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Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla

Author

Listed:
  • Beth Lucas

    (University of Birmingham)

  • Andrea J. White

    (University of Birmingham)

  • Fabian Klein

    (University of Oxford)

  • Clara Veiga-Villauriz

    (University of Oxford)

  • Adam Handel

    (University of Oxford
    University of Oxford)

  • Andrea Bacon

    (University of Birmingham)

  • Emilie J. Cosway

    (University of Birmingham)

  • Kieran D. James

    (University of Birmingham)

  • Sonia M. Parnell

    (University of Birmingham)

  • Izumi Ohigashi

    (Tokushima University)

  • Yousuke Takahama

    (Experimental Immunology Branch, NCI/NIH)

  • William E. Jenkinson

    (University of Birmingham)

  • Georg A. Hollander

    (University of Oxford
    University of Basel and University Children’s Hospital Basel
    ETH Zurich)

  • Wei-Yu Lu

    (University of Edinburgh)

  • Graham Anderson

    (University of Birmingham)

Abstract

The thymus medulla is a key site for immunoregulation and tolerance, and its functional specialisation is achieved through the complexity of medullary thymic epithelial cells (mTEC). While the importance of the medulla for thymus function is clear, the production and maintenance of mTEC diversity remains poorly understood. Here, using ontogenetic and inducible fate-mapping approaches, we identify mTEC-restricted progenitors as a cytokeratin19+ (K19+) TEC subset that emerges in the embryonic thymus. Importantly, labelling of a single cohort of K19+ TEC during embryogenesis sustains the production of multiple mTEC subsets into adulthood, including CCL21+ mTEClo, Aire+ mTEChi and thymic tuft cells. We show K19+ progenitors arise prior to the acquisition of multiple mTEC-defining features including RANK and CCL21 and are generated independently of the key mTEC regulator, Relb. In conclusion, we identify and define a multipotent mTEC progenitor that emerges during embryogenesis to support mTEC diversity into adult life.

Suggested Citation

  • Beth Lucas & Andrea J. White & Fabian Klein & Clara Veiga-Villauriz & Adam Handel & Andrea Bacon & Emilie J. Cosway & Kieran D. James & Sonia M. Parnell & Izumi Ohigashi & Yousuke Takahama & William E, 2023. "Embryonic keratin19+ progenitors generate multiple functionally distinct progeny to maintain epithelial diversity in the adult thymus medulla," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37589-4
    DOI: 10.1038/s41467-023-37589-4
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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. Alexander Raven & Wei-Yu Lu & Tak Yung Man & Sofia Ferreira-Gonzalez & Eoghan O’Duibhir & Benjamin J. Dwyer & John P. Thomson & Richard R. Meehan & Roman Bogorad & Victor Koteliansky & Yuri Kotelevtse, 2017. "Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration," Nature, Nature, vol. 547(7663), pages 350-354, July.
    3. Jennifer E. Cowan & Justin Malin & Yongge Zhao & Mina O. Seedhom & Christelle Harly & Izumi Ohigashi & Michael Kelly & Yousuke Takahama & Jonathan W. Yewdell & Maggie Cam & Avinash Bhandoola, 2019. "Myc controls a distinct transcriptional program in fetal thymic epithelial cells that determines thymus growth," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    4. 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.
    5. 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.
    6. Margaret E. Magaletta & Macrina Lobo & Eric M. Kernfeld & Hananeh Aliee & Jack D. Huey & Teagan J. Parsons & Fabian J. Theis & René Maehr, 2022. "Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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