Rosebrugh Bldg, Toronto, ON M5S 3G9
Room: RS 211
T-cells, white blood cells that are important for immunity, have garnered significant interest in recent years for their ability to be genetically engineered to fight cancer. In humans, T-cells are continuously generated from hematopoietic (blood) stem cells (HSCs) in a specialized organ called the thymus. This ensures a steady supply of T-cells for combating infections and disease. T-cell development in the thymus is a complex process orchestrated by numerous signaling molecules, known as cytokines, and involves cells transitioning through a series of development states, where they are known as progenitor T-cells (proT-cells).
Our lab has developed a system (the DL4+VCAM-1 assay) for producing proT-cells from human cord blood-derived HSCs using only four essential cytokines. This system is the first to be completely defined, with no need for animal serum or co-culture with other cell types, and is thus amenable to clinical translation.
To investigate how other signaling molecules present in the thymus may instruct proT-cell development, a high-content screen has been designed. Using the Design of Experiments (DOE) statistical methodology, cytokines that enhance proT-cell development and expansion are being used to create a quantitative model that will predict the concentration, timing, and duration of cytokines that is optimal as cells progress through each proT-cell development stage. This will enable the design of automated, closed systems that provide cytokines in a sequential manner to maximize proT-cell generation while minimizing the generation of other, undesirable blood cell types.
This seminar provides an overview of the DOE methods being developed to model time-dependent cytokine effects on proT-cell development. It will also summarize how the cytokines combinations discovered using this approach are being used to generate proT-cells in clinically relevant quantities.