Notch Signaling During T Helper 2 Cell-Mediated Inflammation in Allergic Asthma
Notch signalering tijdens T helper 2 cel-gedreven inflammatie bij allergische astma
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 observed that Th2 cells in peripheral blood of asthma patients expressed higher levels of surface Notch1 and Notch2 than Th2 cells of healthy individuals. This increase was more pronounced in patients with uncontrolled asthma than in patients with controlled asthma. These findings show that Notch signalling in T cells is crucial for allergic asthma and indicate that Notch inhibition may be an attractive therapy.
|Keywords||Notch, T cells, Th2, immunology, cytokines, Jagged|
|Promotor||R.W. Hendriks (Rudi)|
|Publisher||Erasmus University Rotterdam|
|Note||For copyright reasons there is a partial embargo for this dissertation|
Tindemans, I. (2018, May 22). Notch Signaling During T Helper 2 Cell-Mediated Inflammation in Allergic Asthma. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/105791