Stier, Matthew T.Bloodworth, Melissa H.Toki, ShinjiNewcomb, Dawn C.Goleniewska, KasiaBoyd, Kelli L.Quitalig, MarcHotard, Anne L.Moore, Martin L.Hartert, Tina V.Zhou, BaohuaMcKenzie, Andrew N.Peebles Jr., R. Stokes2017-07-252017-07-252016-09Stier, M. T., Bloodworth, M. H., Toki, S., Newcomb, D. C., Goleniewska, K., Boyd, K. L., … Peebles, R. S. (2016). Respiratory syncytial virus infection activates IL-13–producing group 2 innate lymphoid cells through thymic stromal lymphopoietin. The Journal of Allergy and Clinical Immunology, 138(3), 814–824.e11. http://doi.org/10.1016/j.jaci.2016.01.050https://hdl.handle.net/1805/13581BACKGROUND: 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.en-USAttribution-NonCommercial-NoDerivs 3.0 United StatesGroup 2 innate lymphoid cellsIL-13IL-33Thymic stromal lymphopoietinRespiratory syncytial virusType 2 immunity (T 2)Article