TH1 CELLS INDUCE AND TH2 INHIBIT ANTIGEN-DEPENDENT IL-12 SECRETION BYDENDRITIC CELLS

Dendritic cells are the most relevant antigen-presenting cells (APC) f or presentation of antigens administered in adjuvant to CD4(+) T cells . Upon interaction with antigen-specific T cells, dendritic cells (DC) expressing appropriate peptide-MHC class II complexes secrete IL-12, a cytokine that drives Th1 cell development. To analyze the T cell-med iated regulation of IL-12 secretion by DC, we have examined their capa city to secrete IL-12 in response to stimulation by antigen-specific T h1 and Th2 DO11.10 TCR-transgenic cells. These cells do not differ eit her in TCR clonotype or CD40 ligand (CD40L) expression. Interaction wi th antigen-specific Th1, but not Th2 cells, induces IL-12 p40 and p75 secretion by DC. The induction of IL-12 production by Th1 cells does n ot depend on their IFN-gamma secretion, but requires direct cell-cell contact mediated by peptide/MHC class II-TCR and CD40-CD40L interactio ns. Th2 cells not only fail to induce IL-12 secretion, but they inhibi t its induction by Th1 cells. Unlike stimulation by Th1, inhibition of IL-12 production by Th2 cells is mediated by soluble molecules, as de monstrated by transwell cultures. Among Th2-derived cytokines, IL-10, but not IL-4 inhibit Th1-driven IL-12 secretion. IL-10 produced by Th2 cells appears to be solely responsible for the inhibition of Th1-indu ced IL-12 secretion, but it does not account for the failure of Th2 ce lls to induce IL-12 production by DC. Collectively, these results demo nstrate that Th1 cells up-regulate IL-12 production by DC via IFN-gamm a-independent cognate interaction, whereas this is inhibited by Th2-de rived IL-10. The inhibition of Th1-induced IL-12 production by Th2 cel ls with the same antigen specificity represents a novel mechanism driv ing the polarization of CD4(+) T cell responses.