Dendritic cell development: a choose-your-own-adventure story

Abstract

Dendritic cells (DCs) are essential components of the immune system and contribute to immune responses by activating or tolerizing T cells. DCs comprise a heterogeneous mixture of subsets that are located throughout the body and possess distinct and specialized functions. Although numerous defined precursors from the bone marrow and spleen have been identified, emerging data in the field suggests many alternative routes of DC differentiation from precursors with multilineage potential. Here, we discuss how the combinatorial expression of transcription factors can promote one DC lineage over another as well as the integration of cytokine signaling in this process.

Figure 1

Gene regulatory networks for cDC and pDC development. Shared gene regulation patterns in (a) and (b). PU.1 upregulates many factors important for DC development, including Id2, GM-CSFR, and Flt3L [26, 27]. The Flt3 pathway phosphorylates STAT3, which can upregulate/downregulate target genes [28]. (a) Gene regulation in cDCs. Id2 expression inhibits E2-2 via protein interaction. GM-CSFR phosphorylates STAT5, which can inhibit IRF-8 expression [29]. Batf3 upregulates E4BP4 [30]. Batf expression in CD8+ cDCs compensates for a lack of Batf3 [31]. E4BP4 negatively modulates IRF-4 expression [30]. (b) Gene regulation in pDCs. Ikaros upregulates Gfi1 [32], which can inhibit Id2 expression [33], allowing for E2-2 function. E2-2 binds to the promoter of Spi-B, IRF-7, and IRF-8 to upregulate gene expression [34]. A yet unidentified mechanism prevents the downstream events of GM-CSFR in pDCs, since STAT5 has been shown to downregulate IRF-8, which is required for pDC development. Proven interactions are indicated in solid bars. Hypothesized interactions are shown in dashed lines.

Figure 2

IRF-8 and Ikaros gene expression in early T cell precursors. Cell subsets were sorted, and qRT-PCR was performed as previously described [35]. Gene expression levels, as determined by qRT-PCR, were normalized to β-actin. Values shown are mean ± standard deviation (n = 3).