The developmental relationship between monocytes, dendritic cells (DCs), and macrophages has been well defined in mice, but human DC development is less well understood and has been hampered by the lack of a suitable culture system. Now, two papers published in this issue describe a novel in vitro culture system for human DC progenitors and the use of this system to elucidate the pathway of human DC development.
The extent to which mouse studies are useful to understand the human immune system is debatable. One expects—and observes—important similarities, but there are also differences in the way the building blocks of the immune system are assembled in different species of vertebrates that have evolved in different contexts and milieus, and with different lifespans. Laboratory mice, maintained as inbred strains under selected housing conditions, are amendable to controlled genetic studies. However, genetic and environmental variations are difficult to control in human studies, and experimental limitations make it difficult to assess whether “mouse” immunology “works” in humans.
The two studies in this issue, by Lee et al. and Breton et al., represent an important advance in the DC field. The work describes, at the population and single cell level, a hierarchy of human myeloid precursors that closely parallel the hierarchy in the mouse bone marrow and blood. The authors used a combination of technically impressive qualitative and quantitative approaches, including in vitro differentiation of human hematopoietic precursors cultured on a stromal cell line with defined sets of cytokines, in vivo “cultures” of human precursors in immunodeficient NOD-scid γ mice, and observational studies in humans. This allowed them to map out the development of monocytes, conventional DCs (cDCs), and plasmacytoid DCs (pDCs), and the sequential relationship between the different precursor populations. They showed that a granulocyte-monocyte-DC progenitor (hGMDP) develops into a monocyte-DC progenitor (hMDP), which itself differentiates into monocytes and into a common DC progenitor (hCDP) that produces the three major human DC subsets (CD1c+ cDCs, CD141+ cDCs, and pDCs). Furthermore, they report the identification of an immediate DC precursor (hpre-cDC) that originates from the hCDP, circulates in the human blood, and increases in response to plasma levels of the cytokine FLT3.
These results are a significant advance in the field. They illustrate the similarities between mice and humans regarding the development of monocytes, cDCs, and pDCs, and provide a guide—and experimental systems—to further interrogate the genetic and molecular control of human monocyte/DC development and their functions in disease. It is possible to imagine that DC-based therapy may benefit from knowledge of the “real thing.”