Dendritic cells activated with products released by schistosome larvae drive Th2-type immune responses, which can be inhibited by manipulation of CD40 costimulation.
The early immune events in response to infective larvae of the parasitic helminth Schistosoma mansoni are poorly understood, but here for the first time we report on the potential of products released by schistosome larvae (material released in the first 3 h after transformation [0-3hRP]) to stimulate the maturation of dendritic cells (DC) and alter their T-cell-polarizing function. This was performed in comparison with lipopolysaccharide (LPS) and zymosan A, which classically activate DC to prime for Th1- and Th2-type responses, respectively. In our study, immature bone marrow-derived DC stimulated in vitro with 0-3hRP exhibited up-regulated expression of major histocompatibility complex class II, CD40, and CD86 and increased production of interleukin 12p40 (IL-12p40) and IL-6, albeit at lower levels than in response to LPS or zymosan A. Using an in vitro ovalbumin peptide-restricted priming assay, DC matured with 0-3hRP exhibited a potent capacity to drive Th2 polarization of CD4(+) cells from DO11.10 transgenic mice. This was characterized by increased IL-4 production (but not gamma interferon) of a magnitude similar to that primed by DC matured with zymosan A. Inoculation of DO11.10 mice with 0-3hRP-activated DC pulsed with ovalbumin peptide also led to the development of a Th2-type polarized response in the skin-draining lymph nodes and spleen. However, ligation of CD40 on DC by anti-CD40 antibody treatment reversed the ability of 0-3hRP-activated DC to prime for Th2-type responses and instead caused the induction of a more Th1-type response.
Jenkins
Stephen John
SJ
Department of Biology (Area 5), University of York, York, YO10 5YW, United Kingdom. apm10@york.ac.uk.
Mountford
Adrian Paul
AP
D000595:Amino Acid Sequence; D000818:Animals; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology; D002454:Cell Differentiation; D016764:Cell Polarity; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012550:Schistosoma mansoni / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*
D019013:CD40 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D023201:CD40 Ligand