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CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-kappaB.

Brendan John O'Sullivan·Ranjeny Thomas
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Abstract

An understanding of the biochemical control of dendritic cell (DC) differentiation/activation is essential for improving T cell immunity by various immunotherapeutic approaches, including DC immunization. Ligation of CD40 enhances DC function, including conditioning for CTL priming. NF-kappaB, and particularly RelB, is an essential control pathway for myeloid DC differentiation. Furthermore, RelB regulates B cell Ag-presenting function. We hypothesized that CD40 ligand (CD40L) and TNF-alpha, which differ in their capacity to condition DC, would also differ in their capacity to activate NF-kappaB. DC differentiated for 2 days from monocytes in the presence of GM-CSF and IL-4 were used as a model, as NF-kappaB activity was constitutively low. The capacity of DC to activate T cells following CD40L treatment was enhanced compared with TNF-alpha treatment, and this was NF-kappaB dependent. Whereas RelB/p50 translocation induced by TNF-alpha was attenuated after 6 h, RelB/p50 nuclear translocation induced by CD40L was sustained for at least 24 h. The mechanism of this difference related to enhanced degradation of IkappaBalpha following CD40L stimulation. However, NF-kappaB activation induced by TNF-alpha could be sustained by blocking autocrine IL-10. These data indicate that NF-kappaB activation is essential for T cell activation by DC, and that this function is enhanced if DC NF-kappaB activation is prolonged. Because IL-10 moderates DC NF-kappaB activation by TNF-alpha, sustained NF-kappaB activation can be achieved by blocking IL-10 in the presence of stimuli that induce TNF-alpha.

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Antigen PresentationCD40 AntigensCD40 LigandDNA-Binding ProteinsDendritic CellsHumansI-kappa B ProteinsInterleukin-10Interleukin-12NF-KappaB Inhibitor alphaNF-kappa BNF-kappa B p50 SubunitPhosphorylationProto-Oncogene ProteinsProto-Oncogene Proteins c-relTranscription Factor RelBTranscription FactorsTranscriptional ActivationTumor Necrosis Factor-alphaJournal ArticleResearch Support, Non-U.S. Gov't

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Brendan John O'Sullivan, Ranjeny Thomas. 2002-06-01. CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-kappaB.. https://doi.org/10.4049/jimmunol.168.11.5491

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