Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines.
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.
Schaller
Matthew A
MA
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. mschalle@umich.edu
Neupane
Rupak
R
Rudd
Brian D
BD
Kunkel
Steven L
SL
Kallal
Lara E
LE
Lincoln
Pamela
P
Lowe
John B
JB
Man
Yunfang
Y
Lukacs
Nicholas W
NW
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D016207:Cytokines / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000502:physiology*; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology; D008024:Ligands; D018357:Respiratory Syncytial Virus Infections / Q000517:prevention & control*; D012136:Respiratory Syncytial Viruses; D018418:Th2 Cells / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; D016207:Cytokines; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D018664:Interleukin-12