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 cells produce several cytokines including IFN-gamma and IL-4. Using umbilical cord blood-derived CD4 T cells as a source of naive T cells, we first report that these cells are capable of producing large amounts of IFN-gamma when cultured with low concentrations of IL-12. The response is time- and dose-dependent, and it is observed at the protein and mRNA levels. IL-12 also induces neonatal CD4 T cells to produce lymphotoxin but not IL-2, TNF-alpha, or IL-4. The production of IFN-gamma by IL-12-stimulated neonatal T cells is associated with a small but significant T cell activation evidenced by DNA synthesis and by the expression of the activation markers CD25, CD71, and HLA-DR; moreover, it is 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 plays a role in this IL-12-induced T cell maturation, as shown by the inhibitory effect of neutralizing IFN-gamma antibodies. Finally, we show that IL-12 supports the production of IFN-gamma during primary stimulation of neonatal T cells via the CD3/TCR complex by means of either immobilized anti-CD3 mAb or superantigen-coated (Staphylococcus enterotoxin B) fixed L cell transfectants expressing HLA-DR. It is suggested that IL-12 is involved in the selection of Th1 type immune responses.