Interleukin‐12 is produced by dendritic cells and mediates T helper 1 development as well as interferon‐γ production by T helper 1 cells

Abstract

Interleukin‐12 (IL‐12), a 70‐kDa heterodimeric cytokine composed of covalently linked p35 and p40 chains, is to date the most critical factor for skewing the immune response towards a T helper 1 (Th1) of cytokine profile [high interferon‐γ (IFN‐γ), 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 migrate to lymphoid organs to sensitize T cells and induce cell‐mediated immunity, we reasoned that DC should constitute a critical source of IL‐12. The criteria used to detect IL‐12 in DC were the demonstration of p40 and p35 mRNA (semiquantitative polymerase chain reaction, Northern blotting, and in situ hybridization) as well as IL‐12 protein (p70 enzyme‐linked immunosorbent assay, p70 antigen capture followed by IFN‐γ bioassay, free p40 chain radioimmunoassay or immunoprecipitation). We found that conventional stimuli such as Staphylococcus aureus induced production of IL‐12 bymurine as well as human DC in amounts comparable to spleen cells, peritoneal macrophages or peripheral blood mononuclear cells. DC exhibited, however, features that had not been seen with other antigen‐presenting cells: they produced bioactive IL‐12 upon antigen‐specific interaction with T cells without any other stimuli; in an allogeneic mixed leukocyte reaction model, neutralizing anti‐IL‐12 antibodies showed that DC‐derived IL‐12 was critical for optimal proliferation and IFN‐γ production by activated Th1 blasts; and finally, the priming of resting, naive allogeneic T cells by DC, followed by restimulation of primed T blasts by DC, skewed the response to Th1 without the need for any exogenous cytokines or stimuli such as microorganisms. 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.