Flt3-ligand and granulocyte colony-stimulating factor mobilize distinct human dendritic cell subsets in vivo

Dendritic tells (DCs) have a unique ability to stimulate naive T cells. Recent evidence suggests that distinct DC subsets direct different classes of immune responses in vitro and in vivo, In humans, the monocyte-derived CD11c(+) DCs induce T cells to produce Th1 cytokines in vitro, whereas the CD11c(-) plasmacytoid T cell-derived DCs elicit the production of Th2 cytokines. In this paper we report that administration of either Flt3-1igand (FL) or G-CSF to healthy human volunteers dramatically increases distinct DC subsets, or DC precursors, in the blood. FL increases both the CD11c(+) DC subset (48-fold) and the CD11c(-) IL-3R(+) DC precursors (13-fold). In contrast, G-CSF only increases the CD11c(-) precursors (>7-fold). Freshly sorted CD11c(+) but not CD11c(-) cells stimulate CD4(+) T cells in an allogeneic MLR, whereas only the CD11c(-) cells can be induced to secrete high levels of IFN-alpha, in response to influenza virus. CD11c(+) and CD11c(-) cells can mature in vitro with GM-CSF + TNF-alpha or with IL-3 + CD40 ligand, respectively. These two subsets up-regulate MHC class II costimulatory molecules as well as the DC maturation marker DC-lysosome-associated membrane protein, and they stimulate naive, allogeneic CD4(+) T cells efficiently, These two DC subsets elicit distinct cytokine profiles in CD4(+) T cells, with the CD11c(-) subset inducing higher levels of the Th2 cytokine IL-10, The differential mobilization of distinct DC subsets or DC precursors by in vivo administration of FL and G-CSF offers a novel strategy to manipulate immune responses in humans.