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Cell Stem Cell. 2019 Jan 4. pii: S1934-5909(18)30601-5. doi: 10.1016/j.stem.2018.12.011. [Epub ahead of print]

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

Author information

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: gcrooks@mednet.ucla.edu.

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

PMID:
30661959
DOI:
10.1016/j.stem.2018.12.011

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