STAT5-induced Lunatic Fringe During Th2 Development Alters Delta-like 4-mediated Th2 Cytokine Production in Respiratory Syncytial Virus-exacerbated Airway Allergic Disease

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2013 Dec 25

PMID 24367028

Citations 12

Authors

Sumanta Mukherjee

Andrew J Rasky

Phil A Lundy

Nicolai A Kittan

Steven L Kunkel

Ivan P Maillard

Paul E Kowalski

Philaretos C Kousis

Cynthia J Guidos

Nicholas W Lukacs

Affiliations

Soon will be listed here.

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.

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