A Single-Cell Transcriptomic Atlas of Thymus Organogenesis Resolves Cell Types and Developmental Maturation

Publication date: Available online 5 June 2018
Source:Immunity
Author(s): Eric M. Kernfeld, Ryan M.J. Genga, Kashfia Neherin, Margaret E. Magaletta, Ping Xu, René Maehr
Thymus development is critical to the adaptive immune system, yet a comprehensive transcriptional framework capturing thymus organogenesis at single-cell resolution is still needed. We applied single-cell RNA sequencing (RNA-seq) to capture 8 days of thymus development, perturbations of T cell receptor rearrangement, and in vitro organ cultures, producing profiles of 24,279 cells. We resolved transcriptional heterogeneity of developing lymphocytes, and genetic perturbation confirmed T cell identity of conventional and non-conventional lymphocytes. We characterized maturation dynamics of thymic epithelial cells in vivo, classified cell maturation state in a thymic organ culture, and revealed the intrinsic capacity of thymic epithelium to preserve transcriptional regularity despite exposure to exogenous retinoic acid. Finally, by integrating the cell atlas with human genome-wide association study (GWAS) data and autoimmune-disease-related genes, we implicated embryonic thymus-resident cells as possible participants in autoimmune disease etiologies. This resource provides a single-cell transcriptional framework for biological discovery and molecular analysis of thymus organogenesis.

Graphical abstract

Teaser

Studies of thymus development typically lack single-cell resolution, use indirect readouts, or target narrow cell subsets. Using single-cell RNA sequencing during thymus organogenesis, Kernfeld and Genga et al. reveal cellular heterogeneity, interrogate developmental dynamics by direct observation, and pinpoint cell-specific expression patterns in stromal and blood populations.


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