Importance of the Notch and Wnt pathways for Th2 cells

• Main Author: Antov, Andrey
• Format: Dissertation
• Language: English
• Subjects: health sciences, immunology
• ISBN: 1109206054; 9781109206050

Development of asthma and allergies, as well as defense against extracellular parasites are controlled by a special subset of white blood cells, called T helper type 2 (Th2). Understanding the molecular mechanisms underpinning the function of these lymphocytes is crucial for developing drug targets for treating malignancies and preventing pathogen-derived illnesses. Here, for the first time, we describe the implications of two distinct signaling pathways, Notch and Wnt pathways, in Th2 differentiation and survival, respectively. Through our experimentation, we revealed how Notch directs Th2 differentiation by facilitating RBP-J driven alternative splicing and consecutive activation of the Th2-specific master regulator of transcription Gata3. In the absence of Gata3 Notch led to a Th1 immune response. Thus Notch, in the presence of Gata3, acts as an activator of the Th2 program, while in its absence triggers a Th1 response. In a separate set of experiments we showed that the Wnt pathway is active in differentiated Th2 cells, but not important for their differentiation or function. In addition, we demonstrated that constitutive activation of Wnt pathway's focal point factor beta-catenin increases Th2 cell death. Together, these two studies shed light on molecular mechanisms and functions of the Notch and Wnt pathways.