IL-9 PRODUCTION OF NAIVE CD4(-CELLS DEPENDS ON IL-2, IS SYNERGISTICALLY ENHANCED BY A COMBINATION OF TGF-BETA AND IL-4, AND IS INHIBITED BYIFN-GAMMA() T)

Dense CD4(+) T cells isolated from naive mice produce only trace amoun ts of IL-9 when stimulated by immobilized anti-CD3 in combination with anti-CD28 Abs. In this situation, IL-9 production is significantly st imulated by TGF-beta and further enhanced by the addition of IL-4, whi ch, by itself, has only a minimal influence. IFN-gamma was found to in hibit the enhancing effect of IL-4. However, increasing amounts of IL- 4 in the presence of a constant concentration of IFN-gamma could overc ome the inhibitory activity of IFN-gamma. The application of CD4(+) T cells isolated from IL-2 knockout mice unequivocally revealed that IL- 2 is essential for the production of IL-9 by T cells. In addition, the use of T cells from IL-4 knockout mice elucidated that the basic (IL- 2 + TGF-beta) mediated IL-9 production is independent of IL-4. Therefo re, our results demonstrate that optimal IL-9 production of naive dens e CD4(+) T cells is positively regulated at different levels: 1) by IL -2, which is essential for IL-9 secretion; 2) followed by TGF-beta, wh ich promotes a considerable increase in IL-9 production above the leve l induced by IL-2; and 3) finally, by IL-4, which requires the presenc e of IL-2 and TGF-beta to strongly enhance the production of IL-9. IFN -gamma inhibits the production of IL-9 mainly at the level of IL-4 by neutralizing the effect of this cytokine.