title: Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy.
abstract: 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 (Il4ra(F709)) 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.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Magali
authors.initials: M
authors.lastname: Noval Rivas
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Burton
authors.affiliation: Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Wise
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Georgiev
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Oettgen
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Rima
authors.initials: R
authors.lastname: Rachid
authors.affiliation: Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: talal.chatila@childrens.harvard.edu.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D000293:Adolescent; D000485:Allergens / Q000276:immunology; D000818:Animals; D065150:Cellular Reprogramming / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005512:Food Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005753:Gastric Mucosa / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007223:Infant; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D000485:Allergens; D018793:Interleukin-13; D015847:Interleukin-4; D011956:Receptors, Cell Surface; D050800:STAT6 Transcription Factor; D016212:Transforming Growth Factor beta; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C494100:Stat6 protein, mouse