Notch signaling in T cells is essential for allergic airway inflammation, but expression of Notch ligands Jagged1 and Jagged2 on dendritic cells is dispensable

Publication date: Available online 19 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Irma Tindemans, Melanie Lukkes, Marjolein J.W. de Bruijn, Bobby W.S. Li, Menno van Nimwegen, Derk Amsen, Alex KleinJan, Rudi W. Hendriks
BackgroundAllergic asthma is characterized by a T helper 2 (Th2) response induced by dendritic cells (DCs) that present inhaled allergen. Although the mechanisms by which they instruct Th2 differentiation are still poorly understood, expression of the Notch ligand Jagged on DCs has been implicated in this process.ObjectiveTo establish whether Notch signaling, induced by DCs, is critical for house-dust mite (HDM) driven allergic airway inflammation (AAI) in vivo.MethodsThe induction of Notch ligand expression on DC subsets by HDM was quantified by qRT-PCR. We used a HDM-driven asthma mouse model to compare the capacity of Jagged1 and Jagged2 single and double-deficient DCs to induce AAI. In addition, we studied AAI in mice with a T cell-specific deletion of RBPJκ, a downstream effector of Notch signaling.ResultsHDM exposure promoted the expression of Jagged1, but not Jagged2, on DCs. In agreement with published findings, in vitro differentiated and HDM-pulsed Jagged1 and Jagged2 double-deficient DCs lacked the capacity to induce AAI. However, following in vivo intranasal sensitization and challenges with HDM, DC-specific Jagged1, Jagged2 single or double-deficient mice developed an eosinophilic airway inflammation and Th2 cell activation phenotype that was not different from that in control littermates. In contrast, RBPJκ-deficient mice failed to develop AAI and airway hyperreactivity.ConclusionOur results show that the Notch signaling pathway in T cells is crucial for the induction of Th2-mediated AAI in a HDM-driven asthma model, but that expression of Jagged1 or Jagged2 on DCs is not required.Clinical ImplicationsThe Notch signaling pathway in T cells is critical for development of house-dust mite driven allergic airway inflammation in mice, indicating it could be a potential therapeutic target in asthma.

Teaser

Although Notch signaling in T cells is critical for development of T helper2 cell-driven house-dust mite mediated allergic airway inflammation in mice, expression of the Notch ligands Jagged1 and Jagged2 on dendritic cells is dispensable.


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