INTERLEUKIN-12 IS PRODUCED BY DENDRITIC CELLS AND MEDIATES T-HELPER 1DEVELOPMENT AS WELL AS INTERFERON-GAMMA PRODUCTION BY T-HELPER-1 CELLS

Interleukin-12 (IL-12), a 70-kDa heterodimeric cytokine composed of co valently linked p35 and p40 chains, is to date the most critical facto r for skewing the immune response towards a T helper 1 (Th 1) of cytok ine profile [high interferon-gamma (IFN-gamma), low IL-4]. Established sources of IL-12 are stimulated macrophages, neutrophils and B cells. As dendritic cells (DC) process antigen in the periphery and then mig rate to lymphoid organs to sensitize T cells and induce cell-mediated immunity, we reasoned that DC should constitute a critical source of I L-12. The criteria used to detect IL-12 in DC were the demonstration o f p40 and p35 mRNA (semiquantitative polymerase chain reaction, Northe rn blotting, and in situ hybridization) as well as IL-12 protein (p70 enzyme-linked immunosorbent assay, p70 antigen capture followed by IFN -gamma bioassay, free p40 chain radioimmunoassay or immunoprecipitatio n). We found that conventional stimuli such as Staphylococcus aureus i nduced production of IL-12, by murine as well as human DC in amounts c omparable to spleen cells. peritoneal macrophages or peripheral blood mononuclear cells. DC exhibited, however, features that had not been s een with other antigen-presenting cells: they produced bioactive IL-12 upon antigen-specific interaction with T cells without any other stim uli: in an allogeneic mixed leukocyte reaction model. neutralizing ant i-IL-12 antibodies showed that DC-derived IL-12 was critical for optim al proliferation and IFN-gamma production by activated Th1 blasts; and finally, the priming of resting, naive allogeneic T cells by DC, foll owed by restimulation of primed T blasts by DC, skewed the response to Th1 without the need for any exogenous cytokines or stimuli such as m icroorganisms. This skewing to Th1 cytokine production, which depended on DC-derived IL-12, but did not require anti-IL-4, exogenous IL-12, or microbes, might be a major function of DC.