A spatial human thymus cell atlas mapped to a continuous tissue axis
T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection<sup>1</sup>. 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.
Authors
- Tom Taghon (ORCID: https://orcid.org/0000-0002-5781-0288)
- Oren Amsalem (ORCID: https://orcid.org/0000-0002-8070-0378)
- Omer Ali Bayraktar (ORCID: https://orcid.org/0000-0001-6055-277X)
- Catherine Tudor (ORCID: https://orcid.org/0000-0003-2093-9683)
- Marita Bosticardo (ORCID: https://orcid.org/0000-0002-1771-4523)
- Vitalii Kleshchevnikov (ORCID: https://orcid.org/0000-0001-9110-7441)
- Justin Engelbert (ORCID: https://orcid.org/0009-0008-0796-6496)
- Sarah Amalia Teichmann (ORCID: https://orcid.org/0000-0002-6294-6366)
- Luigi Daniele Notarangelo (ORCID: https://orcid.org/0000-0002-8335-0262)
- Ken To (ORCID: https://orcid.org/0000-0001-9262-7190)
- Chenqu Suo (ORCID: https://orcid.org/0000-0002-8813-0875)
- Virginie Uhlmann (ORCID: https://orcid.org/0000-0002-2859-9241)
- Elena Prigmore (ORCID: https://orcid.org/0000-0001-8870-0316)
- Minal Patel
- Jolien Van Hulle (ORCID: https://orcid.org/0000-0001-8844-3700)
- Lena Boehme (ORCID: https://orcid.org/0000-0001-7593-7533)
- Andrea J. Radtke (ORCID: https://orcid.org/0000-0003-4379-8967)
- Emily Stephenson (ORCID: https://orcid.org/0000-0002-4244-4019)
- Simon Koplev (ORCID: https://orcid.org/0000-0002-8586-5614)
- Veronika R. Kedlian (ORCID: https://orcid.org/0000-0001-6563-0829)
- John C. Marioni (ORCID: https://orcid.org/0000-0001-9092-0852)
- Brianna T. Wachter (ORCID: https://orcid.org/0000-0002-2950-2683)
- Alexandra Y. Kreins (ORCID: https://orcid.org/0000-0001-8748-5837)
- Laura Richardson (ORCID: https://orcid.org/0000-0002-8075-3816)
- David Crossland (ORCID: https://orcid.org/0000-0003-3517-0483)
- Alexander V. Predeus (ORCID: https://orcid.org/0000-0002-2750-1599)
- Lijiang Fei (ORCID: https://orcid.org/0000-0002-2066-7297)
- Tom Putteman (ORCID: https://orcid.org/0000-0001-5098-4317)
- Rebecca T. Beuschel (ORCID: https://orcid.org/0000-0002-3882-457X)
- Muzlifah A. Haniffa (ORCID: https://orcid.org/0000-0002-3927-2084)
- Francesca Pala (ORCID: https://orcid.org/0000-0003-4537-9061)
- Martin Prete (ORCID: https://orcid.org/0000-0002-5946-821X)
- Shani Perera (ORCID: https://orcid.org/0000-0001-8021-2078)
- Xiaoling He (ORCID: https://orcid.org/0009-0004-1002-8418)
- Nadav Yayon (ORCID: https://orcid.org/0000-0002-7034-0524)
- Filip Van Nieuwerburgh (ORCID: https://orcid.org/0000-0001-8815-5485)
- Emma Dann (ORCID: https://orcid.org/0000-0002-7400-7438)
- Roger A. Barker (ORCID: https://orcid.org/0000-0001-8843-7730)
- Ronald N. Germain (ORCID: https://orcid.org/0000-0003-1495-9143)
- Nana-Jane Chipampe (ORCID: https://orcid.org/0000-0002-8802-0473)
- Fabrizio De Rita (ORCID: https://orcid.org/0000-0002-4717-4644)
- Krzysztof Polański (ORCID: https://orcid.org/0000-0002-2586-9576)
- Elizabeth J. Tuck (ORCID: https://orcid.org/0000-0002-1837-7549)
- Monika Dabrowska
- E. Graham Davies
Institutions
- National Institutes of Health (US)
- European Bioinformatics Institute (GB)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Great Ormond Street Hospital for Children NHS Foundation Trust (GB)
- Ghent University Hospital (BE)
- Cancer Research UK (GB)
- Freeman Hospital (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Ghent University (BE)
- Cancer Research UK Cambridge Center (GB)
- Cancer Research Institute Ghent (BE)
- NIHR Newcastle Biomedical Research Centre (GB)
- National Institute of Allergy and Infectious Diseases (US)
- Bioinformatics Institute (RU)
- Advanced Tissue (United States) (US)
- University College London (GB)
- Newcastle University (GB)
Publication Details
- Journal
- Nature
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41586-024-07944-6
- Citations
- 66
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 15.43
Funders
- Medical Research Council