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 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.
Reis e Sousa
C
C
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA. caetano@nih.gov
Hieny
S
S
Scharton-Kersten
T
T
Jankovic
D
D
Charest
H
H
Germain
R N
RN
Sher
A
A
D000818:Animals; D017951:Antigen Presentation; D000953:Antigens, Protozoan / Q000276:immunology; D023201:CD40 Ligand; D002454:Cell Differentiation; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000502:physiology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000473:pathology
D000953:Antigens, Protozoan; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma