Journal
JOURNAL OF IMMUNOLOGY
Volume 192, Issue 3, Pages 996-1003Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301991
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Funding
- National Institutes of Health [AI073876]
- Canadian Institutes of Health [FRN11530]
- National Heart, Lung, and Blood Institute [K99HL114733]
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Notch activation plays an important role in T cell development and mature T cell differentiation. In this study, we investigated the role of Notch activation in a mouse model of respiratory syncytial virus (RSV)-exacerbated allergic airway disease. During RSV exacerbation, in vivo neutralization of a specific Notch ligand, Delta-like ligand (Dll)-4, significantly decreased airway hyperreactivity, mucus production, and Th2 cytokines. Lunatic Fringe (Lfng), a glycosyltransferase that enhances Notch activation by Dll4, was increased during RSV exacerbation. Lfng loss of function in Th2-skewed cells inhibited Dll4-Notch activation and subsequent IL-4 production. Further knockdown of Lfng in T cells in CD4Cre(+)Lfng(fl/fl) mice showed reduced Th2 response and disease pathology during RSV exacerbation. Finally, we identified STAT5-binding cis-acting regulatory element activation as a critical driver of Lfng transcriptional activation. These data demonstrate that STAT5-dependent amplification of Notchmodifying Lfng augments Th2 response via Dll4 and is critical for amplifying viral exacerbation during allergic airway disease.
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