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Impaired Lung Dendritic Cell Migration and T Cell Stimulation Induced by Immunostimulatory Oligonucleotides Contribute to Reduced Allergic Airway Inflammation¹

Hannelore Constabel^*, Metodi V. Stankov^*, Christina Hartwig, Thomas Tschernig and Georg M. N. Behrens^2,*

^* Clinic for Immunology and Rheumatology, and Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany

CpG-containing oligonucleotides (CpG) have been shown to reduce key features of allergic airway inflammation in mouse models. Given the inhibitory effects of CpG treatment on Ag presentation of subsequently encountered Ags via MHC class I and II molecules by dendritic cells (DC), we hypothesized that intranasal CpG treatment would lead to reduced Ag-specific T cell stimulation in the lung-draining lymph nodes, thereby reducing the inflammatory response in sensitized mice. Intranasal CpG administration led to phenotypic maturation of lung and mediastinal lymph node DC as determined by expression of MHC class II, CD80, and CD86. This was accompanied by a significant reduction in the proliferation of adoptively transferred Ag-specific CD4⁺ and CD8⁺ T cells in mediastinal lymph nodes, when CpG was given before inhalative OVA challenges. DC obtained from mediastinal lymph nodes of CpG-treated mice before OVA inhalation led to reduced T cell stimulation via MHC class I and II molecules. In addition, CpG diminished airway eosinophilia and pulmonary infiltration after sensitization or following adoptive transfer of Ag-specific Th2 cells. These results were explained by reduced CCL21 expression and inhibition of lung DC migration following CpG administration, which could be restored by transfer of bone marrow-derived DC, because CpG had no major impact on the constitutive MHC class II Ag presentation of protein-derived Ag by lung tissue-derived DC. We conclude that CpG treatment can effectively impair the DC-mediated Ag transport from the lungs to the lymph nodes, resulting in reduced T cell activation and blunted 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 This work was supported by the German Research Council (SFB 587, B5) and partially by a grant from the Excellence Cluster "From Regenerative Biology to Reconstructive Therapy" (German Research Foundation; to G.M.N.B.).

² Address correspondence and reprint requests to Dr. Georg M. N. Behrens, Clinic for Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail address: behrens.georg{at}mh-hannover.de

³ Abbreviations used in this paper: DC, dendritic cell; BAL, bronchoalveolar lavage; BMDC, bone marrow-derived DC; HPRT, hypoxanthine guanine phosphoribosyltransferase 1.

⁴ The online version of this article contains supplemental material.