Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells

Fabian Klein, Clara Veiga-Villauriz, Anastasiya Börsch, Stefano Maio, Sam Palmer, Fatima Dhalla, Adam E. Handel, Saulius Zuklys, Irene Calvo-Asensio, Lucas Musette, Mary E. Deadman, Andrea J. White, Beth Lucas, Graham Anderson and Georg A. Holländer ()
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Fabian Klein: University of Oxford
Clara Veiga-Villauriz: University of Oxford
Anastasiya Börsch: University of Basel
Stefano Maio: University of Oxford
Sam Palmer: University of Oxford
Fatima Dhalla: University of Oxford
Adam E. Handel: University of Oxford
Saulius Zuklys: University of Basel and University Children’s Hospital Basel
Irene Calvo-Asensio: University of Basel and University Children’s Hospital Basel
Lucas Musette: University of Basel and University Children’s Hospital Basel
Mary E. Deadman: University of Oxford
Andrea J. White: University of Birmingham
Beth Lucas: University of Birmingham
Graham Anderson: University of Birmingham
Georg A. Holländer: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The network of thymic stromal cells provides essential niches with unique molecular cues controlling T cell development and selection. Recent single-cell RNA sequencing studies have uncovered previously unappreciated transcriptional heterogeneity among thymic epithelial cells (TEC). However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here, using massively parallel flow cytometry and machine learning, we deconvoluted known TEC phenotypes into novel subpopulations. Using CITEseq, these phenotypes were related to corresponding TEC subtypes defined by the cells’ RNA profiles. This approach allowed the phenotypic identification of perinatal cTEC and their physical localisation within the cortical stromal scaffold. In addition, we demonstrate the dynamic change in the frequency of perinatal cTEC in response to developing thymocytes and reveal their exceptional efficiency in positive selection. Collectively, our study identifies markers that allow for an unprecedented dissection of the thymus stromal complexity, as well as physical isolation of TEC populations and assignment of specific functions to individual TEC subtypes.

Date: 2023
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DOI: 10.1038/s41467-023-39722-9

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