In Vivo Permanent Marking of Cells with RAG1 Activation History Demonstrates That Lymphoid and Myeloid Derived Dendritic Cells Operate an Identical Developmental Program after Their Lineage Commitment.

Abstract

Dendritic cells (DCs) have been shown to arise from both myeloid and lymphoid pathways, by evaluating the in vivo reconstituting potential of myeloid- and lymphoid-committed progenitor populations. However, evaluation of DC development after conventional adoptive transfer experiments may not correctly represent normal DC development including lineage contribution toward the formation of the DC pool. By crossing RAG1-Cre knockin with yellow fluorescence protein (YFP)-floxed reporter lines, we developed a mouse line in which cells with a history of RAG activation should be permanently marked with YFP as a result of lymphoid commitment. Lymphoid-derived DCs were successfully marked as YFP+ in vivo. We found that only ∼10% of conventional DCs (cDCs) and ∼20% of plasmacytoid DCs (pDCs) were YFP+, even in the thymus. This is a formal evidence that the majority of DCs in steady-state hematopoiesis originate from stages that have committed to the myeloid lineage. The lineage origin of DCs did not affect their functional abilities, including antigen-presentation and cytokine production. We then profiled the gene expression of the YFP+ and YFP- DCs at a genome wide level by DNA microarray analysis. Unexpectedly, the gene expression profiles of lymphoid and myeloid-derived DCs were virtually identical, irrespective of their organs. In contrast, the genetic programs were apparently different between splenic and thymic DCs, regardless of their lineage origin. Moreover, thymic DCs contained a number of more activated genes, such as MHC class II-related ones, as compared to splenic DCs. These results suggest that lymphoid and myeloid DCs might use a common developmental program that can be activated even after lymphoid or myeloid commitment. Thus, DCs are a unique cell population independent of other conventional lineage cells. Lineage-restricted DCs might be merged into an identical pool, distributed to various tissues, and finally fated by the microenvironment of their sites.