Department: Immunology, University of Toronto
We are interested in understanding how molecular signals in developing tissues induce T-lymphocyte lineage commitment and differentiation of hematopoietic stem cells. In the immune system, the thymus provides a model system for the study of the mechanisms controlling tissue-specific differentiation events and lineage commitment pathways. My research program aims to elucidate the pathways governing the generation of T lymphocytes and the means by which commitment to the T cell lineage by hematopoietic progenitors or embryonic stem cells is regulated.
The main aim of this project is to identify the unique signals provided by the thymus microenvironment, which allows for the development of T cells from stem cells. We recently demonstrated that the expression of the Notch ligand Delta-like-1 on stromal cells (OP9-DL1 cells) enables these cells to induce the differentiation of hematopoietic stem cells into mature functional T cells. We are currently extending our understanding of the requirement for Delta-like/Notch interactions during early thymocyte development to determining the minimal molecular interactions that are necessary for the induction of T cell lineage commitment by hematopoietic stem cells. We are also developing several strategies to adopt our current model system for the induction of T cell differentiation from defined sources of human stem cells. We have already succeeded in generating human T cells from umbilical cord blood-derived hematopoietic stem cells, and are currently characterizing the effectiveness of these in vitro-generated human progenitor T cells, obtained from cord blood-derived stem cells, to reconstitute immune function.