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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"Octamer binding protein 2 (Oct2) was demonstrated to regulate PD-L2 gene expression in B-1 cells through lineage-specific activity of a unique, intronic promoter . Subsequently, PD-L2 cross-linking induced NF-κB -dependent protection of dendritic cells from cell death . "
[Show abstract][Hide abstract]ABSTRACT: The programmed death-1 (PD-1), a coinhibitory receptor expressed on activated T cells and B cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. The cancer patients harboring PD-1 or PD ligand 1 (PD-L1) protein expression have often a poor prognosis and clinical outcome. Currently, targeting PD-1 pathway as a potential new anticancer strategy is attracting more and more attention in cancer treatment. Several monoclonal antibodies against PD-1 or PD-L1 have been reported to enhance anticancer immune responses and induce tumor cell death. Nonetheless, the precise molecular mechanisms by which PD-1 affects various cancers remain elusive. Moreover, this therapy is not effective for all the cancer patients and only a fraction of patients respond to the antibodies targeting PD-1 or PD-L1, indicating these antibodies may only works in a subset of certain cancers. Thus, understanding the novel function of PD-1 and genetic determinants of response to anti-PD-1 therapy will allow us to develop a more effective and individualized immunotherapeutic strategy for cancer.
"NF-κB is a master regulator of inflammation and has been reported to play a key role in guiding DC maturation and immune functions ,  and to mediate protection of DC from death caused by cytokines withdrawal . However, no detailed analysis is available on the role played by different NF-κB subunits in DC survival. "
[Show abstract][Hide abstract]ABSTRACT: Dendritic cells play a central role in keeping the balance between immunity and immune tolerance. A key factor in this equilibrium is the lifespan of DC, as its reduction restrains antigen availability leading to termination of immune responses. Here we show that lipopolysaccharide-driven DC maturation is paralleled by increased nuclear levels of p50 NF-κB, an event associated with DC apoptosis. Lack of p50 in murine DC promoted increased lifespan, enhanced level of maturation associated with increased expression of the proinflammatory cytokines IL-1, IL-18 and IFN-β, enhanced capacity of activating and expanding CD4(+) and CD8(+) T cells in vivo and decreased ability to induce differentiation of FoxP3(+) regulatory T cells. In agreement, vaccination of melanoma-bearing mice with antigen-pulsed LPS-treated p50(-/-) BM-DC boosted antitumor immunity and inhibition of tumor growth. We propose that nuclear accumulation of the p50 NF-κB subunit in DC, as occurring during lipopolysaccharide-driven maturation, is a homeostatic mechanism tuning the balance between uncontrolled activation of adaptive immunity and immune tolerance.
"Still another possibility is that PD-L2 engagement produces retrograde signaling in L2pB1 cells that somehow alters the L2pB1 cell/T cell interaction. Retrograde PD-L2 signaling eventuating in NF-κB activation has, in fact, been reported for dendritic cells, although more recently this work has been questioned (Nguyen et al. 2007; Nguyen et al. 2010 retracted; Radhakrishnan et al., 2003; Radhakrishnan et al., 2007). To verify this, B1-like BRD2 cells that express PD-L2 (Greenwald et al., 2004) were examined for induction of NF-κB after treatment with anti-PD-L2 antibody, as measured by a κBdependent luciferase construct. "
[Show abstract][Hide abstract]ABSTRACT: L2pB1 cells (PD-L2positive B1 cells) are a newly discovered subpopulation of B1 B cells. L2pB1 cells are noted for the expression of PD-L2 (CD273, B7-DC), a ligand for the inhibitory receptor PD-1, which distinguishes this subpopulation from other B1 B cells that lack PD-L2, namely, L2nB1 cells (PD-L2negative B1 cells). PD-L2 gene expression is regulated differently in B1 B cells as compared to macrophages and dendritic cells. L2pB1 cells share many commonly known B1 cell features with L2nB1 cells. These include spontaneous IgM secretion, constitutive ERK activation, elevated co-stimulatory molecule expression, skewing of T cell differentiation, and unique proliferative responsiveness (to LPS, PMA, but not anti-IgM). However, L2pB1 cells express a biased Ig repertoire that is enriched for self-reactivity as compared with L2nB1 cells. Further, L2pB1 cells present antigen more potently than L2nB1 cells. In addition, L2pB1 cells switch Ig isotype more readily from IgM to IgG1 and IgG2b upon cytokine stimulation. Moreover, increased numbers of L2pB1 cells are present in murine models of lupus and this correlates with increased serum anti-dsDNA titers. These characteristics suggest that L2pB1 cells may play a pathophysiological role in autoimmune dyscrasias. In this report we review the special features of L2pB1 cells and how they may contribute to autoimmunity.
Full-text · Article · Dec 2010 · Molecular Immunology