Most previous studies have assumed that the maturation of a particular blood cell type downstream of hematopoietic stem cells follows a singular developmental route; therefore the identification of distinct hematopoietic progenitors with partially overlapping lineage potentials has led to considerable controversy. For example, common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs) both generate dendritic cells upon adoptive transfer in vivo. To determine the molecular mechanisms by which progenitors with partially overlapping lineage potentials arise, we examined the transcriptional changes that occur as lymphoid-primed multipotent progenitors (LMPPs) differentiate into CLPs, and as CMPs differentiate into common dendritic cell progenitors (CDPs). In both of these independent pathways, we determined that the expression of the transcription factor IRF8 was strongly induced. IRF8-/- mice showed reduced numbers of both CLPs and CDPs. Competitive bone marrow reconstitutions also demonstrated cell-intrinsic defects in the generation of CD8a- dendritic cells, previously reported to be normal in IRF8-/- mice. Microarray comparisons between dendritic cells derived from either wild type CMPs or CLPs demonstrated that these cells are identical. Thus, the asynchronous expression of IRF8 leads to the formation of progenitors with partially overlapping developmental potentials, which can resolve themselves to ultimately generate the same mature cell type.
- Copyright © 2011 by The American Association of Immunologists, Inc.