Abstract
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 Notch-modifying Lfng augments Th2 response via Dll4 and is critical for amplifying viral exacerbation during allergic airway disease.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing
-
Allergens / immunology
-
Allergens / toxicity
-
Animals
-
CD4-Positive T-Lymphocytes / immunology
-
CD4-Positive T-Lymphocytes / metabolism
-
Calcium-Binding Proteins
-
Cells, Cultured
-
Chromatin Immunoprecipitation
-
Cockroaches
-
Cytokines / biosynthesis*
-
Cytokines / genetics
-
Disease Models, Animal
-
Glycosyltransferases / antagonists & inhibitors
-
Glycosyltransferases / biosynthesis
-
Glycosyltransferases / genetics
-
Glycosyltransferases / physiology*
-
Insect Proteins / immunology
-
Insect Proteins / toxicity
-
Intracellular Signaling Peptides and Proteins / physiology*
-
Membrane Proteins / physiology*
-
Mice
-
Mice, Inbred BALB C
-
Mice, Inbred C57BL
-
Receptors, Notch / physiology
-
Respiratory Hypersensitivity / complications
-
Respiratory Hypersensitivity / immunology*
-
Respiratory Syncytial Virus Infections / complications
-
Respiratory Syncytial Virus Infections / immunology*
-
STAT5 Transcription Factor / antagonists & inhibitors
-
STAT5 Transcription Factor / immunology
-
STAT5 Transcription Factor / physiology*
-
Signal Transduction / immunology
-
Specific Pathogen-Free Organisms
-
Th2 Cells / immunology
-
Th2 Cells / metabolism*
Substances
-
Adaptor Proteins, Signal Transducing
-
Allergens
-
Calcium-Binding Proteins
-
Cytokines
-
DLL4 protein, mouse
-
Insect Proteins
-
Intracellular Signaling Peptides and Proteins
-
Membrane Proteins
-
Receptors, Notch
-
STAT5 Transcription Factor
-
Stat5a protein, mouse
-
Glycosyltransferases
-
Lfng protein, mouse