title: Generation of mature T cells from human hematopoietic stem and progenitor cells in artificial thymic organoids.
abstract: Studies of human T cell development require robust model systems that recapitulate the full span of thymopoiesis, from hematopoietic stem and progenitor cells (HSPCs) through to mature T cells. Existing in vitro models induce T cell commitment from human HSPCs; however, differentiation into mature CD3+TCR-αβ+single-positive CD8+or CD4+cells is limited. We describe here a serum-free, artificial thymic organoid (ATO) system that supports efficient and reproducible in vitro differentiation and positive selection of conventional human T cells from all sources of HSPCs. ATO-derived T cells exhibited mature naive phenotypes, a diverse T cell receptor (TCR) repertoire and TCR-dependent function. ATOs initiated with TCR-engineered HSPCs produced T cells with antigen-specific cytotoxicity and near-complete lack of endogenous TCR Vβ expression, consistent with allelic exclusion of Vβ-encoding loci. ATOs provide a robust tool for studying human T cell differentiation and for the future development of stem-cell-based engineered T cell therapies.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine (DGSOM), University of California Los Angeles (UCLA), Los Angeles, California, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Seet
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Chongbin
authors.initials: C
authors.lastname: He
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology (Caltech), Pasadena, California, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bethune
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Suwen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Chick
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Gschweng
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Immunology and Molecular Genetics, DGSOM, UCLA, Los Angeles, California, USA.|Division of Pediatric Hematology-Oncology, Department of Pediatrics, DGSOM, UCLA, Los Angeles, California, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California, USA.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology (Caltech), Pasadena, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.|Division of Pediatric Hematology-Oncology, Department of Pediatrics, DGSOM, UCLA, Los Angeles, California, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, California, USA.|Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, USA.
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
authors.affiliation: Department of Pathology and Laboratory Medicine, DGSOM, UCLA, Los Angeles, California, USA.
authors.forename: Amélie
authors.initials: A
authors.lastname: Montel-Hagen
mesh_terms: D001187:Artificial Organs; D001709:Biotechnology / Q000379:methods; D002454:Cell Differentiation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006801:Humans; D009940:Organoids / Q000166:cytology* / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology