REGULATION OF NK CELL FUNCTIONS BY TGF-BETA-1

The contribution of exogenous and endogenous TGF-beta 1 to human perip heral blood NK cell proliferation and activity in vitro was investigat ed. Exogenous bioactive TGF-beta 1 inhibited NK cell DNA synthesis and production of IFN-gamma, TNF-alpha, and granulocyte-macrophage CSF (G M-CSF) by NK cultures consisting of >98% CD56(+) cells. The cytotoxic activity of NK cells was also weakly inhibited by exogenous TGF-beta 1 . All TGF-beta 1-induced inhibitory effects occurred in the absence an d presence of the NK cell-activating cytokines IFN-alpha, IL-2, and IL -12. Unstimulated NK cell cultures expressed steady state TGF-beta 1 m RNA detected by Northern blot analysis and produced TGF-beta protein ( 1.6 ng/ml), as determined by ELISA. When NK cell proliferation was ind uced by IL-2, IL-12, IFN-alpha, or a combination of IL-2 and IL-12, ex pression of TGF-beta 1 mRNA and protein was moderately and consistentl y reduced by approximately 20%, as compared with unstimulated control cultures. Unstimulated and rapidly proliferating NK cell cultures secr eted primarily latent TGF-beta into their culture medium, as determine d by the Mv1 Lu bioassay. These results indicate that, in vitro, endog enous NK cell-derived TGF-beta 1 has no negative autocrine effect upon activation of NK cells by various cytokines.