The immune system is our body’s major defense mechanism against invading pathogens, as well as against tumor cells. One of the critical white blood cells that plays a central role in the immune system comprises T lymphocytes. They are generated from blood forming stem cells that undergo a series of discrete developmental stages within a specific organ called the thymus. This organ controls their proper development and results in the generation of T cells that have two distinct types of T cell receptors on their surface, either an αβ or a γδ T cell receptor. Both cell types have important but distinct roles in our immune system and these properties may be selectively required and used for particular purposes such as for immune therapy to treat cancer. However, little is known on the precise mechanisms through which they are generated from common immature precursors. This is the subject of this proposal and is important because understanding their precise developmental requirements will enable us to selectively generate such αβ or γδ T cells for cell therapy approaches. Thus, our work will provide important novel insights into how T cells are generated in human which will facilitate the future design of protocols for cellular therapies. Since we study this in human, our work will have a strong translational impact on immune function, immune reconstitution and cancer treatment.