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 Polański, 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 De 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 Haniffa, Virginie Uhlmann, Luigi D. Notarangelo, Ronald N. Germain, Andrea J. Radtke, John C. Marioni, Tom Taghon, Sarah A. Teichmann
Abstract
. 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.