D91-09 The Role of Stem Cell Factor in ILC2 Activation During RSV Infection

Rationale Respiratory syncytial virus (RSV) is the primary cause of bronchiolitis in children worldwide. Severe RSV infection is associated with childhood wheezing, increased asthma risk, and long-term impairment of lung function. Adults over 60 years are also susceptible to severe RSV disease, resulting in significant morbidity and hospitalization. Although effective vaccines exist, limited uptake continues to hinder prevention efforts. RSV infection and RSV-induced asthma exacerbation are characterized by strong type 2 immune responses. Group 2 innate lymphoid cells (ILC2s), which express c-KIT, contribute to mucosal injury and airway hyperreactivity through production of IL-13, IL-5, and IL-4. Stem cell factor (SCF), the ligand for c-KIT, regulates hematopoietic development, but its role in ILC differentiation and RSV-induced inflammation remains unclear. Methods To evaluate the role of SCF in type 2 pulmonary disease, we generated a tamoxifen-inducible whole-body SCF knockout mouse (Kitl^fl/fl UBC-CreERT2; SCFKO). Mice were treated intraperitoneally with tamoxifen (75 mg/kg) for 5 days, then infected intratracheally with RSV (1 × 10^5 PFU/mouse). Lung pathology, mucus deposition, cytokine gene expression, and ILC2 numbers were assessed. To study the specific contribution of the proinflammatory SCF248 isoform, we generated a monoclonal antibody recognizing exon 6 of membrane-bound SCF248. Adult BALB/c mice were infected with RSV and treated intraperitoneally with α-SCF248 (20 mg/kg) or control IgG on days 3 and 5. Lungs were collected on day 7 for histopathology and qPCR of type 2 and mucus-related genes. Results SCFKO Cre+ mice showed reduced lung inflammation, mucus deposition, and decreased expression of Il13, Il4, and Il5 compared with Cre− controls. SCF248 expression was high in Cre− but reduced in Cre+ mice, and ILC2 numbers in the lung were significantly decreased, indicating that SCF deletion attenuates RSV immunopathology. Similarly, RSV-infected mice treated with α-SCF248 showed significantly lower IL-13 expression and modestly reduced Gob5 and Il4 expression compared with RSV + IgG controls. Histopathology confirmed reduced airway inflammation, mucus deposition, and fewer ILC2s in α-SCF248-treated mice. Conclusion SCF, particularly the membrane-associated SCF248 isoform, promotes ILC2 activation and type 2 inflammation during RSV infection. Targeting SCF-c-KIT signaling attenuates airway inflammation and mucus hypersecretion, suggesting a novel therapeutic strategy to limit RSV-induced lung immunopathology This abstract is funded by: NIH