1. Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines.
- Author
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Schaller MA, Neupane R, Rudd BD, Kunkel SL, Kallal LE, Lincoln P, Lowe JB, Man Y, and Lukacs NW
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Calcium-Binding Proteins, Disease Models, Animal, Humans, Intercellular Signaling Peptides and Proteins biosynthesis, Interleukin-12 immunology, Interleukin-12 physiology, Ligands, Respiratory Syncytial Viruses, Cytokines physiology, Dendritic Cells immunology, Intercellular Signaling Peptides and Proteins physiology, Respiratory Syncytial Virus Infections prevention & control, Th2 Cells immunology
- Abstract
Recent data have indicated that an important instructive class of signals regulating the immune response is Notch ligand-mediated activation. Using quantitative polymerase chain reaction, we observed that only Delta-like 4 (dll4) was up-regulated on bone marrow-derived dendritic cells after respiratory syncytial virus (RSV) infection, and that it was dependent on MyD88-mediated pathways. Using a polyclonal antibody specific for dll4, the development of RSV-induced disease was examined. Animals treated with anti-dll4 had substantially increased airway hyperresponsiveness compared with control antibody-treated animals. When the lymphocytic lung infiltrate was examined, a significant increase in total CD4+ T cells and activated (perforin+) CD8+ T cells was observed. Isolated lung CD4+ T cells demonstrated significant increases in Th2-type cytokines and a decrease in interferon gamma, demonstrating an association with increased disease pathogenesis. Parallel in vitro studies examining the integrated role of dll4 with interleukin-12 demonstrated that, together, both of these instructive signals direct the immune response toward a more competent, less pathogenic antiviral response. These data demonstrate that dll4-mediated Notch activation is one regulator of antiviral immunity.
- Published
- 2007
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