title: CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-kappaB.
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.
authors.affiliation: Center for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
authors.forename: Brendan John
authors.initials: BJ
authors.lastname: O'Sullivan
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
mesh_terms: D017951:Antigen Presentation; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D019013:CD40 Antigens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C497593:RELB protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000072000:NF-KappaB Inhibitor alpha; D023201:CD40 Ligand; D051841:Transcription Factor RelB; D018664:Interleukin-12