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 6

WASP-deficient FOXP3+ Tregs fail to suppress Th2-type lymphoproliferation in vivo.

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WASP-deficient FOXP3+ Tregs fail to suppress Th2-type lymphoproliferatio...
(A) Quantification by flow cytometry of FOXP3+ Tregs amongst CD4+ T cells obtained from MLNs or PPs of WT (open circles, n = 5), Was–/– (gray circles, n = 6) and Wasfl/fl Foxp3-Cre (black circles, n = 4) mice. (B) Production of IL-2 by CD4+ mesenteric T lymphocytes stimulated with anti-CD3/CD28 ex vivo. Each dot represents the average cytokine production from triplicate cell suspensions from a single mouse. (C) Total CD4+ T cell numbers obtained from MLNs and PPs. (D) Gating strategy of GATA3+ICOS+ Th2-type effector cells within the parent gate of effector memory T cells from MLNs of representative samples, with quantification and statistical testing in the right panels. (E) Fraction of T-bet+ and RORγt+ effector memory T cells. (F) Production of IL-4, IL-13, IFN-γ and IL-17a by CD4+ mesenteric T lymphocytes stimulated with anti-CD3/CD28 ex vivo. Each data point represents the average cytokine production from triplicate cell suspensions from a single mouse. (G) Serum levels of anti-soy specific IgE and IgG1, and MCPT1 in Was–/– mice on the 129SvEv background with either Il4+/+ (gray circles, n = 10 or 15) or Il4–/– alleles (gray squares, n = 8). (H) Anti-soy IgG2b titer as determined by ELISA in 1:1,000 serum dilution. 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 or 1-way ANOVA with Tukey’s multiple comparisons test. In B and F, data were log-transformed prior to statistical testing. Data from 2 pooled experiments (C, G, and H) or representative results from ≥ 2 independent experiments (A, B, and D–F) are shown.