Classical and monocyte-derived DCs require distinct transcriptional programs for cross-presentation.

Classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs) cross-present cell associated antigens, but whether these cells use a universal program for this process is unknown. In examining the requirements for cross-presentation by Mo-DCs, we discovered that TremL4 identifies two Ly-6C hi monocyte populations, of which only Ly-6C hi TremL4 − monocytes can differentiate into Zbtb46 + Mo-DCs in response to GM-CSF and IL-4 in vitro . By contrast, Ly-6C hi TremL4 + monocytes lost Mo-DC potential and instead were committed to development of Ly-6C lo TremL4 + monocytes. Further, we found that differentiation of monocytes with GM-CSF required addition of IL-4 to generate Zbtb46 + Mo-DCs that cross-presented as efficiently as CD8α + cDCs in vitro. However, unlike CD8α + cDCs, Mo-DCs required only IRF4, and not Batf3, to cross-present cell-associated antigens. Further, Irf4 − / − monocytes treated with GM-CSF and IL-4 could not differentiate into Zbtb46 + Mo-DCs, and instead developed into macrophages. Thus, distinct transcriptional programs are used by CD8α + cDCs and Mo-DCs for cross-presentation which may drive different antigen-processing pathways.