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IL-12 and PGE2 are two immunomodulators produced by accessory cells (AC) in response to various stimuli. IL- 12 enhances IFN-gamma production by activated CD4+ T cells, whereas PGE2 inhibits the secretion of this cytokine. Because these AC-derived factors exert clearly opposite modulatory effects on IFN-gamma production, we examined 1) the net-IFN-gamma production of CD4+ T cells, stimulated in the presence of both IL-12 and PGE2, 2) the susceptibility of activated CD4+ T cells in time by adding these modulators at different timepoints after stimulation, and 3) the relative contributions of AC-derived IL-12 and PGE2 to IFN-gamma levels by stimulating CD4+ T cells in the presence of LPS-activated monocytes and inhibitors of PGE2 or IL-12. Here, we demonstrate that 1) IL-12 and PGE2 do not abrogate the modulatory action of each other and that the net-IFN-gamma production is determined by their concentration ratio, 2) T cells become insensitive to PGE2, whereas susceptibility to IL-12 is retained after activation, and 3) activated monocytes potently modulate IFN-gamma levels of stimulated CD4+ T cells via release of IL-12 and PGE2. The relative contributions of these AC-derived factors shift in time, due to different production kinetics, from a dominant IL-12 effect to a mixed IL-12/PGE2 effect. Because the net IFN-gamma production of CD4+ T cells is largely determined by the ratio of IL-12 and PGE2 at the timepoint of T cell activation, an imbalance in the production of these immunomodulators may, therefore, lead to immunologic dysfunction.