Sex-biased human thymic architecture guides T cell development through spatially defined niches

• Published in: Developmental cell
• Main Authors: Stankiewicz, Laura N, Salim, Kevin, Flaschner, Emily A, Wang, Yu Xin, Edgar, John M, Durland, Lauren J, Lin, Bruce Z B, Bingham, Grace C, Major, Matthew C, Jones, Ross D, Blau, Helen M, Rideout, Elizabeth J, Levings, Megan K, Zandstra, Peter W, Rossi, Fabio M V
• Format: Journal Article
• Language: English
• Published: United States 03.10.2024
• Subjects: postnatal; thymus; multidimensional imaging; spatial multiomics; CITE-seq; T cell; multiomics; ATAC-seq; CODEX; sex differences
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2024.09.011

Within the thymus, regulation of the cellular crosstalk directing T cell development depends on spatial interactions within specialized niches. To create a spatially defined map of tissue niches guiding human postnatal T cell development, we employed the multidimensional imaging platform co-detection by indexing (CODEX) as well as cellular indexing of transcriptomes and epitopes sequencing (CITE-seq) and assay for transposase accessible chromatin sequencing (ATAC-seq). We generated age-matched 4- to 5-month-old human postnatal thymus datasets for male and female donors, identifying significant sex differences in both T cell and thymus biology. We demonstrate a possible role for JAG ligands in directing thymic-like dendritic cell development, identify important functions of a population of extracellular matrix (ECM) fibroblasts, and characterize the medullary niches surrounding Hassall's corpuscles. Together, these data represent an age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, providing an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.