title: An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells.
abstract: Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the gene encoding the interleukin (IL)-4 receptor alpha chain (Il4ra(R576)) promotes conversion of induced Treg (iTreg) cells toward a T helper 17 (TH17) cell fate. This skewing is mediated by the recruitment by IL-4Rα(R576) of the growth-factor-receptor-bound protein 2 (GRB2) adaptor protein, which drives IL-17 expression by activating a pathway that involves extracellular-signal-regulated kinase, IL-6 and the transcription factor STAT3. Treg cell-specific deletion of genes that regulate TH17 cell differentiation, including Il6ra and RAR-related orphan receptor gamma (Rorc), but not of Il4 or Il13, prevented exacerbated airway inflammation in mice expressing Il4ra(R576) (hereafter referred to as Il4ra(R576) mice). Furthermore, treatment of Il4ra(R576) mice with a neutralizing IL-6-specific antibody prevented iTreg cell reprogramming into TH17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed TH2-TH17 cell inflammation in genetically prone individuals and point to interventions that stabilize iTreg cells as potentially effective therapeutic strategies.
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Amir Hossein
authors.initials: AH
authors.lastname: Massoud
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Lopez
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Phipatanakul
authors.affiliation: Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D051380:GRB2 Adaptor Protein / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology; D018793:Interleukin-13 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C504000:IL4R protein, human; C504002:Il4ra protein, mouse; D018793:Interleukin-13; D020381:Interleukin-17; D053662:Interleukin-4 Receptor alpha Subunit; D015850:Interleukin-6; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011956:Receptors, Cell Surface; D019947:Receptors, Interleukin-6; C539901:Rorc protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse