IL-12, AS AN ADJUVANT, PROMOTES A T-HELPER-1 CELL, BUT DOES NOT SUPPRESS A T-HELPER-2 CELL RECALL RESPONSE

IL-12 is a potent inducer of NK and cytolytic T cell activity, IFN-gam ma production, and T cell proliferation, and is necessary for differen tiation of naive T cells to the Th1 subset. We have previously shown t hat IL-12 promotes a primary Th1 response and suppresses a primary Th2 response in lymph nodes of mice primed with a model hapten-protein co njugate, 2,4,6-trinitrophenyl (TNP)-keyhole limpet hemocyanin (KLH). W e have now extended these studies to determine the Th phenotype of the recall response following immunization with soluble Ag and IL-12. For these experiments, mice were primed with TNP-KLH with or without trea tment with IL-12, allowed to progress beyond the primary immune respon se, and challenged by i.p. injection of TNP-KLH. The phenotype of the recall response was monitored by measuring ex vivo production of IFN-g amma and IL-4 in Ag-stimulated lymph node and spleen cell cultures. Ti ter and isotype of TNP-specific serum Abs were also evaluated. Mice pr imed with Ag + IL-12 developed a Th1 recall response, as detected by K LH-specific IFN-gamma production from cultured spleen cells and the pr esence of TNP-specific IgG2a Ab in serum. However, they also developed an Ag-specific Th2 recall response, as characterized by Ag-induced IL -4 production from spleen cells and the presence of high titers of ant i-TNP IgG1 in the serum, Studies of the cytokine profile during the pr imary response revealed that IL-12 induced in spleen cells the capacit y to express both IL-4 and IFN-gamma. CD4(+) T cells are necessary for production of IL-4 in the spleens of IL-12-treated mice, and most lik ely account for the Th2 recall response detected in mice primed with A g + IL-12. These results indicate that the Th1 phenotype induced by im munization with IL-12 and Ag is maintained so that a Th1 recall respon se is expressed upon subsequent challenge with Ag, However, immunizati on with IL-12 also supports the development of a Th2 recall response, indicating that the Th1-inducing effect of IL-12 in vivo is not accomp anied by a long lasting suppression of Th2 development.