Generation of thymus-reconstituting T cell progenitors from human pluripotent stem cells.

Generating a large number of progenitors that can repopulate the immune system of a recipient is one of the key steps toward efficient cancer immunotherapy. Here, we describe the engineering of T cell progenitors capable of direct and long-term reconstitution of the thymus. In the thymus, human pluripotent stem cell (hPSC)-derived progenitor T cells (pro-T cells) developed into single-positive human T cells that entered circulation and settled in the spleen. Single-cell transcriptome analysis of differentiating hPSCs attested to the emergence of cells that displayed the transcription signature of the early T cell progenitors. Comparative transcription profiling revealed the similarity of the hPSC-pro-T cells with the early T cell precursors of the human thymus. The in vitro generation of T cell progenitors provides a powerful model for studying the molecular mechanisms of human T cell development and improves the perspectives for T cell regenerative medicine, including chimeric antigen receptor T (CAR-T) cell therapies.