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

Amélie Montel-Hagen; Christopher S Seet; Suwen Li; Brent Chick; Yuhua Zhu; Patrick Chang; Steven Tsai; Victoria Sun; Shawn Lopez; Ho-Chung Chen; Chongbin He; Chee Jia Chin; David Casero; Gay M Crooks

doi:10.1016/j.stem.2018.12.011

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.

Authors

Affiliations

¹ Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA.
² Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA.
³ Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA.
⁴ Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Molecular Biology Interdepartmental Program, UCLA, Los Angeles, CA, USA.
⁵ Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
⁶ Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA; Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. Electronic address: [email protected].

Abstract

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

Substances

Receptors, Antigen, T-Cell

Abstract

Publication types

MeSH terms

Substances

Grants and funding