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Comparative genomics analysis of mononuclear phagocyte subsets confirms similarity between lymphoid tissue-resident and dermal XCR1+ DCs in mouse and human and distinguishes them from Langerhans cells.

ABSTRACT: Dendritic cells (DC) are mononuclear phagocytes which exhibit a dendritic morphology and excel at naïve T cell activation. DC encompass several subsets initially identified by their expression of specific cell surface molecules and later shown to possess distinct functions. DC subset differentiation is guided by different transcription factors and cytokines. Identifying DC subsets is challenging as very few cell surface molecules are uniquely expressed on any one of these cell populations and conventional flow cytometry analysis using limited antigens is biased and potentially misleading. Moreover, the antigens currently used to define mononuclear phagocyte subsets vary depending on the tissue and animal species studied and even between laboratories. This has led to confusion in the definition of the identity of myeloid cell subsets across tissues and between species. Here we report a comparative genomics strategy that enables universal definition of DC subsets and other myeloid cell types across species. We have developed a novel, simple and user friendly software, BubbleGUM, which generates and integrates gene signatures for high throughput gene set enrichment analysis. We illustrate the use of BubbleGUM by re-analyzing 3 concatenated public datasets of blood/spleen and skin/cutaneous lymph node myeloid cell subsets in humans and in mice. This analysis demonstrates the equivalence between human and mouse skin XCR1+ DCs, and between mouse and human Langerhans cells.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE74316 | GEO | 2017/02/14

SECONDARY ACCESSION(S): PRJNA299655

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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Comparative genomics analysis of mononuclear phagocyte subsets confirms similarity between lymphoid tissue-resident and dermal XCR1+ DCs in mouse and human and distinguishes them from Langerhans cells.

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