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

Author

Listed:
  • 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
    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
    University of Basel and University Children’s Hospital Basel
    ETH Zurich)

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.

Suggested Citation

  • 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 , 2023. "Combined multidimensional single-cell protein and RNA profiling dissects the cellular and functional heterogeneity of thymic epithelial cells," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39722-9
    DOI: 10.1038/s41467-023-39722-9
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    References listed on IDEAS

    as
    1. Beth Lucas & Andrea J. White & Emilie J. Cosway & Sonia M. Parnell & Kieran D. James & Nick D. Jones & Izumi Ohigashi & Yousuke Takahama & William E. Jenkinson & Graham Anderson, 2020. "Diversity in medullary thymic epithelial cells controls the activity and availability of iNKT cells," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Corey N. Miller & Irina Proekt & Jakob Moltke & Kristen L. Wells & Aparna R. Rajpurkar & Haiguang Wang & Kristin Rattay & Imran S. Khan & Todd C. Metzger & Joshua L. Pollack & Adam C. Fries & Wint W. , 2018. "Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development," Nature, Nature, vol. 559(7715), pages 627-631, July.
    3. Anja Nusser & Sagar & Jeremy B. Swann & Brigitte Krauth & Dagmar Diekhoff & Lesly Calderon & Christiane Happe & Dominic Grün & Thomas Boehm, 2022. "Developmental dynamics of two bipotent thymic epithelial progenitor types," Nature, Nature, vol. 606(7912), pages 165-171, June.
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