Multitissue Transcriptomics Delineates the Diversity of Airway T Cell Functions in Asthma

• Published in: American journal of respiratory cell and molecular biology Vol. 58; no. 2; pp. 261 - 270
• Main Authors: Singhania, Akul, Wallington, Joshua C., Smith, Caroline G., Horowitz, Daniel, Staples, Karl J., Howarth, Peter H., Gadola, Stephan D., Djukanović, Ratko, Woelk, Christopher H., Hinks, Timothy S. C.
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.02.2018
• Subjects: Adult; Aged; Antigens, Neoplasm - metabolism; Asthma; Asthma - genetics; Asthma - immunology; Bacterial infections; CCL3 protein; CD14 antigen; CD3 antigen; Cell activation; Cell Adhesion Molecules - metabolism; Chemokines; Chemokines - metabolism; Chemotactic factors; Chloride channels (calcium-gated); Chloride Channels - metabolism; Chronic obstructive pulmonary disease; Corticosteroids; Cystatins - metabolism; Cytokines; Disease; Epithelial Cells - immunology; Epithelium; Female; Flow cytometry; Gelatinase B; Gene expression; Gene Expression Profiling; Humans; Inflammation; Interleukin 13; Interleukin 17; Interleukin 8; Interleukin-13 - immunology; Interleukin-17 - immunology; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Male; Middle Aged; Monocytes; Mucin; Neutrophilia; Neutrophils; Nitric oxide; Nitric-oxide synthase; Original Research; Oxidative stress; Phenotypes; R&D; Receptors, Colony-Stimulating Factor - metabolism; Research & development; Respiratory Mucosa - immunology; Respiratory tract; Serpins - metabolism; Smooth muscle; Sputum; Sputum - metabolism; T-Lymphocytes - immunology; Tissues; Toll-like receptors; Young Adult; transcriptomics; epithelial brushings; asthma; sputum; BAL
• ISSN: 1044-1549; 1535-4989; 1535-4989
• DOI: 10.1165/rcmb.2017-0162OC

Asthma arises from the complex interplay of inflammatory pathways in diverse cell types and tissues. We sought to undertake a comprehensive transcriptomic assessment of the epithelium and airway T cells that remain understudied in asthma and investigate interactions between multiple cells and tissues. Epithelial brushings and flow-sorted CD3 T cells from sputum and BAL were obtained from healthy subjects (n = 19) and patients with asthma (mild, moderate, and severe asthma; n = 46). Gene expression was assessed using Affymetrix HT HG-U133 PM GeneChips, and results were validated by real-time quantitative PCR. In the epithelium, IL-13 response genes (POSTN, SERPINB2, and CLCA1), mast cell mediators (CPA3 and TPSAB1), inducible nitric oxide synthase, and cystatins (CST1, CST2, and CST4) were upregulated in mild asthma, but, except for cystatins, were suppressed by corticosteroids in moderate asthma. In severe asthma-with predominantly neutrophilic phenotype-several distinct processes were upregulated, including neutrophilia (TCN1 and MMP9), mucins, and oxidative stress responses. The majority of the disease signature was evident in sputum T cells in severe asthma, where 267 genes were differentially regulated compared with health, highlighting compartmentalization of inflammation. This signature included IL-17-inducible chemokines (CXCL1, CXCL2, CXCL3, IL8, and CSF3) and chemoattractants for neutrophils (IL8, CCL3, and LGALS3), T cells, and monocytes. A protein interaction network in severe asthma highlighted signatures of responses to bacterial infections across tissues (CEACAM5, CD14, and TLR2), including Toll-like receptor signaling. In conclusion, the activation of innate immune pathways in the airways suggests that activated T cells may be driving neutrophilic inflammation and steroid-insensitive IL-17 response in severe asthma.