Single-Cell RNA-Seq Mapping of Human Thymopoiesis Reveals Lineage Specification Trajectories and a Commitment Spectrum in T Cell Development

• Published in: Immunity (Cambridge, Mass.) Mass.), 2020-06, Vol.52 (6), p.1105-1118.e9
• Main Authors: Le, Justin, Park, Jeong Eun, Ha, Vi Luan, Luong, Annie, Branciamore, Sergio, Rodin, Andrei S., Gogoshin, Grigoriy, Li, Fan, Loh, Yong-Hwee Eddie, Camacho, Virginia, Patel, Sweta B., Welner, Robert S., Parekh, Chintan
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; CD34 antigen; CD7 antigen; Cell culture; Cell cycle; Cell Differentiation - genetics; Cell Lineage - genetics; Cluster analysis; Clustering; Computational Biology; Differentiation; early thymic progenitors; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Gene sequencing; Genomics; High-Throughput Nucleotide Sequencing - methods; human thymopoiesis; Humans; Immunophenotyping; Lymphocytes; Lymphocytes T; Lymphopoiesis - genetics; Mapping; Mice; Population; Priming; Ribonucleic acid; RNA; Single-Cell Analysis; single-cell transcriptomes; Specifications; Stem cells; T-lineage commitment; T-lineage specification; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Thymocytes - cytology; Thymocytes - metabolism; Thymopoiesis; Thymus; Thymus gland; Transcription; Transcriptome
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.05.010

The challenges in recapitulating in vivo human T cell development in laboratory models have posed a barrier to understanding human thymopoiesis. Here, we used single-cell RNA sequencing (sRNA-seq) to interrogate the rare CD34+ progenitor and the more differentiated CD34– fractions in the human postnatal thymus. CD34+ thymic progenitors were comprised of a spectrum of specification and commitment states characterized by multilineage priming followed by gradual T cell commitment. The earliest progenitors in the differentiation trajectory were CD7– and expressed a stem-cell-like transcriptional profile, but had also initiated T cell priming. Clustering analysis identified a CD34+ subpopulation primed for the plasmacytoid dendritic lineage, suggesting an intrathymic dendritic specification pathway. CD2 expression defined T cell commitment stages where loss of B cell potential preceded that of myeloid potential. These datasets delineate gene expression profiles spanning key differentiation events in human thymopoiesis and provide a resource for the further study of human T cell development. [Display omitted] •CD34+ human thymic progenitors present a spectrum of specification and commitment states•Earliest progenitors are CD7– and exhibit stem-cell-like and T-primed transcriptomes•Loss of B-potential precedes that of myeloid and NK potentials during T-commitment•A CD34+ subpopulation of cells is primed for the plasmacytoid dendritic lineage Le et al. use single-cell RNA-seq to interrogate the rare CD34+ progenitor and the more differentiated CD34– fractions in the human postnatal thymus, identifying a CD34+ subpopulation primed for the plasmacytoid dendritic lineage and revealing multilineage priming followed by gradual commitment to the T cell lineage during the initial stages of thymopoiesis.