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Airway Epithelial IL-15 Transforms Monocytes into Dendritic Cells

Pediatric Respiratory Medicine, and Respiratory Medicine, University Hospital of Berne, Berne; Division of Immunology and Allergy, and Laboratory of Clinical Investigation III, Department of Pediatrics, University Hospitals, Geneva, Switzerland

Correspondence and requests for reprints should be addressed to Prof. L. P. Nicod, Division of Respiratory Medicine, University Hospital of Berne, Freiburgstr. 15, CH-3010 Berne, Switzerland. E-mail: Laurent.Nicod{at}insel.ch

IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1, IFN-, or TNF-. Airway epithelial cell supernatants induced an increase of IL-15R gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15R gene expression up to 300-fold. Airway epithelial cell–conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80–, CD83+, CD86+, CCR3+, CCR6⁺, CCR7–). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1^–, CD1a–) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell–conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.

Key Words: interleukin-15 • airway epithelial cells • dendritic cells • human studies

CLINICAL RELEVANCE We show that IL-15 produced by airway epithelial cells induces the differentiation and maturation of monocytes into functional dendritic cells. This indicates an important role of epithelial IL-15 in innate and adaptive lung immunity.