IL-12 INDUCES THE PRODUCTION OF IFN-GAMMA BY NEONATAL HUMAN CD4 T-CELLS

A major difference between ''naive'' and ''memory'' or ''effector'' Th cells is the spectrum of cytokines that they are capable of producing . After stimulation naive cells produce only IL-2, whereas memory cell s produce several cytokines including IFN-gamma and IL-4. Using umbili cal cord blood-derived CD4 T cells as a source of naive T cells, we fi rst report that these cells are capable of producing large amounts of IFN-gamma when cultured with low concentrations of IL-1 2. The respons e is time- and dose-dependent, and it is observed at the protein and m RNA levels. IL-1 2 also induces neonatal CD4 T cells to produce lympho toxin but not IL-2, TNF-alpha, or IL-4. The production of IFN-gamma by IL-1 2-stimulated neonatal T cells is associated with a small but sig nificant T cell activation evidenced by DNA synthesis and by the expre ssion of the activation markers CD25, CD71, and HLA-DR; moreover, it i s inhibited by hydrocortisone, cyclosporin A, and transforming growth factor-beta. The response to IL-12 is enhanced and is much more rapid when CD4 T cells are cultured in the presence of accessory cells or of exogenous IL-1, IL-2, or TNF-alpha. Using a three-step culture system , we next show that IL-12 induces the maturation of resting naive CD4 T cells into cells producing both IL-2 and IFN-gamma but not IL-4 upon stimulation with PMA and ionomycin. Endogenously produced IFN-gamma p lays a role in this IL-12-induced T cell maturation, as shown by the i nhibitory effect of neutralizing IFN-gamma antibodies. Finally, we sho w that IL-12 supports the production of IFN-gamma during primary stimu lation of neonatal T cells via the CD3/TCR complex by means of either immobilized anti-CD3 mAb or superantigen-coated (Staphylococcus entero toxin B) fixed L cell transfectants expressing HLA-DR. It is suggested that IL-12 is involved in the selection of Th1 type immune responses.