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Definition of Natural Killer cell heterogeneity in humans and mice by high-throughput single-cell RNA sequencing

ABSTRACT: Natural Killer (NK) cells are innate lymphoid cells (ILCs) involved in antimicrobial and antitumoral responses. Several NK cell subsets have been reported in humans and mice, but their heterogeneity across organs and species remains poorly characterized. We assessed the diversity of human and mouse NK cells by single-cell RNA sequencing on thousands of individual cells isolated from spleen and blood. Unbiased transcriptional clustering revealed two distinct signatures differentiating between splenic and blood NK cells. This analysis at single-cell resolution identified three subpopulations in mouse spleen and four in human spleen, and two subsets each in mouse and human blood. A comparison of transcriptomic profiles within and between species highlighted the similarity of the two major subsets, NK1 and NK2, across organs and species. This unbiased approach provides new insight into the biology of NK cells and establishes a rationale for the translation of mouse studies to human physiology and disease.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE119562 | GEO | 2018/09/07

REPOSITORIES: GEO

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Project description:Dendritic cells (DCs) are a complex group of cells which play a critical role in vertebrate immunity. Spleen or lymph node resident DCs are subdivided into conventional DC (cDC) subsets (CD11b and CD8alpha in mouse; BDCA1 and BDCA3 in man) and plasmacytoid DCs (pDCs). It is currently unclear if these various DC populations belong to a unique hematopoietic lineage and if the subsets identified in the mouse and human systems are evolutionary homologs. To bring novel insights into these questions, we sought conserved genetic signatures for these DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes. We show through clustering analysis that all spleen resident DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionary conserved in all these DC subsets. Moreover we identify a large gene expression program shared between mouse and human plasmacytoid DCs, and smaller conserved profiles shared between mouse and human cDC subsets. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs (IKDCs) and lin-CD16+HLA-DR+ cells, which have both been claimed to be DCs, and show that these cells are more closely linked to NK or myeloid cells, respectively. Our study thus provides a unique resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs. Experiment Overall Design: This study includes data from cell sort purified dendritic cells, B cells, NK cells, and CD8 T cells. 2 or 3 independent replicates were made for each cell type. The genearray was performed in an attempt to investigate the relationships between DCs subsets and with other leukocytes, in mouse, in human, and between these 2 species. To this end, public data for mouse CD4 T cells and macrophages, as well as public data for human leukocyte subsets were also used in the analysis. The results have led to the identification of specific transcriptional programs conserved between human and mouse dendritic cell subsets.

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Definition of Natural Killer cell heterogeneity in humans and mice by high-throughput single-cell RNA sequencing

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