IL-12 induction by a Th1-inducing adjuvant in vivo: Dendritic cell subsetsand regulation by IL-10

IL-12 induction is critical for immune responses against many viruses and i ntracellular bacterial pathogens. Recent studies suggest that IL-12-secreti ng dendritic cells (DC) are potent Th1-inducing APC. However, controversy e xists concerning the function of DC subsets. Murine studies have suggested that CD8(+) DC preferentially induce Th1 responses, whereas CD8(-) DC induc e Th2 development; in this model, different DC subsets prime different resp onses. Alternatively, the propensity of DC subsets to prime a Th1 response could depend upon the type of initial stimulus. We used a prototypic Th1-in ducing adjuvant, heat-killed Brucella abortus (HKBA) to assess stimulation of DC subsets, relationship between Ag burden and IL-12 production, and dow n-regulation of DC subset IL-12 production by IL-10. In this study, we show that DC were sole producers of IL-12, although most HKBA uptake was by spl enic macrophages and granulocytes. More CD8(-) than CD8(+) DC produced IL-1 2 after HKBA challenge, whereas only CD8(+) DC produced IL-12 after injecti on of another Th1-promoting microbial substance, soluble Toxoplasma gondii Ags. Studies in IL-10-deficient mice revealed that IL-10 down-regulates fre quency and duration of IL-12 production by both DC subsets. In the absence of IL-10, IL-12 expression is enabled in CD11c(low) cells, but not in macro phages or granulocytes. These findings support the concept of DC as the maj or IL-12 producers in spleens, but challenge the notion that CD8(+) and CD8 (-) DC are destined to selectively induce Th1 or Th2 responses, respectivel y. Thus, the nature of the stimulating substance is important in determinin g which DC subsets are activated to produce IL-12.