CD8− and CD8+ dendritic cells (DCs) are distinct subsets of mouse splenic accessory cells with opposite but flexible programs of Ag presentation, leading to immunogenic and tolerogenic responses, respectively. In this study, we show that the default tolerogenic function of CD8+ DCs relies on autocrine TGF-β, which sustains the activation of IDO in response to environmental stimuli. CD8− DCs do not produce TGF-β, yet externally added TGF-β induces IDO and turns those cells from immunogenic into tolerogenic cells. The acquisition of a suppressive phenotype by CD8− DCs correlates with activation of the PI3K/Akt and noncanonical NF-κB pathways. These data are the first to link TGF-β signaling with IDO in controlling spontaneous tolerogenesis by DCs.