Respiratory syncytial virus infection activates IL-13-producing group 2 innate lymphoid cells through thymic stromal lymphopoietin

• Type of Material: Article
• Authors: Matthew T. Stier, Vanderbilt University; Melissa H. Bloodworth, Vanderbilt University; Shinji Toki, Vanderbilt University; Dawn C. Newcomb, Vanderbilt University; Kasia Goleniewska, Vanderbilt University; Kelli L. Boyd, Vanderbilt University; Marc Quitalig, Vanderbilt University; Anne L. Hotard, Emory University; Martin Moore, Emory University; Tina V. Hartert, Vanderbilt University; Baohua Zhou, Indiana University School of Medicine; Andrew N. McKenzie, University of Cambridge; R. Stokes Peebles, Vanderbilt University
• Language: English
• Date: 2016-09-01
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2016 The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaci.2016.01.050
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology
• ISSN: 0091-6749
• Volume: 138
• Issue: 3
• Start Page: 814
• End Page: +
• Grant/Funding Information: The VMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404).; Supported by National Institutes of Health (NIH) grant R01 AI 111820 (to R.S.P.), United States Department of Veterans Affairs 2I01BX000624 (to R.S.P.), NIH U19 AI 095227-02 (to R.S.P.), NIH R01 HL 090664-04 (to R.S.P.), NIH T32 GM07347–Vanderbilt MSTP, NIH F30 AI114262 (to M.T.S.), NIH R01 AI085046 (to B.Z.), and NIH K24 AI77930 (to T.V.H.).; We thank The Vanderbilt Antibody and Protein Resource, which is supported by the Vanderbilt Institute of Chemical Biology and the Vanderbilt Ingram Cancer Center (P30 CA68485).
• Keywords: Group 2 innate lymphoid cells; CYTOKINE PRODUCTION; TYPE-2 IMMUNITY; ADAPTIVE IMMUNITY; ASTHMA EXACERBATIONS; IL-13; respiratory syncytial virus; type 2 immunity (T(H)2); Allergy; thymic stromal lymphopoietin; T-LYMPHOCYTES; AIRWAY EPITHELIAL-CELLS; CONTROLLED-TRIAL; ALLERGIC LUNG INFLAMMATION; IL-33; TSLP; Life Sciences & Biomedicine; Science & Technology; MICE; Immunology
• Research Categories: Biology, Microbiology; Health Sciences, Pathology

Abstract

Background: Respiratory syncytial virus (RSV) is a major health care burden with a particularly high worldwide morbidity and mortality rate among infants. Data suggest that severe RSV-associated illness is in part caused by immunopathology associated with a robust type 2 response. Objective: We sought to determine the capacity of RSV infection to stimulate group 2 innate lymphoid cells (ILC2s) and the associated mechanism in a murine model. Methods: Wild-type (WT) BALB/c, thymic stromal lymphopoietin receptor (TSLPR) knockout (KO), or WT mice receiving an anti-TSLP neutralizing antibody were infected with the RSV strain 01/2-20. During the first 4 to 6 days of infection, lungs were collected for evaluation of viral load, protein concentration, airway mucus, airway reactivity, or ILC2 numbers. Results were confirmed with 2 additional RSV clinical isolates, 12/11-19 and 12/12-6, with known human pathogenic potential. Results RSV induced a 3-fold increase in the number of IL-13–producing ILC2s at day 4 after infection, with a concurrent increase in total lung IL-13 levels. Both thymic stromal lymphopoietin (TSLP) and IL-33 levels were increased 12 hours after infection. TSLPR KO mice did not mount an IL-13–producing ILC2 response to RSV infection. Additionally, neutralization of TSLP significantly attenuated the RSV-induced IL-13–producing ILC2 response. TSLPR KO mice displayed reduced lung IL-13 protein levels, decreased airway mucus and reactivity, attenuated weight loss, and similar viral loads as WT mice. Both 12/11-19 and 12/12-6 similarly induced IL-13–producing ILC2s through a TSLP-dependent mechanism. Conclusion: These data demonstrate that multiple pathogenic strains of RSV induce IL-13–producing ILC2 proliferation and activation through a TSLP-dependent mechanism in a murine model and suggest the potential therapeutic targeting of TSLP during severe RSV infection.