Yayon Nadav, Kedlian Veronika R, Boehme Lena, Suo Chenqu, Wachter Brianna, 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, Patel Minal, Davies Graham E, Haniffa Muzlifah A, Uhlmann Virginie, Notarangelo Luigi D, Germain Ronald N, Radtke Andrea J, Marioni John C, Taghon Tom, Teichmann Sarah A
Wellcome Sanger Institute, Cellular Genetics, Cambridge, United Kingdom.
European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, United Kingdom.
bioRxiv. 2023 Oct 27:2023.10.25.562925. doi: 10.1101/2023.10.25.562925.
T cells develop from circulating precursors, which enter the thymus and migrate throughout specialised sub-compartments to support maturation and selection. This process starts already in early fetal development and is highly active until the involution of the thymus in adolescence. To map the micro-anatomical underpinnings of this process in pre- vs. post-natal states, we undertook a spatially resolved analysis and established a new quantitative morphological framework for the thymus, the Cortico-Medullary Axis. Using this axis in conjunction with the curation of a multimodal single-cell, spatial transcriptomics and high-resolution multiplex imaging atlas, we show that canonical thymocyte trajectories and thymic epithelial cells are highly organised and fully established by post-conception week 12, pinpoint TEC progenitor states, find that TEC subsets and peripheral tissue genes are associated with Hassall's Corpuscles and uncover divergence in the pace and drivers of medullary entry between CD4 vs. CD8 T cell lineages. These findings are complemented with a holistic toolkit for spatial analysis and annotation, providing a basis for a detailed understanding of T lymphocyte development.
T细胞由循环前体发育而来，这些前体进入胸腺并在整个特殊的亚区室中迁移，以支持成熟和选择。这个过程在胎儿早期发育时就已开始，并且在青春期胸腺退化之前一直高度活跃。为了描绘出生前和出生后状态下这一过程的微观解剖学基础，我们进行了空间分辨分析，并为胸腺建立了一个新的定量形态学框架——皮质-髓质轴。结合多模态单细胞、空间转录组学和高分辨率多重成像图谱的整理，利用这个轴，我们表明典型的胸腺细胞轨迹和胸腺上皮细胞在受孕后第12周时高度有序且已完全建立，确定了胸腺上皮细胞祖细胞状态，发现胸腺上皮细胞亚群和外周组织基因与哈氏小体相关，并揭示了CD4与CD8 T细胞谱系在髓质进入的速度和驱动因素上的差异。这些发现得到了一个用于空间分析和注释的整体工具包的补充，为详细了解T淋巴细胞发育提供了基础。
