Transcriptional Control of Dendritic Cell Development

Abstract

The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow.

Keywords: common dendritic progenitor; dendritic cell; lineage commitment; transcription factors.

Figure 1. Dendritic cell subsets serve distinct immune effector modules

Transcription factor dependencies identify four subsets of DC whose actions are directed primarily toward distinct immune effector modules. Irf8+ DCs comprise plasmacytoid DC (pDC) and one branch of classical DC (cDC). Irf4+ DCs are heterogeneous by surface markers, but display at least two transcriptional programs directed at different types of immune responses.

Figure 2. Correspondence between murine and human DC subsets

Selected markers of the indicated cell types are shown for mouse (blue) and human (pink). Markers shared between mouse and human DCs are indicated by the overlap (purple).

Figure 3. Bias in lineage potential of LMPPs revealed by cell bar-coding

a) An abbreviated schematic for stages of differentiation of an LMPP (blue) through two progenitor stages (red, yellowa) into dendritic cell (DC), monocyte (M), or lymphoid lineages (T, B). b) The fate history of an individual LMMP cell that exhibits clonal bias for DC lineages. c) The fate history of an LMMP clone showing combined monocyte and lymphoid potential.

Figure 4. Cell cycle regulation by PU.1 promotes myeloid divergence

PU.1 can act to decrease the rate of cell division. Because PU.1 is relatively stable, long interphase promoted the accumulation of PU.1 protein, which then more efficiently acts to reduce proliferation. Rapid division of lymphoid progenitors prevents PU.1 levels from crossing a threshold (dashed line) sufficient for positive feedback by PU.1.

Figure 5. Stages and transcription factors for DC development

A scheme showing myeloid lineage development from the CMP, indicating transcription factors required for particular transitions between stages. Although unresolved, we show a scheme with GMP and MDP divergence from the CMP. Commitment to Irf8 and Irf4 branches of cDCs can occur in the bone marrow. Relative levels of cKit of progenitors is indicated by vertical position.