Grant: Project Grant

T cells are central players in regulating and mediating immune responses to pathogens and cancer. Novel and effective immunotherapies have been developed that take advantage of the effector function of mature T cells, which can carry re-directed specificities, as in chimeric antigen receptor (CAR) T cells, or by using checkpoint inhibitors, such as anti-PD1/anti-CTL4. We have developed new culture methods for the generation of T cells from stem cells, which can provide an unlimited "off the shelf" source of effector T cells for new cell-based immunotherapies. One key aspect of newly generated T cells created in culture is that they mirror the cells that emerge from the thymus as recent thymic emigrants (RTEs). It is known that RTE cells are nascent T cells that continue their post-thymic maturation in the periphery and dominate T cell immune responses in early life and in adults having undergone lymphodepletion regimens used in cancer immunotherapies. However, the events that govern their maturation and their functionality as they transition to mature naïve T (MNT) cells or regulatory T cells have not been clearly defined. Using mice in which we can precisely control the production of T cells in the thymus, we will identify different stages of RTE maturation and interrogate their immune function in vivo. Additionally, we will be able to test whether Notch signals are critical during RTE cell maturation or during their effector / regulatory activity as they gain functional competence, and elucidate the pathways regulated by Notch signaling at these critical and underappreciated stages of T cell differentiation. Our findings will serve to mechanistically inform new methods for generating effective T cell-based immunotherapies for cancer and autoimmune diseases.