Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling

Abstract

Background: Dendritic cells (DCs) are a complex group of cells that play a critical role in vertebrate immunity. Lymph-node resident DCs (LN-DCs) are subdivided into conventional DC (cDC) subsets (CD11b and CD8alpha in mouse; BDCA1 and BDCA3 in human) 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 gain novel insights into these questions, we sought conserved genetic signatures for LN-DCs and in vitro derived granulocyte-macrophage colony stimulating factor (GM-CSF) DCs through the analysis of a compendium of genome-wide expression profiles of mouse or human leukocytes.

Results: We show through clustering analysis that all LN-DC subsets form a distinct branch within the leukocyte family tree, and reveal a transcriptomal signature evolutionarily conserved in all LN-DC subsets. Moreover, we identify a large gene expression program shared between mouse and human pDCs, and smaller conserved profiles shared between mouse and human LN-cDC subsets. Importantly, most of these genes have not been previously associated with DC function and many have unknown functions. Finally, we use compendium analysis to re-evaluate the classification of interferon-producing killer DCs, lin-CD16+HLA-DR+ cells and in vitro derived GM-CSF DCs, and show that these cells are more closely linked to natural killer and myeloid cells, respectively.

Conclusion: Our study provides a unique database resource for future investigation of the evolutionarily conserved molecular pathways governing the ontogeny and functions of leukocyte subsets, especially DCs.

Figure 1

Clustering of mouse and human leukocyte subsets. Hierarchical clustering with complete linkage was performed on the indicated cell populations isolated from: (a) mouse, (b) human, and (e) mouse and human. PCA was performed on the indicated cell populations isolated from: (c) mouse and (d) human. Mono, monocytes; neu, neutrophils.

Figure 2

FCM partitional clustering. FCM partitional clustering was performed on the mouse and human gene chip datasets. (a) FCM partitional clustering for mouse data. (b) FCM partitional clustering for human data. The color scale for relative expression values as obtained after log₁₀ transformation and median centering of the values across cell samples for each gene is given below the heat map.

Figure 3

Conserved genetic signatures between mouse and human DC subsets. Hierarchical with complete linkage clustering was performed on the indicated DC populations isolated from mouse and human.

Figure 4

Clustering of mouse IKDCs and human CD16 cells. Hierarchical clustering with complete linkage was performed on the indicated cell populations isolated from: (a) mouse and (b) human. Mono, monocytes; neu, neutrophils.

Figure 5

Clustering of in vitro GM-CSF derived DCs with monocytes, macrophages and LN-resident DCs. Hierarchical clustering with complete linkage was performed on the indicated cell populations isolated from: (a) mouse, (b) human, and (c) both. The heat maps used for illustration were selected as the two clusters of genes encompassing either Flt3 or Mafb, with a correlation cut-off for similarity of gene expression within each cluster at 0.8.