FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy
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
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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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 3

Commensals are dispensable for spontaneous sensitization to food in Was–/– mice but shape the isotype composition of the humoral anti-food response.

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Commensals are dispensable for spontaneous sensitization to food in Was–...
(A) Comparison of total IgE and total IgG1 serum levels in 4- to 6-month-old WT (open circles, n = 5) or Was–/– (gray circles) on the 129SvEv background that were housed under either SPF (n = 10) or GF (n = 14) conditions. (B) Food-specific IgE and IgG1 for the 5 main chow constituents in IgE (serum dilution 1:100) or IgG1 (1:5,000) from SPF (n = 8) and GF (n = 7) Was–/– mice. (C) Comparison of serum MCPT1 levels. (D) Comparison of cumulative anti-food titers of IgE, IgG1, IgG2a (1:1,000), IgG2b (1:1,000), IgG3 (1:200), and IgA (1:5,000) in SPF (n = 8) and GF (n = 7) Was–/– animals. 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. Results are shown from sera obtained from mice from ≥ 3 independent cohorts.