Palatine tonsils are secondary lymphoid organs representing the first line of immunological defense against inhaled or ingested pathogens. Here, we present a comprehensive census of cell types forming the human tonsil by applying single-cell transcriptome, epigenome, proteome and adaptive immune repertoire sequencing as well as spatial transcriptomics, resulting in an atlas of >357,000 cells. We provide a glossary of 121 annotated cell types and states, and disentangle gene regulatory mechanisms that drive cells through specialized lineage trajectories. Exemplarily, we stratify multiple tonsil-resident myeloid slancyte subtypes, establish a distant BCL6 superenhancer as locally active in both follicle-associated T and B cells, and describe SIX5 as a potentially novel transcriptional regulator of plasma cell maturation. Further, our atlas is a reference map to understand alterations observed in disease. Here, we discover immune-phenotype plasticity in tumoral cells and microenvironment shifts of mantle cell lymphomas (MCL). To facilitate such reference-based analysis, we develop HCATonsilData and SLOcatoR, a computational framework that provides programmatic and modular access to our dataset; and allows the straightforward annotation of future single-cell profiles from secondary lymphoid organs.
Despite the large number of publicly available single-cell datasets, there is a limited understanding of the distinct resident immune cells and their concomitant features in diverse human organs. To address this, we compiled a dataset of 114,275 CD45+ immune cells from 14 organs from healthy donors. Although the transcriptome of immune cells is constant across organs, organ-specific gene expression changes were detected revealing unique expression in certain organs (GTPX3 in kidney, DNTT and ACVR2B in thymus). These alterations are associated with different transcriptional factor activities and pathways including metabolism. TNF-alpha signaling through the NFkB pathway was found in various organs and immune compartments including distinct expression profiles of NFkB family genes and their target genes such as cytokines indicating their role in cell positioning. Taken together, immune cells not only protect the organs but also adapt to the host organ environment and contribute to its function and homeostasis.
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