The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/12/1819/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 11, December 1, 1997 1819-1829

Articles

In Vivo Microbial Stimulation Induces Rapid CD40 Ligand–independent Production of Interleukin 12 by Dendritic Cells and their Redistribution to T Cell Areas

Caetano Reis e Sousa{ddagger}, Sara Hieny*, Tanya Scharton-Kersten*, Dragana Jankovic*, Hugues Charest*, Ronald N. Germain{ddagger}, and Alan Sher*

From the * Immunobiology Section, Laboratory of Parasitic Diseases, and {ddagger} Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892

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{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+ 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{Phi} 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 {gamma} 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{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 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.

Address correspondence to Dr. Caetano Reis e Sousa, LBS/LI/NIAID/DIR, Bldg 10, Rm 11N311, 10 Center Dr, MSC 1892, National Institutes of Health, Bethesda, MD 20892-1892. Phone: 301-496-4047; FAX: 301-480-7352; E-mail: caetano{at}nih.gov

C. Reis e Sousa is supported by a Visiting Fellowship from the Fogarty International Center, National Institutes of Health.

1 Abbreviations used in this paper: DAB, diaminobenzidine; DC, dendritic cell(s); HRP, horseradish peroxidase; IDC, interdigitating DC; KO, knockout, L, ligand; LOD, low density spleen cells; M{Phi}, macrophage(s); OVA, ovalbumin; PALS, periarteriolar lymphoid sheath; PEC, peritoneal exudate cells; STAg, soluble Toxoplasma gondii tachyzoite extract; thio-, thioglycol-late-elicited; Thp, Th precursor.


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