Organoid-Induced Differentiation of Conventional T Cells from Human Pluripotent Stem Cells

Cell Stem Cell. 2019 Mar 7;24(3):376-389.e8. doi: 10.1016/j.stem.2018.12.011. Epub 2019 Jan 17.


The ability to generate T cells from pluripotent stem cells (PSCs) has the potential to transform autologous T cell immunotherapy by facilitating universal, off-the-shelf cell products. However, differentiation of human PSCs into mature, conventional T cells has been challenging with existing methods. We report that a continuous 3D organoid system induced an orderly sequence of commitment and differentiation from PSC-derived embryonic mesoderm through hematopoietic specification and efficient terminal differentiation to naive CD3+CD8αβ+ and CD3+CD4+ conventional T cells with a diverse T cell receptor (TCR) repertoire. Introduction of an MHC class I-restricted TCR in PSCs produced naive, antigen-specific CD8αβ+ T cells that lacked endogenous TCR expression and showed anti-tumor efficacy in vitro and in vivo. Functional assays and RNA sequencing aligned PSC-derived T cells with primary naive CD8+ T cells. The PSC-artificial thymic organoid (ATO) system presented here is an efficient platform for generating functional, mature T cells from human PSCs.

Keywords: 3D organoids; T cell development; conventional T cells; hematopoiesis; human pluripotent stem cells; immunotherapy; in vitro; lymphopoiesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cells, Cultured
  • Humans
  • K562 Cells
  • Mice
  • Mice, Inbred NOD
  • Organoids / cytology*
  • Organoids / immunology
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / immunology
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology


  • Receptors, Antigen, T-Cell