Notch Signaling During T Helper 2 Cell-Mediated Inflammation in Allergic Asthma

Abstract

Enhanced activation of T helper-2 (Th2) cells producing Th2-cytokines (IL-4/IL-5/IL-13) explains many hallmarks of allergic asthma, including eosinophilic airway inflammation and bronchial hyperreactivity. Th2 cell differentiation is thought to be instructed by interaction of Notch on the T cell surface with its ligand Jagged on dendritic cells (DCs). Therefore, we studied the role of Notch signaling in allergic airway inflammation in vivo. In acute and chronic mouse models of house dust mite (HDM)-mediated allergic asthma, we found that expression of Notch and its nuclear effector RBPJκ in T cells is essential for disease development. Our findings suggest that Notch signaling is involved in migration of Th2 cells into the lung. Transgenic overexpression of the key Th2 transcription factor Gata3 in the absence of Notch was not sufficient to induce allergic inflammation, indicating that Notch signaling has additional downstream targets next to Gata3. Mice lacking Jagged1/2 on DCs, T cells or lymph node stromal cells still developed HDM-driven airway inflammation. Importantly, hallmarks of asthma could be suppressed by the Notch inhibitory peptide SAHM1 – which interferes with RBPJκ function - but not by a control peptide. Finally, we obs