B7-DC/PD-L2 cross-linking induces NF-kappaB-dependent protection of dendritic cells from cell death.
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.
Radhakrishnan
Suresh
S
Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Nguyen
Loc T
LT
Ciric
Bogoljub
B
Van Keulen
Virginia P
VP
Pease
Larry R
LR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000276:immunology*; D016923:Cell Death; D003432:Cross-Linking Reagents / Q000494:pharmacology* / Q000627:therapeutic use; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000502:physiology*; D010455:Peptides / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D000906:Antibodies; D018122:B7-1 Antigen; D003432:Cross-Linking Reagents; D007075:Immunoglobulin M; D016328:NF-kappa B; C556977:PDCD1LG2 protein, human; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt