ACCESSORY CELL-DERIVED IL-12 AND PROSTAGLANDIN E(2) DETERMINE THE IFN-GAMMA LEVEL OF ACTIVATED HUMAN CD4(-CELLS() T)

IL-12 and PGE(2) are two immunomodulators produced by accessory cells (AC) in response to various stimuli, IL-12 enhances IFN-gamma producti on by activated CD4(+) T cells, whereas PGE(2) inhibits the secretion of this cytokine. Because these AC-derived factors exert clearly oppos ite 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 PGE(2), 2) the susceptibility of activated CD4(+) T ce lls in time by adding these modulators at different timepoints after s timulation, and 3) the relative contributions of AC-derived IL-12 and PGE(2) to IFN-gamma levels by stimulating CD4(+) T cells in the presen ce of LPS-activated monocytes and inhibitors of PGE(2) or IL-12. Here, we demonstrate that 1) IL-12 and PGE(2) do not abrogate the modulator y action of each other and that the net-IFN-gamma production is determ ined by their concentration ratio, 2) T cells become insensitive to PG E(2), whereas susceptibility to IL-12 is retained after activation, an d 3) activated monocytes potently modulate IFN-gamma levels of stimula ted CD4(+) T cells via release of IL-12 and PGE(2). The relative contr ibutions of these AC-derived factors shift in time, due to different p roduction kinetics, from a dominant IL-12 effect to a mixed IL-12/PGE( 2) effect. Because the net IFN-gamma production of CD4(+) T cells is l argely determined by the ratio of IL-12 and PGE(2) at the timepoint of T cell activation, an imbalance in the production of these immunomodu lators may, therefore, lead to immunologic dysfunction.