Abstract
Dendritic cells (DCs) are the major specialized antigen-presenting cells, thereby connecting innate and adaptive immunity. Because of their role in establishing adaptive immunity, they constitute promising targets for immunotherapy. Monocytes can differentiate into DCs in vitro in the presence of colony-stimulating factor 2 (CSF2) and interleukin 4 (IL4), activating four signalling pathways (MAPK, JAK/STAT, NFKB and PI3K). However, the downstream transcriptional programme responsible for DC differentiation from monocytes (moDCs) remains unknown. By analysing the scientific literature on moDC differentiation, we established a preliminary logical model that helped us identify missing information regarding the activation of genes responsible for this differentiation, including missing targets for key transcription factors (TFs). Using ChIP-seq and RNA-seq data from the Blueprint consortium, we defined active and inactive promoters, together with differentially expressed genes in monocytes, moDCs and macrophages, which correspond to an alternative cell fate. We then used this functional genomic information to predict novel targets for previously identified TFs. By integrating this information, we refined our model and recapitulated the main established facts regarding moDC differentiation. Prospectively, the resulting model should be useful to develop novel immunotherapies targeting moDCs.
Highlights
Dendritic cells (DCs) are the main antigen-presenting cells [1]
We focused on monocyte to moDC differentiation studies carried primarily on human cells, in particular on experiments where colony-stimulating factor 2 (CSF2) and interleukin 4 (IL4) were used alone or in combination in otherwise similar culture conditions
We predicted that TLR6 and TLR8 are regulated by STAT6, another essential transcription factors (TFs) in moDCs [7], we acknowledge that TLRs genes are not specific for moDCs; their transcriptional regulatory mechanisms are not fully understood and our results provided useful insights for future studies
Summary
Dendritic cells (DCs) are the main antigen-presenting cells [1]. By presenting antigens to the naïve lymphocytes, they initiate the immune response against various kinds of pathogens [2]. This capacity of DCs to activate the adaptive immune response opens interesting prospects for immunotherapies [3]. Circulating in the peripheral blood, monocytes are accessible and can be differentiated into dendritic cells, called moDCs (for monocyte-derived DCs), using an established protocol [4]. The protocol to differentiate monocytes into moDCs consists in cultivating monocytes with colony-stimulating factor 2 (CSF2) and interleukin 4 (IL4) [4,5]. It is known that CSF2 royalsocietypublishing.org/journal/rsfs Interface Focus 11: 20200061
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