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Jagged1 on Dendritic Cells and Notch on CD4⁺ T Cells Initiate Lung Allergic Responsiveness by Inducing IL-4 Production^1,2

Masakazu Okamoto^*, Hiroyuki Matsuda^*, Anthony Joetham^*, Joseph J. Lucas^*, Joanne Domenico^*, Koji Yasutomo, Katsuyuki Takeda^* and Erwin W. Gelfand^3,*

^* Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206; and Department of Immunology and Parasitology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan

Jagged1, a Notch ligand, and Notch have been implicated in Th2 differentiation, but their role in initiating IL-4 production and Th2 differentiation in vivo and the development of allergic airway responses has not been defined. In this study, we show that Jagged1 is up-regulated on bone marrow-derived dendritic cells (BMDCs) pulsed with allergen and that the transfer of these BMDCs before allergen challenge induces airway hyperresponsiveness (AHR) and eosinophilic airway inflammation. Treatment of CD4⁺ T cells with a -secretase inhibitor (GSI), which inhibits Notch signaling, resulted in decreased cytokine production when the cells were cocultured with allergen-pulsed, Jagged1-expressing BMDCs and, after the transfer of allergen-pulsed BMDCs, IL-4-deficient (IL-4^–/–) recipients of GSI-treated naive CD4⁺ T cells developed lower levels of AHR, reduced numbers of eosinophils, and lower Th2 cytokine levels when challenged with allergen. In vivo treatment of wild-type mice with Jagged1-Fc enhanced AHR and airway inflammation, whereas the transfer of BMDC transfected with Jagged1 small interfering RNA (siRNA) cells into WT or IL-4^–/– mice before transfer of CD4⁺ T cells resulted in decreased AHR, inflammation, and Th2 cytokines, indicating the critical role for Jagged1 expression on APCs. These data identify the essential role of the interactions between Notch on CD4⁺ T cells and Jagged1 on APCs in the initiation of IL-4 production and Th2 differentiation for the development of AHR and allergic airway inflammation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The project described in this article was supported by National Institutes of Health Grants HL-36577, HL-61005, and AI-77609.

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lungs, and Blood Institute or the National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Erwin W. Gelfand, National Jewish Health, 1400 Jackson Street, Denver, CO 80206. E-mail address: gelfande{at}njc.org

⁴ Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; GSI, -secretase inhibitor; MCh, methacholine; R_L, lung resistance; siRNA, small interfering RNA; WT, wild type.