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

• 成果类型: Article
• 署名作者: Yayon, Nadav; Kedlian, Veronika R.; Boehme, Lena; Suo, Chenqu; Wachter, Brianna T.; Beuschel, Rebecca T.; Amsalem, Oren; Polanski, Krzysztof; Koplev, Simon; Tuck, Elizabeth; Dann, Emma; Van Hulle, Jolien; Perera, Shani; Putteman, Tom; Predeus, Alexander V.; Dabrowska, Monika; Richardson, Laura; Tudor, Catherine; Kreins, Alexandra Y.; Engelbert, Justin; Stephenson, Emily; Kleshchevnikov, Vitalii; De Rita, Fabrizio; Crossland, David; Bosticardo, Marita; Pala, Francesca; Prigmore, Elena; Chipampe, Nana-Jane; Prete, Martin; Fei, Lijiang; To, Ken; Barker, Roger A.; He, Xiaoling; Van Nieuwerburgh, Filip; Bayraktar, Omer Ali; Patel, Minal; Davies, E. Graham; Haniffa, Muzlifah A.; Uhlmann, Virginie; Notarangelo, Luigi D.; Germain, Ronald N.; Radtke, Andrea J.; Marioni, John C.; Taghon, Tom; Teichmann, Sarah A.
• 署名单位: Wellcome Trust Sanger Institute; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Ghent University; University of Cambridge; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Division of Intramural Research (DIR); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID); Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of London; University College London; Newcastle University - UK; Newcastle University - UK; Newcastle Freeman Hospital; University of Cambridge; University of Cambridge; Ghent University; Ghent University; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Newcastle University - UK; Newcastle Upon Tyne Hospitals NHS Foundation Trust; Newcastle University - UK; CRUK Cambridge Institute; University of Cambridge; Cancer Research UK; University of Cambridge
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5315
• DOI: 10.1038/s41586-024-07944-6
• 发表日期: 2024-11-21
• 关键词: hassalls corpuscles; t-cells; differentiation; progenitor; reveals; COMMITMENT; DYNAMICS

摘要

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. A quantitative morphological framework for the human thymus reveals the establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions in fetal and paediatric thymic development.