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Interleukin-12 p40 Secretion by Cutaneous CD11c⁺ and F4/80⁺ Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity to Schistosoma mansoni

Department of Biology (Area 5), The University of York, York YO10 5YW, United Kingdom

Received 21 November 2002/ Returned for modification 3 February 2003/ Accepted 12 March 2003

Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1 and interleukin-1ß (IL-1ß) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10^-/- mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40⁺ cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia⁺, consistent with their being antigen-presenting cells. Labeling of IL-12⁺ cells for CD11c, CD205, CD8, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c^- F4/80⁺, suggesting that macrophages were an additional source of IL-12 in the skin.

Editor: W. A. Petri, Jr.

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