Journal Article

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

Pala, Francesca, Fei, Lijiang, Boehme, Lena, Prigmore, Elena, Beuschel, Rebecca T., Dabrowska, Monika, Kreins, Alexandra Y., Crossland, David, He, Xiaoling, Teichmann, Sarah A., Wachter, Brianna T., Van Hulle, Jolien, Tuck, Elizabeth, Predeus, Alexander V., Marioni, John C., Chipampe, Nana-Jane, Putteman, Tom, Tudor, Catherine, Van Nieuwerburgh, Filip, Germain, Ronald N., Davies, E Graham, Uhlmann, Virginie, Suo, Chenqu, Amsalem, Oren, Perera, Shani, Notarangelo, Luigi D., Kedlian, Veronika R., Kleshchevnikov, Vitalii, Radtke, Andrea J., Engelbert, Justin, De Rita, Fabrizio, Bayraktar, Omer Ali, Patel, Minal, Polanski, Krzysztof, To, Ken, Barker, Roger A., Dann, Emma, Yayon, Nadav, Taghon, Tom, Haniffa, Muzlifah A., Bosticardo, Marita, Richardson, Laura, Koplev, Simon, Stephenson, Emily, Prete, Martin

2024

Overview

T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection 1 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/31 / 13/51 / 14 / 14/1 / 14/105 / 14/32 / 14/34 / 14/35 / 14/63 / 38 / 38/35 / 38/39 / 38/71 / 38/91 / 45 / 631/114/2397 / 631/114/2401 / 631/114/794 / 631/136/232/2058 / 631/250/2152/1566/2493 / Annotations / Atlases as Topic / CD4 antigen / CD4-Positive T-Lymphocytes - cytology / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / Cell Lineage / Corpuscles / Cytokines / Cytokines - metabolism / Data Analysis / Data Curation / Developmental stages / Epithelial cells / Epithelial Cells - cytology / Epithelial Cells - metabolism / Epithelium / Fetal Development / Fetuses / Genomics / Humanities and Social Sciences / Humans / Image resolution / Infant, Newborn / Lymphocytes / Lymphocytes T / Male / Morphology / multidisciplinary / Organ Specificity / Pediatrics / Postpartum period / Progenitor cells / Proteins / Science / Science (multidisciplinary) / Single-Cell Analysis / Spatial data / T cell receptors / Thymic involution / Thymocytes - cytology / Thymocytes - metabolism / Thymus / Thymus gland / Thymus Gland - cytology / Thymus Gland - embryology / Transcriptome / Transcriptomics