Transforming growth factor-{beta} inhibits IL-4 and IFN-{gamma} production by stimulated human T cells

The present study investigates the effect of transforming growthfactor (TGF-ß on the production of IL-4 and IFN- bythe leukemia T_h0 type cell line HUT78, by freshly Isolated humanT cells, and by antigen specific human T cell clones. We foundthat IL-4 and IFN-ß, but not IL-2, production by stimulatedHUT78 cells was inhibited by TGF-ß1. TGF-ß1also reduced the accumulation of IL-4 and IFN- specific mRNAin stimulated HUT78 cells. However, IL-2 and IL-7 co-stimulatedIL-4 and IFN- production, whereas IL-1, IL-3, IL-5, IL-6, IL-8,tumor necrosis factor- or granulocyte macrophage colony stimulatingfactor had no effect. Because IL-2 is an Important helper cytokinefor the production of IL-4 and IFN-, we investigated whethersignal transductlon through the IL-2 receptor is Impaired byTGF-ß1. We found that tyrosine phosphorylatlon inresponse to IL-2 In HUT78 cells was strongly inhibited by ashort prelncubatlon with TGF-ß1. Evidence for an antagonisticrole for TGF-ß1 and IL-2 comes from the finding thathigh doses of IL-2 could partially overcome TGF-ß1mediated inhibition of IL-4 and IFN- production. Similar toIts effect on HUT78 cells, TGF-ß1 also inhibited IL-4and IFN- production by freshly Isolated T cells as well as byhuman T cell clones. Taken together, our experiments show thatthe IL-2 dependent cytokines IL-4 and IFN- are both negativelycontrolled by TGF-ß under conditions where IL-2 productionIs unaffected by a mechanism which partially involves an inhibitionof IL-2/1L-2R signal transductlon. These data Identify TGF-ßand IL-2 as mutual antagonists in the regulation of IL-4 andIFN- production.