The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online
doi:10.1084/jem.20070661
The Journal of Experimental Medicine, Vol. 204, No. 12, 2925-2934
The Rockefeller University Press, 0022-1007 $30.00
© Schaller et al.
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ARTICLE

 Notch ligand Delta-like 4 regulates disease pathogenesis during respiratory viral infections by modulating Th2 cytokines

Matthew A. Schaller1, Rupak Neupane1, Brian D. Rudd1, Steven L. Kunkel1, Lara E. Kallal1, Pamela Lincoln1, John B. Lowe2, Yunfang Man2, and Nicholas W. Lukacs1

1 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109
2 Department of Pathology, Case Western Reserve, Cleveland, OH 44106

CORRESPONDENCE Matthew Schaller: mschalle{at}umich.edu

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. Parellel 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.

Abbreviations used: AHR, airway hyperresponsiveness; BMDC, bone marrow–derived DC; DN, double-negative; MOI, multiplicity of infection; RSV, respiratory syncytial virus; TLR, Toll-like receptor.


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