A Cell Atlas of Human Thymic Development Defines T Cell Repertoire Formation
Summary
The interaction of T cells with various thymic cell types orchestrates the differentiation and selection of T cells, which takes place in the thymus. They counted the cells in the human thymus across the lifespan using single-cell RNA sequencing and reconstruct the trajectories of T cell differentiation and the kinetics of TCR recombination. In situ CD8aa+ T cell populations, thymic fibroblast subtypes, and activated dendritic cell states were all identified and located using this method. The genomic position and the kinetics of lineage commitment are also implicated in a bias in TCR recombination and selection. Together, their data offer a thorough atlas of the human thymus throughout life and a new understanding of the maturation of human T cells.
Fig.1 Graphical abstract. (Park, 2020)
Research Criteria
They used dissociated cells from the human thymus during development, childhood, and adulthood to perform single-cell RNA sequencing (scRNA-seq). They sampled 15 embryonic and fetal thymi from 7 to 17 post-conception weeks and nine postnatal thymi from pediatric and adult individuals. Diverse sorting schemes increased coverage of underrepresented cell populations. Single-molecule fluorescence in situ hybridization spatially localized cell states using marker genes from single-cell transcriptomes (smFISH). They generated single-cell data on postnatal mouse thymi and combined it with mouse datasets to compare humans and mice. Finally, they enriched TCR sequences for single-cell library generation to study human TCR repertoire recombination and selection bias.
Sample Type
Embryos and fetal thymus tissue at 7-17 weeks. Thymic tissue in children and adults. Mouse thymic tissue.
Result—Mapping the Human Thymus
The researchers sequenced single cells from 15 embryonic and fetal thymus tissues ranging in age from 7 to 17 weeks, as well as from 9 children and adults. The data was filtered to produce 255,901 single cells, yielding a detailed atlas of thymus development annotated with cell types and the identification of 42 cell subpopulations. Two new fibroblast subpopulations and two new epithelial cell subpopulations were identified, and their spatial location in the thymus was determined using in situ sequencing (RNA smFISH).
Fig.2 Cellular composition of the developing human thymus. (Park, 2020)
Result—Building T cell Developmental Trajectories
The developmental trajectory of T cells, including conventional and unconventional T cells, was constructed based on the single-cell transcriptome results, and a regulatory network of transcription factors related to T cell lineage development was drawn.
Fig.3 Thymic seeding of early thymic progenitors and T cell differentiation trajectory. (Park, 2020)
Result—TCR Recombination and Selection Preference
During the process of T cell receptor (TCR) formation, there appears to be a strong preference for the use of the V(D)J gene, as shown by the analysis of single-cell transcriptome and single-cell TCR sequencing data. This preference was validated in multiple T cell subpopulations. Because of the presence of this preference, the organism is able to react to a variety of different combinations of pMHC, which may have a significant impact on the way the organism reacts to antigens.
Fig.4 Intrinsic bias in human TCR repertoire formation and selection. (Park, 2020)
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Reference
- Park, J.E.; et al. A cell atlas of human thymic development defines T cell repertoire formation. Science. 2020, 364(6490): eaay3224.
