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Airway Epithelial Cells Regulate the Functional Phenotype of Locally Differentiating Dendritic Cells: Implications for the Pathogenesis of Infectious and Allergic Airway Disease¹

Angela Rate^*, John W. Upham^*,, Anthony Bosco^*, Kathy L. McKenna^* and Patrick G. Holt^2,*

^* Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, University of Western Australia, West Perth, Australia; and School of Medicine, The University of Queensland, Brisbane, Australia

Atopic asthma pathogenesis is driven by the combined effects of airway inflammation generated during responses to viral infections and aeroallergens, and both these pathways are regulated by dendritic cells (DC) that differentiate locally from monocytic precursors. These DCs normally exhibit a sentinel phenotype characterized by active Ag sampling but attenuated presentation capability, which limits the intensity of local expression of adaptive immunity. How this tight control of airway DC functions is normally maintained, and why it breaks down in some atopics leading to immunopathological changes in airway tissues, is unknown. We postulated that signals from adjacent airway epithelial cells (AEC) contribute to regulation of local differentiation of DC. We tested this in a coculture model containing both cell types in a GM-CSF-IL-4-enriched cytokine milieu characteristic of the atopic asthmatic airway mucosa. We demonstrate that contact with AEC during DC differentiation up-regulates expression of the function-associated markers MHC class II, CD40, CD80, TLR3, and TLR4 on DCs with concomitant up-regulation of Ag uptake/processing. Moreover, the AEC-conditioned DCs displayed increased LPS responsiveness evidenced by higher production of IL-12, IL-6, IL-10, and TNF-. The Th2 memory-activating properties of AEC-conditioned DCs were also selectively attenuated. Data from microarray and blocking experiments implicate AEC-derived type 1 IFNs and IL-6 in modulation of DC differentiation. Collectively, these findings suggest that resting AECs modulate local DC differentiation to optimize antimicrobial defenses in the airways and in the process down-modulate capacity for expression of potentially damaging Th2 immunity.

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 This work was supported by the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Patrick G. Holt, Division of Cell Biology, Telethon Institute for Child Health Research, P.O. Box 855, West Perth, WA 6872, Australia. E-mail address: patrick{at}ichr.uwa.edu.au

³ Abbreviations used in this paper: DC, dendritic cell; AEC, airway epithelial cell; HDM, house dust mite; MDDC, monocyte-derived DC; poly(IC), polyinosinic-polycytidylic acid; MFI, mean fluorescence intensity; PI, propidium iodide.

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