Grant: Foundation Grant

The proposed research focuses on blood cell development, and, in particular, on how a subset of white blood cells, known as T lymphocytes, are generated. T cells are important effectors and master regulators of the immune system, which protects us from cancer and infectious diseases. The thymus is where T cells are generated from progenitor cells that arrive from the bone marrow. The proposed research program aims to understand the molecular controls that initiate and regulate the development of T cells. We have made important breakthroughs by identifying the key molecular interactions (Notch signaling) for inducing T cell development in the thymus, which led to the creation of a simple tissue culture system for the generation of T cells from any source of stem cells. Our work has provided a deeper understanding of the signaling cascades employed during normal thymocyte differentiation, in particular at a stage when T cell lineages bifurcate. Lastly, as mutations in components of these signaling pathways may result in primary immunodeficiencies or lead to oncogenic events, the research to be carried out has clear clinical implications. The overall research program direction is also guided by our recent work showing that transplanting in vitro-generated human progenitor T cells along with bone marrow stem cells into immunodeficient mice results in a dramatic increase in the ability of stem cell-derived cells to give rise to new T cells in the host thymus. This is an important discovery given that stem cell transplants in humans typically fail to regenerate new T cells. The proposed work will ensure that we continue to make important fundamental discoveries as to how Notch signals induce and regulate T cell development, improve upon on how to employ those insights for the generation of human T cells from stem cells, and enable us apply our advances to realize important cell-based immune-reconstitution and immune-therapeutic clinical applications.