In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas

• Published in: The Journal of experimental medicine Vol. 186; no. 11; pp. 1819 - 1829
• Main Authors: Reis e Sousa, C, Hieny, S, Scharton-Kersten, T, Jankovic, D, Charest, H, Germain, R N, Sher, A
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 01.12.1997
• Subjects: AIDS/HIV; Animals; Antigen Presentation; Antigens, Protozoan - immunology; CD40 Ligand; Cell Differentiation; Cell Movement; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Gene Expression Regulation; Interferon-gamma - physiology; Interleukin-12 - biosynthesis; Interleukin-12 - deficiency; Interleukin-12 - genetics; Interleukin-12 - metabolism; Lipopolysaccharides - pharmacology; Macrophages - immunology; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Spleen - immunology; Spleen - pathology; Th1 Cells - immunology; Toxoplasmosis, Animal - immunology; Toxoplasmosis, Animal - pathology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.186.11.1819

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 (MPhi) 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 MPhi 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 MPhi 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.