Myb-transformed hematopoietic cells as a model for monocyte differentiation into dendritic cells and macrophages

Immune induction is effected through the interaction of antigen‐presenting cells with specific receptors on the surface of thymus‐derived lymphocytes. Cells most able to ingest, process, and present antigen appear to be related to the mononuclear phagocyte/neutrophil series. For example dendritic cells (DC) can be found in colonies of GM‐CSF‐responsive bone marrow cells, and under experimental conditions are routinely expanded as a population in vitro from GM‐CSF‐responsive progenitor cells. To address the question of DC lineage and to determine what genes are involved in lineage commitment, we have generated a series of GM‐CSF‐responsive cell lines that can be induced to differentiate in a homogeneous manner in vitro. The cloned cell lines are derived from 12‐day fetal liver and are transformed with a truncated form of c‐myb, which lacks the normal autoregulatory sequences. As far as we know, these myb‐transformed hemopoietic cells (MTHC) differ from normal only in the unregulated expression of myb, a gene whose expression is obligatory for proliferation of hemopoietic cells. MTHC in the presence of TNF‐α and IL‐4 will differentiate into cells that have many of the properties of macrophages. When the same MTHC lines are exposed to TNF‐α in combination with IFN‐γ, the cells instead become DC. The differentiated DC are potent presenters of antigen in mixed lymphocyte reactions and of soluble antigen to specific T cell lines. Thus, cells with the properties of both macrophages and DC can be derived from a single type of GM‐CSF‐responsive progenitor cell. We have used this MTHC system to analyze differences in gene expression as the cells mature along the DC and macrophage pathways. A distinctive pattern of differentially expressed cDNAs is evident where macrophage‐specific cDNAs are homologous to genes encoding cytoskeletal and cell‐surface proteins, whereas the DC‐specific cDNAs are homologous to signaling, chemokine, and IFN‐γ‐inducible genes. We discuss the utility of MTHC in analyzing the relationships between DC and macrophages, and suggest that DC and macrophages represent extreme phenotypes in a spectrum of antigen handling cells that are somewhat interchangeable, depending on their immediate environment. J. Leukoc. Biol. 66: 217–223; 1999.