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Thymus Single-Cell Transcriptome Profile Elucidates T Cell Development

NEW YORK – A team of researchers from the UK and Belgium has developed a comprehensive, single-cell transcriptomic atlas of the human thymus, providing a high-resolution census of T cell development.
"We now have a very detailed understanding of how T cells form in healthy tissue," Ghent University Professor Tom Taghon, senior author on a study published Friday in Science, said in a statement. "We have been able to identify a similar population of precursor cells in the developing thymus and liver, and we believe that these precursors are important for initiating T cell development in the fetus, and for the establishment of a fully competent thymus organ."
The thymus is a critical organ for T cell development and T cell receptor (TCR) repertoire formation, which shapes adaptive immunity, the researchers wrote. T cell development in the thymus is spatially coordinated, and this process is orchestrated by diverse cell types in the thymic microenvironment. 
In order to create a comprehensive atlas of thymic cells across human life, the researchers performed single-cell RNA sequencing on dissociated cells from samples of human thymus during development, childhood, and adult life. They sampled 15 embryonic and fetal thymi spanning thymic developmental stages between seven and 17 post-conception weeks, as well as nine postnatal thymi from pediatric and adult individuals. 
After quality control including doublet removal, the researchers obtained a total of 138,397 cells from developing thymus and 117,504 cells from postnatal thymus. They annotated cell clusters into more than 40 different cell types or cell states.
To compare their findings in human thymus to mouse thymus, they then generated a comprehensive mouse thymus single-cell atlas of postnatal murine samples at four, eight, or 24 weeks old, and combined these data with a published prenatal mouse thymus scRNA-seq dataset. An integrative analysis of mature T cells from human and mouse showed that cell states were well mixed across species. The analysis showed that GNG4+ CD8αα+ T cells in humans were most similar to the mouse intraepithelial lymphocyte precursor type A. However, there were also highly differentially expressed genes between them, suggesting a potential difference in function. 
The researchers also investigated whether differential TCR repertoire bias existed between cell types by comparing the TCR repertoire of different cell types. They observed a clear separation of CD8+ T cells and other cell types, a trend that was consistent in all individual donor samples. This was largely similar to what they saw in naïve CD4+/CD8+ T cells isolated from peripheral blood. 
"We identified more than 50 different cell states in the human thymus," the authors wrote. "Human thymus cell states dynamically change in abundance and gene expression profiles across development and during pediatric and adult life."
The researchers also identified novel subpopulations of human thymic fibroblasts and epithelial cells and located them in situ. Further, they computationally predicted the trajectory of human T cell development from early progenitors in the hematopoietic fetal liver into diverse mature T cell types, and used this trajectory to construct a framework of putative transcription factors driving T cell fate determination. 
"Our single-cell transcriptome profile of the thymus across the human lifetime and across species provides a high-resolution census of T cell development within the native tissue microenvironment," they concluded. "Systematic comparison between the human and mouse thymus highlights human-specific cell states and gene expression signatures. Our detailed cellular network of the thymic niche for T cell development will aid the establishment of in vitro organoid culture models that faithfully recapitulate human in vivo thymic tissue."
In a statement, senior author and Newcastle University Professor Muzlifah Haniffa also noted that the thymus cell atlas could help researchers elucidate cellular signals of the developing thymus, "revealing which genes need to be switched on to convert early immune precursor cells into specific T cells. This is really exciting as in the future, this atlas could be used as a reference map to engineer T cells outside the body with exactly the right properties to attack and kill a specific cancer, creating tailored treatments for tumors."