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Immunosurveillance of Lung Melanoma Metastasis in EBI-3-Deficient Mice Mediated by CD8⁺ T Cells¹

Kerstin A. Sauer^*, Joachim H. Maxeiner^2,*, Roman Karwot^2,*, Petra Scholtes^2,*, Hans A. Lehr, Mark Birkenbach, Richard S. Blumberg and Susetta Finotto^3,*

^* Laboratory of Cellular and Molecular Immunology of the Lung, I. Medical Clinic, University of Mainz, Germany; Institute of Pathology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland; Department of Pathology and Department of Anatomy, Eastern Virginia Medical School, Norfolk, VA 23501; and Department of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02115

EBV-induced gene 3 (EBI-3) codes for a soluble type I receptor homologous to the p40 subunit of IL-12 that is expressed by APCs following activation. In this study, we assessed the role of EBI-3 in a model of lung melanoma metastasis. Intravenous injection of the B16-F10 cell line resulted in a significant reduction of lung tumor metastasis in EBI-3^–/– recipient mice compared with wild-type mice. The immunological finding accompanying this effect was the expansion of a newly described cell subset called IFN- producing killer dendritic cells associated with CD8⁺ T cell responses in the lung of EBI-3^–/– mice including IFN- release and TNF--induced programmed tumor cell death. Depletion of CD8⁺ T cells as well as targeting T-bet abrogated the protective effects of EBI-3 deficiency on lung melanoma metastases. Finally, adoptive transfer of EBI-3^–/– CD8⁺ T cells into tumor bearing wild-type mice inhibited lung metastasis in recipient mice. Taken together, these data demonstrate that targeting EBI-3 leads to a T-bet-mediated antitumor CD8⁺ T cell responses in the lung.

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 Graduiertenkolleg 1043 (Antigenspezifische Immuntherapie) and the ICE-Immunology Cluster of Excellence-Immunointervention.

² J.H.M., R.K., and P.S. contributed equally to this work.

³ Address correspondence and reprint requests to Prof. Susetta Finotto, Laboratory of Cellular and Molecular Lung Immunology, I. Medical Clinic, University of Mainz, Obere Zahlbacher Strasse 63, Room 2-110, Mainz, Germany. E-mail address: finotto{at}mail.uni-mainz.de

⁴ Abbreviations used in this paper: DC, dendritic cell; IK-DC, IFN- producing killer DC; EBI-3, EBV induced gene 3; BALF, bronchoalveolar lavage fluid; pDC, plasmacytoid dendritic cell.