From pluripotent stem cells to T cells

The generation of T cells from human pluripotent stem cells (PSCs) opens a valuable experimental window into developmental hematopoiesis and raises the possibility of a new therapeutic approach for T-cell immunotherapy. After directing PSCs through mesoderm and early hematopoietic developmental stages, commitment to the T-cell lineage has been achieved by several groups using coculture with stromal cells that express a notch ligand, recapitulating the critical signals that initiate the first stages of normal T-cell differentiation in the thymus. However, positive selection and the production of mature T cells from human PSCs have been limited to date. Nonetheless, T-lineage cells have been generated from PSCs with tumor antigen specificity either through a prearranged clonal T-cell receptor (TCR) or lentiviral-mediated expression of chimeric antigen receptors. The recent development of a 3D artificial organoid model has demonstrated that PSCs can generate mature conventional T cells that are fully functional and express a diverse TCR repertoire. Introduction of a transgenic TCR at the PSC stage allows for the production of tumor-antigen-specific, mature conventional T cells. The tools of gene editing in PSCs are ideally suited to produce off-the-shelf universal products for T-cell immunotherapy. In this review, we describe the studies that have led to this exciting moment in PSC biology and discuss translation to clinical applications.