Respiratory Syncytial Virus Induces IL-13+ Group 2 Innate Lymphoid Cells Via TSLP

Abstract

Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalization and is correlated with the subsequent development of childhood asthma. Clinical disease ranges from mild upper respiratory tract infection to bronchiolitis, viral pneumonia, and potentially death. Several lines of evidence support a role for inappropriate or excessive immune responses in the development of RSV-induced airway dysfunction. In the mouse model of RSV infection, IL-13 stimulates mucus production and enhanced airway reactivity. Recently described group 2 innate lymphoid cells (ILC2) are resident in the lungs and can potently produce IL-13. We hypothesized that ILC2 contribute to early production of IL-13 during RSV infection. We infected 8-week old BALB/c, IL-33-deficient, or TSLP receptor-deficient mice with RSV clinical isolate strain 01/2-20 and harvested lungs for flow cytometry or ELISA in accordance with approved animal protocols. We identified a threefold increase in the number of IL-13+ ILC2 in the lungs in RSV-infected mice compared to mice infected with vehicle or UV-inactivated virus at day 4 post infection. Concurrent with this finding, we identified an increase in the total concentration of IL-13 in the lungs. Additionally, we identified significant increases in the concentration of ILC2 stimulatory cytokines IL-33 and TSLP in the lungs by 12 hours post infection. Moreover, TSLP receptor-deficient mice, but not IL-33-deficient mice, showed reduced numbers of IL-13+ ILC2 after RSV infection. These data suggest ILC2 are a significant source of IL-13 early during RSV infection via a TSLP-dependent mechanism.