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* Genomics and Immunoregulation, Institute for Life and Medical Sciences, University of Bonn, Bonn, Germany;
Institute for Medical Microbiology, Immunology and Hygiene,
Institute for Pathology, and
Institute for Neurophysiology, University of Cologne, Cologne, Germany;
¶ National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan; and
|| Institute of Medical Microbiology, University of Giessen, Giessen, Germany
Myeloid dendritic cells (DC) and macrophages play an important role in pathogen sensing and antimicrobial defense. In this study we provide evidence that myeloid DC respond to infection with Listeria monocytogenes with simultaneous induction of multiple stimulatory and inhibitory molecules. However, the overall impact of infected DC during T cell encounter results in suppression of T cell activation, indicating that inhibitory pathways functionally predominate. Inhibitory activity of infected DC is effected mainly by IL-10 and cyclooxygenase 2-mediated mechanisms, with soluble CD25 acting as an IL-2 scavenger as well as by the products of tryptophan catabolism. These inhibitory pathways are strictly TNF-dependent. In addition to direct infection, DC bearing this regulatory phenotype can be induced in vitro by a combination of signals including TNF, TLR2, and prostaglandin receptor ligation and by supernatants derived from the infected cells. Both infection-associated DC and other in vitro-induced regulatory DC are characterized by increased resistance to infection and enhanced bactericidal activity. Furthermore, myeloid DC expressing multiple regulatory molecules are identified in vivo in granuloma during listeriosis and tuberculosis. Based on the in vivo findings and the study of in vitro models, we propose that in granulomatous infections regulatory DC may possess dual function evolved to protect the host from disseminating infection via inhibition of granuloma destruction by T cells and control of pathogen spreading.
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1 This work was supported by a Sofja Kovalevskaja Award from the Alexander von Humboldt Foundation (to J.L.S.), a Köln Fortune Grant (to J.L.S. and T.S.), grants of the Bundesministerium fuer Bildung and Forschung NGFN 01GS0111 (to T.C.) and NGFN N1K3-S24T27 (to J.L.S.) and grants from the Deutsche Forschungsgemeinschaft SFB704 (to J.L.S.), SFB589 (to C.W.), and SFB670 (to M.K. and O.U.).
2 A.P. and J.D. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Joachim L. Schultze, Laboratory for Genomics and Immunoregulation, Program Unit Molecular Immune and Cell Biology, LIMES (Life and Medical Sciences Bonn), University of Bonn, Karlrobert-Kreitenstrasse 13, D-53115 Bonn, Germany. E-mail address: j.schultze{at}uni-bonn.de
4 Abbreviations used in this paper: L.m., Listeria monocytogenes; COX-2, cyclooxygenase 2; DC, dendritic cells; DCreg, regulatory DC; immDC, immature DC; infDC, infected DC; matDC, mature DC; mo-DC, monocyte-derived DC; Pam3, Pam3Cys-Ser-(Lys)4.trihydrochloride; PGE2, prostaglandin E2; PGE2-DC, mature inhibitory DC stimulated with PGE2; rhIL-2, recombinant human IL-2; sCD25, soluble CD25.
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