title: STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease.
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.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Sumanta
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rasky
authors.forename: Phil A
authors.initials: PA
authors.lastname: Lundy
authors.forename: Nicolai A
authors.initials: NA
authors.lastname: Kittan
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Ivan P
authors.initials: IP
authors.lastname: Maillard
authors.forename: Paul E
authors.initials: PE
authors.lastname: Kowalski
authors.forename: Philaretos C
authors.initials: PC
authors.lastname: Kousis
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens / Q000276:immunology / Q000633:toxicity; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003058:Cockroaches; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D016695:Glycosyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019476:Insect Proteins / Q000276:immunology / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051880:Receptors, Notch / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000276:immunology*; D018357:Respiratory Syncytial Virus Infections / Q000150:complications / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000485:Allergens; D002135:Calcium-Binding Proteins; D016207:Cytokines; C519665:DLL4 protein, mouse; D019476:Insect Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; D016695:Glycosyltransferases; C498392:Lfng protein, mouse