IN-VIVO MICROBIAL STIMULATION INDUCES RAPID CD40 LIGAND-INDEPENDENT PRODUCTION OF INTERLEUKIN-12 BY DENDRITIC CELLS AND THEIR REDISTRIBUTION TO T-CELL AREAS

The early induction of interleukin (IL)-12 is a critical event in dete rmining the development of both innate resistance and adaptive immunit y to many intracellular pathogens. Previous in vitro studies have sugg ested that the macrophage (M Phi) is a major source of the initial IL- 12 produced upon microbial stimulation and that this response promotes the differentiation of protective T helper cell 1 (Th1) CD4(+) lympho cytes from precursors that are primed on antigen-bearing dendritic cel ls (DC). Here, we demonstrate by immunolocalization experiments and fl ow cytometric analysis that, contrary to expectation, DC and not M Phi are the initial cells to synthesize IL-12 in the spleens of mice expo sed in vivo to an extract of Toxoplasma gondii or to lipopolysaccharid e, two well characterized microbial stimulants of the cytokine. import antly, this production of IL-12 occurs very rapidly and is independent of interferon gamma priming or of signals from T cells, such as CD40 ligand. IL-12 production by splenic DC is accompanied by an increase i n number of DCs, as well as a redistribution to the T cell areas and t he acquisition of markers characteristic of interdigitating dendritic cells. The capacity of splenic DC but not M Phi to synthesize de novo high levels of IL-12 within hours of exposure to microbial products in vivo, as well as the ability of the same stimuli to induce migration of DC to the T cell areas, argues that DC function simultaneously as b oth antigen-presenting cells and IL-12 producing accessory cells in th e initiation of cell-mediated immunity to intracellular pathogens. Thi s model avoids the need to invoke a three-cell interaction for Th1 dif ferentiation and points to the DC as both a sentinel for innate recogn ition and the dictator of class selection in the subsequent adaptive r esponse.