Dendritic cells, but not macrophages, produce IL-12 immediately following Leishmania donovani infection.
Infection with Leishmania, an obligate intracellular parasite of mononuclear phagocytes, stimulates the production of IFN-gamma from NK cells, via a pathway which is dependent upon IL-12 and IL-2. IL-12 is also essential for the development of host protective T cell responses to this parasite. However, previous in vitro studies have indicated that macrophages fail to make IL-12 following infection with Leishmania, and that subsequent to infection, macrophages become refractory to normal IL-12-inducing stimuli. We have used an in situ approach to attempt to resolve this apparent paradox, and by immunostaining for IL-12 p40 protein, we now demonstrate for the first time, that dendritic cells (DC) are the critical source of early IL-12 production following Leishmania infection. IL-12 production by DC is transient, peaking at 1 day post infection and returning to the levels seen in uninfected mice by day 3. Although resident tissue macrophages fail to produce IL-12 after Leishmania infection, these cells are not totally refractory to cytokine inducing stimuli, as TNF-alpha production is induced by day 3 post infection. Not only do these data satisfactorily explain the differences between in vivo and in vitro data by identifying the cellular source of IL-12, but they also suggest a novel model for NK cell activation; namely that in response to pathogens which fail to trigger IL-12 production by macrophages, DC-T cell clusters provide the microenvironment for initial NK cell activation.
Gorak
P M
PM
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, GB.
Engwerda
C R
CR
Kaye
P M
PM
D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000469:parasitology; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis*; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000469:parasitology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12