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An Anti-Inflammatory Role for Plasmacytoid Dendritic Cells in Allergic Airway Inflammation¹

Mirjam Kool^*, Menno van Nimwegen^*, Monique A. M. Willart, Femke Muskens^*, Louis Boon, Joost J. Smit, Anthony Coyle^¶, Björn E. Clausen^||, Henk C. Hoogsteden^*, Bart N. Lambrecht^*, and Hamida Hammad^2,

^* Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands; Laboratory of Immunoregulation and Mucosal Immunology, Ghent University, Ghent, Belgium; Bioceros, Utrecht, the Netherlands; Institute for Risk Assessment Studies, Utrecht University, Utrecht, the Netherlands; ^¶ MedImmune, Gaithersburg, MD 20878; and ^|| Department of Immunology, Erasmus MC, Rotterdam, the Netherlands

It was previously shown that administration of recombinant human Fms-like tyrosine kinase receptor-3 ligand (Flt3L) before allergen challenge of sensitized mice suppresses the cardinal features of asthma through unclear mechanisms. Here, we show that Flt3L dramatically alters the balance of conventional to plasmacytoid dendritic cells (pDCs) in the lung favoring the accumulation of pDCs. Selective removal of pDCs abolished the antiinflammatory effect of Flt3L, suggesting a regulatory role for these cells in ongoing asthmatic inflammation. In support, we found that immature pDCs are recruited to the lungs of allergen-challenged mice irrespective of Flt3L treatment. Selective removal of pDCs during allergen challenge enhanced airway inflammation, whereas adoptive transfer of cultured pDCs before allergen challenge suppressed inflammation. Experiments in which TLR9 agonist CpG motifs were administered in vitro or in vivo demonstrated that pDCs were antiinflammatory irrespective of their maturation state. These effects were mediated through programmed death-1/programmed death ligand 1 interactions, but not through ICOS ligand, IDO, or IFN-. These findings suggest a specialized immunoregulatory role for pDCs in airway inflammation. Enhancing the antiinflammatory properties of pDCs could be employed as a novel strategy in asthma treatment.

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 a grant of the Netherlands Asthma Foundation to M.K., and by a Dutch Organization for Scientific Research Vidi grant to B.N.L. and B.E.C., and a Veni grant to H.H. B.E.C. is supported by a career development grant from the Landsteiner Foundation for Blood Transfusion Research. B.N.L. is a recipient of the European Respiratory Society "Romain Pauwels" Grant and of an Odysseus Grant of the Flemish Government.

² Address correspondence and reprint requests to Dr. Hamida Hammad, Laboratory of Immunoregulation and Mucosal Immunology, MRB1, University Hospital Ghent, De Pintelaan 185, B9000 Ghent, Belgium. E-mail address: hamida.hammad{at}ugent.be

³ Abbreviations used in this paper: Flt3L, Fms-like tyrosine kinase receptor-3 ligand; alum, aluminum hydroxide; BAL, bronchoalveolar lavage; BM, bone marrow; cDC, conventional dendritic cell; DC, dendritic cell; ICOS-L, ICOS ligand; i.t., intratracheal; MLN, mediastinal lymph node; pDC, plasmacytoid dendritic cell; PD-L, programmed death ligand; WT, wild type.