Jaeyop Lee,1,* Gaelle Breton,2,* Thiago Yukio Kikuchi Oliveira,2 Yu Jerry Zhou,1 Arafat Aljoufi,1 Sarah Puhr,1 Mark J. Cameron,4 Rafick-Pierre Sekaly,4 Michel C. Nussenzweig,2,3,** and Kang Liu1,**
1Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032
2Laboratory of Molecular Immunology and 3Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065
4Case Western Reserve University, Cleveland, OH 44106
* J. Lee and G. Breton contributed equally to this paper.
** K. Liu and M.C. Nussenzweig contributed equally to this paper.
CORRESPONDENCE Kang Liu OR Michel C. Nussenzweig
Abstract
In mice, two restricted dendritic cell (DC) progenitors, macrophage/dendritic progenitors (MDPs) and common dendritic progenitors (CDPs), demonstrate increasing commitment to the DC lineage, as they sequentially lose granulocyte and monocyte potential, respectively. Identifying these progenitors has enabled us to understand the role of DCs and monocytes in immunity and tolerance in mice. In humans, however, restricted monocyte and DC progenitors remain unknown. Progress in studying human DC development has been hampered by lack of an in vitro culture system that recapitulates in vivo DC hematopoiesis. Here we report a culture system that supports development of CD34+ hematopoietic stem cell progenitors into the three major human DC subsets, monocytes, granulocytes, and NK and B cells. Using this culture system, we defined the pathway for human DC development and revealed the sequential origin of human DCs from increasingly restricted progenitors: a human granulocyte-monocyte-DC progenitor (hGMDP) that develops into a human monocyte-dendritic progenitor (hMDP), which in turn develops into monocytes, and a human CDP (hCDP) that is restricted to produce the three major DC subsets. The phenotype of the DC progenitors partially overlaps with granulocyte-macrophage progenitors (GMPs). These progenitors reside in human cord blood and bone marrow but not in the blood or lymphoid tissues.