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J. Exp. Med.,
Volume 186, Number 11, December 1, 1997 1819-1829
By


From the * Immunobiology Section, Laboratory of Parasitic Diseases, and The early induction of interleukin (IL)-12 is a critical event in determining the development of
both innate resistance and adaptive immunity to many intracellular pathogens. Previous in vitro
studies have suggested that the macrophage (M
Lymphocyte Biology
Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland 20892-1892
) 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+ lymphocytes from precursors that are primed on antigen-bearing dendritic cells (DC). Here, we demonstrate by immunolocalization experiments and
flow cytometric analysis that, contrary to expectation, DC and not M
are the initial cells to
synthesize IL-12 in the spleens of mice exposed in vivo to an extract of Toxoplasma gondii or to
lipopolysaccharide, two well characterized microbial stimulants of the cytokine. Importantly,
this production of IL-12 occurs very rapidly and is independent of interferon
priming or of signals from T cells, such as CD40 ligand. IL-12 production by splenic DC is accompanied by
an increase in number of DCs, as well as a redistribution to the T cell areas and the acquisition of markers characteristic of interdigitating dendritic cells. The capacity of splenic DC but not
M
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 both antigen-presenting cells and IL-12 producing
accessory cells in the initiation of cell-mediated immunity to intracellular pathogens. This
model avoids the need to invoke a three-cell interaction for Th1 differentiation and points to
the DC as both a sentinel for innate recognition and the dictator of class selection in the subsequent adaptive response.
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