Journal Article

An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells

Phipatanakul, Wanda, Massoud, Amir Hossein, Charbonnier, Louis-Marie, Lopez, David, Pellegrini, Matteo, Chatila, Talal A

2016

Overview

An IL4R polymorphism associated with severe asthma drives conversion of regulatory T cells to T H 17 cells; this can be inhibited by neutralizing interleukin-6. Mechanisms by which regulatory T (T reg ) 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 T reg (iT reg ) cells toward a T helper 17 (T H 17) 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. T reg cell–specific deletion of genes that regulate T H 17 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 iT reg cell reprogramming into T H 17-like cells and protected against severe airway inflammation. These findings identify a previously unknown mechanism for the development of mixed T H 2–T H 17 cell inflammation in genetically prone individuals and point to interventions that stabilize iT reg cells as potentially effective therapeutic strategies.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13 / 14/63 / 38 / 38/91 / 64/60 / 692/698/1543/1565/1597/554/1898/1271 / 692/699/1785/31 / 96 / Adolescent / Adult / Airway management / Airway obstruction / Analysis / Animals / Antibodies, Neutralizing - pharmacology / Asthma / Asthma - genetics / Asthma - immunology / Biomedicine / Cancer Research / Case-Control Studies / Cell differentiation / Cell Differentiation - drug effects / Cell Differentiation - immunology / Cells / Child / Complications and side effects / Disease Models, Animal / Female / Flow Cytometry / Gene Expression Profiling / GRB2 Adaptor Protein - immunology / Humans / Immunoblotting / Immunoprecipitation / Infectious Diseases / Inflammation - immunology / Inflammatory diseases / Interleukin-13 - immunology / Interleukin-17 - immunology / Interleukin-4 Receptor alpha Subunit - genetics / Interleukin-4 Receptor alpha Subunit - immunology / Interleukin-6 - immunology / Lung - immunology / Male / Metabolic Diseases / Mice / Middle Aged / Molecular Medicine / Neurosciences / Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics / Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology / Polymorphism, Genetic / Real-Time Polymerase Chain Reaction / Receptors, Cell Surface - genetics / Receptors, Interleukin-6 - genetics / Receptors, Interleukin-6 - immunology / Respiratory Hypersensitivity - immunology / Reverse Transcriptase Polymerase Chain Reaction / Risk factors / STAT3 Transcription Factor - immunology / T cells / T-Lymphocytes, Regulatory - drug effects / T-Lymphocytes, Regulatory - immunology / Th17 Cells - drug effects / Th17 Cells - immunology / Young Adult