Final maturation of dendritic cells is associated with impaired responsiveness to IFN-gamma and to bacterial IL-12 inducers: Decreased ability of mature dendritic cells to produce IL-12 during the interaction with Th cells

Activation of immature CD83(-) dendritic cells (DC) in peripheral tissues i nduces their maturation and migration to lymph nodes, Activated DC become p otent stimulators of Th cells and efficient inducers of Th1- and Th2-type c ytokine production. This study analyzes the ability of human monocyte-deriv ed CD1a(+) DC at different stages of IL-1 beta and TNF-alpha-induced matura tion to produce the major Th1-driving factor IL-12, DC at the early stages of maturation (2 and 4 h) produced elevated amounts of IL-12 p70 during int eraction with CD40 ligand-bearing Th cells or, after stimulation with the T cell-replacing factors, soluble CD40 ligand and IFN-gamma, The ability to produce IL-12 was strongly down-regulated at later time points, 12 h after the induction of DC maturation, and in fully mature CD83(+) cells, at 48 h, In contrast, the ability of mature DC to produce IL-6 was preserved or eve n enhanced, indicating their intact responsiveness to CD40 triggering. A re duced IL-12-producing capacity of mature DC resulted mainly from their impa ired responsiveness to IFN-gamma, a cofactor in CD40-induced IL-12 p70 prod uction. This correlated with reduced expression of IFN-gamma R (CD119) by m ature DC. In addition, while immature DC produced IL-12 and IL-6 after stim ulation with LPS or Staphylococcus aureus Cowan I strain, mature DC became unresponsive to these bacterial stimuli. Together with the previously descr ibed ability of IL-10 and PGE(2) to stably down-regulate the ability to pro duce IL-12 in maturing, but not in fully mature, DC, the current data indic ate a general resistance of mature DC to IL-12-modulating factors.