Sex-biased human thymic architecture guides T cell development through spatially defined niches
Laura N Stankiewicz, Kevin Salim, Emily A Flaschner, Yu Xin Wang, John M. Edgar, Lauren J. Durland, Bruce Z B Lin, Grace C. Bingham, Matthew C. Major, Ross D. Jones, Helen M. Blau, Elizabeth J. Rideout, Megan K. Levings, Peter W. Zandstra, Fábio Rossi
Abstract
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. • Spatial multiomics show sex differences in early postnatal T cell development • JAG1 skews early thymic progenitor development toward thymic dendritic cells • Thymocytes may self-select to support positive selection of αβT cells • Hassall’s corpuscles organize negative selection niches in the medulla Stankiewicz et al. generate a spatial multiomic resource of human postnatal thymus. Using a niche-centric approach, they show that sex-based differences in thymus biology and T cell development arise before puberty, providing an essential contribution to our understanding of the mechanisms underlying immune function and dysfunction in males and females.