 0.01, ***P < 0.001. NS, not significant as determined by 2-tailed Student’s t test (A) or 1-way ANOVA with Tukey’s multiple comparisons test (C and D). BDL, below detection limit. Data in C and D are representative of 2 independent cohorts.