Macrophages and myeloid dendritic cells (DCs) represent alternative differentiation options of bone marrow progenitors and blood monocytes. This choice profoundly influences the immune response under normal and pathological conditions, but the underlying transcriptional events remain unresolved. Here, we show that experimental activation of the transcription factors PU.1 and MafB in transformed chicken myeloid progenitors triggered alternative DC or macrophage fate, respectively. PU.1 activation also was instructive for DC fate in the absence of cytokines in human HL-60 cell-derived myeloid progenitor and monocyte clones. Differentiation of normal human monocytes to DCs led to a rapid increase of PU.1 to high levels that preceded phenotypic changes, but no MafB expression, whereas monocyte-derived macrophages expressed MafB and only moderate levels of PU.1. DCs inducing levels of PU.1 inhibited MafB expression in monocytes, which appeared to be required for DC specification, since constitutive MafB expression inhibited DC differentiation. Consistent with this, PU.1 directly bound to MafB, inhibited its transcriptional activity in macrophages, and repressed its ability to induce macrophage differentiation in chicken myeloid progenitors. We propose that high PU.1 activity favors DCs at the expense of macrophage fate by inhibiting expression and activity of the macrophage factor MafB. IntroductionDendritic cells (DCs) serve a crucial function in the immune system as the major antigen presenting cells with the unique ability to activate naive T cells, 1 a capacity that has made them the major target of therapeutic manipulation in vaccination and cancer immunotherapy protocols. 1 They can develop from myeloid progenitors in the bone marrow or circulating blood monocytes. 2 When exiting the blood stream, monocytes can give rise to inflammatory macrophages or to antigen presenting DCs. 3 A disturbance of this balance in favor of DC differentiation has been observed in autoimmune disease, 4 whereas tumors can skew it toward the macrophage option. 5 Cytokine conditions favoring outgrowth of DCs in vitro have been well defined in mouse and human cells, most commonly culture of bone marrow progenitors with granulocyte-macrophage colony-stimulating factor (GM-CSF), CD34 ϩ progenitors with GM-CSF and tumor necrosis factor ␣ (TNF␣), or stimulation of blood monocytes with GM-CSF and interleukin-4 (IL-4). 2 By contrast M-CSF, 5 5,[6][7][8][9][10]7 and interferon-␥ (IFN-␥) 8 favor macrophage differentiation at the expense of DC fate.In contrast to the cytokine requirements, the transcriptional events controlling the choice of macrophage versus DC fate have remained unresolved. Some transcription factor knockout mice show defects in DC differentiation 9,10 but also in other lineages, making it difficult to determine at what stage the differentiation block occurred. Certain transcription factor oncogenes have been shown to be capable of transforming DCs or their progenitors, but how this relates to the normal differentiation prog...

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