B7-DC/PD-L2 Cross-Linking Induces NF-κB-Dependent Protection of Dendritic Cells from Cell Death

Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
The Journal of Immunology (Impact Factor: 4.92). 03/2007; 178(3):1426-32. DOI: 10.4049/jimmunol.178.3.1426
Source: PubMed


Cross-linking cell surface molecules with IgM Abs is a specific approach for activating cells in vitro or in vivo. Dendritic cells (DC) activated with a human B7-DC (PD-L2)-specific IgM Ab can induce strong antitumor responses and block inflammatory airway disease in experimental models, yet the Ab-mediated molecular events promoting these responses remain unclear. Analysis of human or mouse DC treated with the B7-DC cross-linking Ab revealed PI3K-dependent phosphorylation of AKT accompanied by mobilization of NF-kappaB. Ab-activated DC up-regulated expression of cytokine and chemokine genes in an NF-kappaB-dependent manner. Importantly, PI3K-->AKT-->NF-kappaB activation was found to be indispensable for B7-DC cross-linking Ab-mediated protection of DC from cell death caused by cytokine withdrawal. Although other DC activators similarly protect DC from cell death, a synergy between cross-linking B7-DC and ligating RANK was observed. The parallel signaling events induced in human and mouse DC demonstrate that activation of cells using IgM Ab results in a response governed by a common mechanism and support the hypothesis that B7-DC cross-linking using this Ab may provide beneficial therapeutic immune modulation in human patients similar to those seen in animal models.

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    • "NF-κB is a master regulator of inflammation and has been reported to play a key role in guiding DC maturation and immune functions [16], [17] and to mediate protection of DC from death caused by cytokines withdrawal [18]. However, no detailed analysis is available on the role played by different NF-κB subunits in DC survival. "
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