Regulatory T Cell Reprogramming toward a Th2-Cell-like Lineage Impairs Oral Tolerance and Promotes Food Allergy

• Published in: Immunity (Cambridge, Mass.) Vol. 42; no. 3; pp. 512 - 523
• Main Authors: Noval Rivas, Magali, Burton, Oliver T., Wise, Petra, Charbonnier, Louis-Marie, Georgiev, Peter, Oettgen, Hans C., Rachid, Rima, Chatila, Talal A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2015; Elsevier Limited
• Subjects: Adolescent; Allergens - immunology; Allergies; Animals; Cellular Reprogramming - immunology; Child; Child, Preschool; Children & youth; Disease prevention; Evacuations & rescues; Female; Food; Food allergies; Food Hypersensitivity - genetics; Food Hypersensitivity - immunology; Food Hypersensitivity - pathology; Gastric Mucosa - immunology; Gastric Mucosa - pathology; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Immune Tolerance; Immunity, Mucosal; Immunology; Infant; Interleukin-13 - deficiency; Interleukin-13 - genetics; Interleukin-13 - immunology; Interleukin-4 - deficiency; Interleukin-4 - genetics; Interleukin-4 - immunology; Lymphocytes; Male; Mast Cells - immunology; Mast Cells - pathology; Mice; Mice, Transgenic; Pathogenesis; Population; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Rodents; Signal Transduction; STAT6 Transcription Factor - genetics; STAT6 Transcription Factor - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Th2 Cells - immunology; Th2 Cells - pathology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2015.02.004

Oral immunotherapy has had limited success in establishing tolerance in food allergy, reflecting failure to elicit an effective regulatory T (Treg) cell response. We show that disease-susceptible (Il4raF709) mice with enhanced interleukin-4 receptor (IL-4R) signaling exhibited STAT6-dependent impaired generation and function of mucosal allergen-specific Treg cells. This failure was associated with the acquisition by Treg cells of a T helper 2 (Th2)-cell-like phenotype, also found in peripheral-blood allergen-specific Treg cells of food-allergic children. Selective augmentation of IL-4R signaling in Treg cells induced their reprogramming into Th2-like cells and disease susceptibility, whereas Treg-cell-lineage-specific deletion of Il4 and Il13 was protective. IL-4R signaling impaired the capacity of Treg cells to suppress mast cell activation and expansion, which in turn drove Th2 cell reprogramming of Treg cells. Interruption of Th2 cell reprogramming of Treg cells might thus provide candidate therapeutic strategies in food allergy. [Display omitted] •Treg cells manifest a Th2-cell-like phenotype in food allergy•Th2-cell-like reprogramming of Treg cells promotes food allergy•Inactivation of Th2 cell pathways in Treg cells protects against food allergy Food allergy is characterized by failure of oral-tolerance mechanisms. Chatila and colleagues demonstrate that in food allergy, regulatory T (Treg) cells acquire a T helper 2 (Th2)-cell-like phenotype that plays a pathogenic role in disease.