Year: 2016
Type: article
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.
DOI: 10.1172/jci85129
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
Institutions: Boston Children's Hospital, Harvard University, National Institutes of Health, National Institute of Allergy and Infectious Diseases, University of Virginia Health System, University of Virginia, Ludwig-Maximilians-Universität München, National Human Genome Research Institute, National Cancer Institute, Leidos Biomedical Research Inc. (United States), Leiden University, Leiden University Medical Center, Erasmus MC, Great Ormond Street Hospital, University College London, Brigham and Women's Hospital
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G2887981597, SIGNALING AND CYTOSKELETAL ORGANIZATION IN BLOOD CELLS, Studies of Fc-epsilon-RI as an antigen presentation structure at mucosal surfaces, G386607036, G5888954722, Exploring Regulatory T Cell Dysfunction in a Murine Model of Colitis, Exploring Regulatory T Cell Dysfunction in a Murine Model of Colitis, G9000138047, G9000180280, G9000188744, Training in Pediatric Gastroenterology, Hepatology, and Nutrition, Integrated Epithelial and Muscosal Biology, Studies on Fc-epsilon-RI as an antigen presentation structure at mucosal surfaces
OpenAlex ID: W2519743187