Transcription factor networks in dendritic cell development

Abstract

Dendritic cells (DCs) are a heterogeneous population within the mononuclear phagocyte system (MPS) that derive from bone marrow precursors. Commitment and specification of hematopoietic progenitors to the DC lineage is critical for the proper induction of both immunity and tolerance. This review summarizes the important cytokines and transcription factors required for differentiation of the DC lineage as well as further diversification into specific DC subsets. We highlight recent advances in the characterization of immediate DC precursors arising from the common myeloid progenitor (CMP). Particular emphasis is placed on the corresponding temporal expression of relevant factors involved in regulating developmental options.

Figure 1. The temporal expression of genes in DCs and their precursors

The expression of key surface markers used for the identification of mature dendritic cells (DCs) and their bone marrow precursors is depicted. In addition, the expression of important growth factors required for the development of DC subsets is shown.

Figure 2. Stages of DC development

DCs derive from bone marrow–resident hematopoietic progenitors. Following differentiation of the hematopoietic stem cell (HSC) into the common myeloid progenitor (CMP), alternate myeloid fates are extinguished in the subsequent macrophage-dendritic progenitor (MDP). Commitment to the DC lineage occurs at the next stage termed the common dendritic progenitor (CDP). The CDP has the potential to develop into both plasmacytoid dendritic cells (pDC) and conventional dendritic cells (cDC). This choice occurs as the CDP transitions into either of the intermediates for each lineage: the pre-pDC (not shown) or the pre-cDC. pDCs complete their maturation in the bone marrow and then circulate to secondary lymphoid organs through the blood. In contrast, pre-cDCs seed both lymphoid and non-lymphoid organs and undergo one final fate choice into either CD8⁺ or CD4⁺ DCs; or CD103⁺ or CD11b⁺ equivalents in the periphery, respectively. The developmental similarity between lymphoid-organ and peripheral DC subsets has been shown using mice deficient in the transcription factors Id2, IRF8, and Batf3. Additionally, monocytes can give rise to DCs in inflammatory settings although the transcriptional mechanism for this process is poorly characterized.

Figure 3. Transcription factor networks control DC development

A number of transcription factors regulate the commitment and survival of dendritic cells at various stages of development. However, the coordinated action of these factors with respect to one another as well as to relevant progenitor stages has not been well defined. One plausible network of these factors is depicted alongside the cellular stage in which they likely exert their functions. Solid arrows indicate connections that have been proven or suggested within original reports. Dotted arrows indicate hypothesized relationships.

Figure 4. CDPs are “pDC-primed.”

CDPs represent the last common precursor for both cDCs and pDCs, and thus a likely stage of specification into either lineage. This decision is dependent on a mutually antagonist balance between the transcription factors E2-2 and Id2. Gene expression analysis of progenitor populations reveals that CDPs express a number of pDC-specific transcription factors. Shown is the expression of pDC factors (E2-2, Bcl11a, and Runx2) in comparison to cDC factors (Id2, Batf3, and Bcl6). Expression of pDC factors and the lack of expression of cDC factors in the CDP points to a “default” pDC pathway during DC differentiation. Re-direction into the cDC lineage requires the induction of Id2 and repression of pDC factors in the pre-cDC.