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

BJ O'Sullivan, R Thomas - The Journal of Immunology, 2002 - journals.aai.org
BJ O'Sullivan, R Thomas
The Journal of Immunology, 2002journals.aai.org
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-κB, 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-α, which differ in their capacity to condition DC, would …
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-κB, 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-α, which differ in their capacity to condition DC, would also differ in their capacity to activate NF-κB. DC differentiated for 2 days from monocytes in the presence of GM-CSF and IL-4 were used as a model, as NF-κB activity was constitutively low. The capacity of DC to activate T cells following CD40L treatment was enhanced compared with TNF-α treatment, and this was NF-κB dependent. Whereas RelB/p50 translocation induced by TNF-α 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 IκBα following CD40L stimulation. However, NF-κB activation induced by TNF-α could be sustained by blocking autocrine IL-10. These data indicate that NF-κB activation is essential for T cell activation by DC, and that this function is enhanced if DC NF-κB activation is prolonged. Because IL-10 moderates DC NF-κB activation by TNF-α, sustained NF-κB activation can be achieved by blocking IL-10 in the presence of stimuli that induce TNF-α.
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