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

Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905

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-B. Ab-activated DC up-regulated expression of cytokine and chemokine genes in an NF-B-dependent manner. Importantly, PI3KAKTNF-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Larry R. Pease, Professor and Chair, Department of Immunology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905. E-mail address: pease.larry{at}mayo.edu

² Abbreviations used in this paper: DC, dendritic cell; RANK, receptor activator of the NF-B; NBD, NEMO-binding domain; DAPI, 4',6'-diamidino-2-phenylindale.

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