ICMI 2015

OR.36 Notch Signaling in CD4+ T Cells is Required for the Induction of Allergic Asthma in vivo

Thursday, July 16, 2015: 11:30 AM
Hall C Berlin, Ground Floor (Maritim Hotel)
Irma Tindemans, MSc , Erasmus MC, Rotterdam, The NETHERLANDS
Alex KleinJan, PhD , Erasmus MC, Rotterdam, Netherlands
Marjolein J.W. de Bruijn, BASc , Erasmus MC, Rotterdam, Netherlands
Melanie Lukkes, BASc , Erasmus MC, Rotterdam, Netherlands
Bobby W.S. Li, MSc , Erasmus MC, Rotterdam, Netherlands
Ingrid M. Bergen, BASc , Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Menno van Nimwegen, BASc , Erasmus MC, Rotterdam, Netherlands
Henk C. Hoogsteden, Prof, PhD, MD , Erasmus MC, Rotterdam, Netherlands
Derk Amsen, PhD , Sanquin, Amsterdam, Netherlands
Rudi W. Hendriks, Prof, PhD , Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Introduction

Differentiation and activation of T helper 2 (Th2) cells is critical in allergic asthma. Binding of Notch ligands on dendritic cells (DCs) to Notch molecules on T cells can instruct differentiation of naïve T helper cells through direct induction of the key Th2 transcription factor Gata3, via the downstream protein RBPJ: Delta-like ligands and Jagged induce Th1 and Th2 differentiation, respectively. However, it remains unknown whether Notch signaling induced by DCs is critical for Th2-mediated allergic airway inflammation (AAI) in vivo.

Materials & Methods

To analyze the role of Notch signaling in vivo, we employed mice with CD4-cre mediated T cell-specific deletion of the Rbpj gene or both Notch1 and Notch2 genes, as well as mice lacking Jagged1, Jagged2 or both Jagged molecules in DCs (CD11c-cre mediated) in a house-dust mite-mediated asthma model.

Results

In contrast to wild-type mice, RBPJ-deficient mice failed to develop AAI, characterized by eosinophilic inflammation, Th2 cytokines, Gata3 induction in T cells and serum IgE. Likewise, Notch1 and 2 deficient mice failed to develop any signs of Th2 inflammation. Remarkably, conditional Jagged1, Jagged2 or Jagged1 and 2 KO mice developed AAI symptoms that were similar to those in WT mice. We are currently investigating which cells induce Th2 inflammation via Notch signaling in a house-dust mite-mediated asthma model.

Conclusion 

Although future experiments should establish which cells express crucial Th2-inducing Notch ligands, we conclude that Notch signaling in T cells is required for AAI induction in mice.