Notch3 and pre-TCR interaction differentially regulate T cell development and leukemogenesis

Combinatorial interaction among signaling pathways is believed to determine hemopoietic cell fate. Notch proteins are a wide-expressed family of transmembrane receptors that have been shown to influence cell fate decisions and tumorigenesis in multiple systems, including T cells. We previously generated Notch3-IC transgenic mice and demonstrated that altered Notch3 signaling impairs the developmentally regulated interplay between pre-TCR and NF-jB signalling and allows the disruption of thymocyte differentiation and the development of T cell leukaemia. Moreover, by utilizing Notch3-IC transgenic mice and Notch3-IC/pTa-/- double mutant mice, which do not develop leukemia, we demonstrated that, while pre-TCR is required for thymocytes proliferation and leukemogenesis, it is dispensable for Notch3-induced thymocyte differentiation. We will discuss new genetic and biochemical evidence that Notch3, depending on its interaction with pre- TCR, triggers multiple NF-jB activation pathways and regulates SCL/Tal1 and Ikaros transcription factor functions, thus regulating early T cell differentiation and leukemogenesis. We also will show that cooperation between Notch3 and pTa appears to be required for correct development and function of T regulatory cells, thus suggesting its role in lineage fate decision.