A spatial human thymus cell atlas mapped to a continuous tissue axis

Nadav Yayon, Veronika R. Kedlian, Lena Boehme, Chenqu Suo, Brianna T. Wachter, Rebecca T. Beuschel, Oren Amsalem, Krzysztof Polanski, Simon Koplev, Elizabeth Tuck, Emma Dann, Jolien Van Hulle, Shani Perera, Tom Putteman, Alexander V. Predeus, Monika Dabrowska, Laura Richardson, Catherine Tudor, Alexandra Y. Kreins, Justin Engelbert, Emily Stephenson, Vitalii Kleshchevnikov, Fabrizio Rita, David Crossland, Marita Bosticardo, Francesca Pala, Elena Prigmore, Nana-Jane Chipampe, Martin Prete, Lijiang Fei, Ken To, Roger A. Barker, Xiaoling He, Filip Van Nieuwerburgh, Omer Ali Bayraktar, Minal Patel, E Graham Davies, Muzlifah A. Haniffa, Virginie Uhlmann, Luigi D. Notarangelo, Ronald N. Germain (), Andrea J. Radtke (), John C. Marioni (), Tom Taghon () and Sarah A. Teichmann ()
Additional contact information
Nadav Yayon: Wellcome Sanger Institute
Veronika R. Kedlian: Wellcome Sanger Institute
Lena Boehme: Ghent University
Chenqu Suo: Wellcome Sanger Institute
Brianna T. Wachter: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Rebecca T. Beuschel: National Institute of Allergy and Infectious Diseases (NIH)
Oren Amsalem: Harvard Medical School, Beth Israel Deaconess Medical Center
Krzysztof Polanski: Wellcome Sanger Institute
Simon Koplev: Wellcome Sanger Institute
Elizabeth Tuck: Wellcome Sanger Institute
Emma Dann: Wellcome Sanger Institute
Jolien Van Hulle: Ghent University
Shani Perera: Wellcome Sanger Institute
Tom Putteman: Ghent University
Alexander V. Predeus: Wellcome Sanger Institute
Monika Dabrowska: Wellcome Sanger Institute
Laura Richardson: Wellcome Sanger Institute
Catherine Tudor: Wellcome Sanger Institute
Alexandra Y. Kreins: Great Ormond Street Hospital for Children NHS Foundation Trust
Justin Engelbert: Newcastle University
Emily Stephenson: Wellcome Sanger Institute
Vitalii Kleshchevnikov: Wellcome Sanger Institute
Fabrizio Rita: Freeman Hospital
David Crossland: Freeman Hospital
Marita Bosticardo: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Francesca Pala: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Elena Prigmore: Wellcome Sanger Institute
Nana-Jane Chipampe: Wellcome Sanger Institute
Martin Prete: Wellcome Sanger Institute
Lijiang Fei: Wellcome Sanger Institute
Ken To: Wellcome Sanger Institute
Roger A. Barker: University of Cambridge
Xiaoling He: University of Cambridge
Filip Van Nieuwerburgh: Ghent University
Omer Ali Bayraktar: Wellcome Sanger Institute
Minal Patel: Wellcome Sanger Institute
E Graham Davies: Great Ormond Street Hospital for Children NHS Foundation Trust
Muzlifah A. Haniffa: Wellcome Sanger Institute
Virginie Uhlmann: European Bioinformatics Institute, European Molecular Biology Laboratory
Luigi D. Notarangelo: National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH)
Ronald N. Germain: National Institute of Allergy and Infectious Diseases (NIH)
Andrea J. Radtke: National Institute of Allergy and Infectious Diseases (NIH)
John C. Marioni: European Bioinformatics Institute, European Molecular Biology Laboratory
Tom Taghon: Ghent University
Sarah A. Teichmann: Wellcome Sanger Institute

Nature, 2024, vol. 635, issue 8039, 708-718

Abstract: Abstract T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection1. In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the microanatomical underpinnings of this process in pre- and early postnatal stages, we established a quantitative morphological framework for the thymus—the Cortico-Medullary Axis—and used it to perform a spatially resolved analysis. Here, by applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions by the beginning of the the second trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall’s corpuscles and identify divergence in the timing of medullary entry between CD4 and CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation and OrganAxis construction (TissueTag), which can be applied to any tissue.

Date: 2024
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DOI: 10.1038/s41586-024-07944-6

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